Evidence Report/Technology Assessment 

Number 100 

Criteria to Determine Disability Related to Multiple 

Sclerosis 

Prepared for: 

Agency for Healthcare Research and Quality 

U.S. Department of Health and Human Services 

540 Gaither Road 

Rockville, MD 20850 

www.ahrq.gov 

Contract No. 290-02-0025 

Prepared by: 

Duke Evidence-based Practice Center, Durham, North Carolina 

Investigators 

Douglas C. McCrory, MD, MHS 

Lisa A. Pompeii, PhD, COHN-S 

Mark B. Skeen, MD 

Sam D. Moon, MD, MPH 

Rebecca N. Gray, DPhil 

Jane T. Kolimaga, MA 

David B. Matchar, MD 

AHRQ Publication No. 04-E019-2 

May 2004 
This report may be used, in whole or in part, as the basis for development of clinical practice 

guidelines and other quality enhancement tools, or a basis for reimbursement and coverage 

policies. AHRQ or U.S. Department of Health and Human Services endorsement of such 

derivative products may not be stated or implied. 

AHRQ is the lead Federal agency charged with supporting research designed to improve the 

quality of health care, reduce its cost, address patient safety and medical errors, and broaden access 

to essential services. AHRQ sponsors and conducts research that provides evidence-based 

information on health care outcomes; quality; and cost, use, and access. The information helps 

health care decisionmakers—patients and clinicians, health system leaders, and policymakers—

make more informed decisions and improve the quality of health care services. 
ii

This document is in the public domain and may be used and reprinted without permission except 

those copyrighted materials noted for which further reproduction is prohibited without the 

specific permission of copyright holders. 

Suggested Citation: 

McCrory DC, Pompeii LA, Skeen MB, Moon SD, Gray RN, Kolimaga JT, Matchar DB. Criteria 

to Determine Disability Related to Multiple Sclerosis. Evidence Report/Technology Assessment 

No. 100. (Prepared by the Duke Evidence-based Practice Center, Durham, NC, under Contract 

No. 290-02-0025.) AHRQ Publication No. 04-E019-2. Rockville, MD: Agency for Healthcare 

Research and Quality. May 2004. 
Preface 

The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-Based 

Practice Centers (EPCs), sponsors the development of evidence reports and technology 

assessments to assist public- and private-sector organizations in their efforts to improve the 

quality of health care in the United States. This report on Criteria to Determine Disability 

Related to Multiple Sclerosis was requested and funded by the Social Security Administration. 

The reports and assessments provide organizations with comprehensive, science-based 

information on common, costly medical conditions and new health care technologies. The EPCs 

systematically review the relevant scientific literature on topics assigned to them by AHRQ and 

conduct additional analyses when appropriate prior to developing their reports and assessments. 

To bring the broadest range of experts into the development of evidence reports and health 

technology assessments, AHRQ encourages the EPCs to form partnerships and enter into 

collaborations with other medical and research organizations. The EPCs work with these partner 

organizations to ensure that the evidence reports and technology assessments they produce will 

become building blocks for health care quality improvement projects throughout the Nation. The 

reports undergo peer review prior to their release. 

AHRQ expects that the EPC evidence reports and technology assessments will inform 

individual health plans, providers, and purchasers as well as the health care system as a whole by 

providing important information to help improve health care quality. 

We welcome written comments on this evidence report. They may be sent to: Director, 

Center for Outcomes and Evidence, Agency for Healthcare Research and Quality, 540 Gaither 

Road, Rockville, MD 20850. 

Jean Slutsky, P.A., M.S.P.H. 

Acting Director, Center for Outcomes and 

Evidence 

Agency for Healthcare Research and Quality 

Carolyn M. Clancy, M.D. 

Director

Agency for Healthcare Research and Quality 

Jo Anne B. Barnhart 

Commissioner 

Social Security Administration 

The authors of this report are responsible for its content. Statements in the report 

should not be construed as endorsement by the Agency for Healthcare Research and 

Quality or the U.S. Department of Health and Human Services of a particular drug, 

device, test, treatment, or other clinical service. 

iii


Structured Abstract 

Context: The Social Security Administration (SSA) processes more than 3.5 million claims for 

disability benefits each year. Multiple sclerosis (MS) is the third most common neurological 

diagnosis cited as the cause for disability. SSA requested evidence on whether current medical 

knowledge supports its MS disability policies. 

Objectives: Our first major objective was to identify, review, and evaluate the medical literature 

on five major topics: reliability of MS diagnostic criteria; predictors of physical and mental 

impairments; effect of treatment and symptom management therapies; association of clinical 

findings with work ability; and impact of environmental factors on work capacity. Our second 

objective was to describe information needed to address any data insufficiencies, if any, in these 

five areas. 

Data Sources: Nearly 1500 English-language articles were identified, principally from searches 

of MEDLINE®, CINAHL®, and Web of Science. The term multiple sclerosis was merged with 

concepts specific to the topic areas. 

Study Selection: Nearly 50 percent, or 739 articles, initially met the selection criteria; of these, 

168 (23 percent) passed three levels of screening (titles and abstracts; full-text articles; data 

abstraction). Inclusion requirements included a population with MS, relevance to specific 

question(s) based on appropriate thresholds, and satisfactory level of evidence. 

Data Extraction: Descriptive data were partially abstracted into standardized evidence tables 

by a non-clinician abstractor and then completed by two clinicians (primary abstractor and overreader). Methodological quality of each article was assessed for internal and external validity 

and reported in the evidence tables. 

Data Synthesis: In two recent high-quality studies, the McDonald criteria identified a high 

proportion of patients presenting with clinically isolated syndrome who will go on to develop 

clinically definite MS over 1-4 years of follow up, with a specificity of 83 to 87 percent. We

found few prospective studies describing prediction of changes in physical and mental 

impairments over a 9- to 24-month time frame. In clinical trials, few patients improved with 

disease-modifying treatments and then only in the range of 1.0 point on the Extended Disability 

Status Scale (EDSS); rehabilitation and symptomatic treatment of spasticity, fatigue, depression, 

voiding dysfunction, and cognitive impairments resulted in symptom and functional status 

improvement. Work ability has been little studied, and few data link it to symptoms or objective 

physical and cognitive measures. We found no studies linking thermal sensitivity and work 

ability. 

Conclusions: McDonald criteria appear to have substantial evidence for validity and inter-rater

reliability in diagnosing MS; clinical data are poor at predicting 1-year clinical outcomes. 

Treatments do not result in improvements in impairments, but symptomatic treatments can result 

in improvements in functional status. Further research is required to understand the associations 

between clinical data and work status or work ability. 

v
Contents 

Evidence Report................................................................................................................... 1 

Chapter 1. Introduction....................................................................................................... 3 

 Purpose ....................................................................................................................... 3 

 Background...................................................................................................................... 3 

Research Questions.......................................................................................................... 4 

Reliability of MS Diagnostic Criteria ........................................................................ 5 

Predictors of Physical and Mental Impairments at 12 Months.................................. 5 

Effect of Treatment and Symptom Management on Disease Course ........................ 5 

 Association of Clinical Findings with Work Ability ................................................. 6 

 Environmental Factors and Work Ability.................................................................. 6 

Limitations of Report....................................................................................................... 6 

Chapter 2. Methods ............................................................................................................. 9 

Literature Search and Review.......................................................................................... 9 

 Sources....................................................................................................................... 9 

Search Strategies........................................................................................................ 9

 Abstract and Full-text Screening Criteria .................................................................. 9 

Data Abstraction and Development of Evidence Tables................................................. 10 

Quality Assessment Criteria ............................................................................................ 10 

Peer Review Process........................................................................................................ 12

Chapter 3. Results............................................................................................................... 15 

 Diagnostic Reliability of McDonald Criteria................................................................... 15 

 Introduction................................................................................................................ 15 

 Results ........................................................................................................................ 17 

Inter-rater Reliability of Diagnosis with McDonald and Poser criteria........................... 18 

 Introduction................................................................................................................ 18 

 Results ........................................................................................................................ 18 

Predictors of Physical and Mental Impairments at 12 Months........................................ 19 

 Introduction................................................................................................................ 19 

 Results ........................................................................................................................ 20 

Disease-modifying Therapies and Long-term Improvement........................................... 22 

 Introduction................................................................................................................ 22 

 Results ........................................................................................................................ 23 

Symptom Management and Improvement....................................................................... 24 

 Introduction................................................................................................................ 24 

 Results ........................................................................................................................ 24 

Association of Clinical Findings with Work Ability ....................................................... 30 

 Introduction................................................................................................................ 30 

 Results ........................................................................................................................ 30 

 Environmental Factors and Work Ability........................................................................ 36 

 Introduction................................................................................................................ 36 

 Results ........................................................................................................................ 37 

vii
Chapter 4. Discussion .......................................................................................................... 65 

Discussion of Evidence.................................................................................................... 65

Reliability of Criteria for Diagnosing MS (Questions 1a and 1b)............................. 65 

Predictors of Physical and Mental Impairments at 12 Months (Question 2)............. 66 

Disease-modifying Therapies and Long-term Improvement (Question 3a).............. 66 

Symptom Management and Improvement (Question 3b).......................................... 67 

 Association of Clinical Findings with Work Ability (Question 4)............................ 69 

 Environmental Factors and Work Ability (Question 5)............................................. 73 

Knowledge Gaps and Future Research Recommendations............................................. 74 

References Cited in the Evidence Report .......................................................................... 77 

Listing of Included Studies.................................................................................................. 87

Listing of Excluded Studies................................................................................................. 95

List of Acronyms/Abbreviations......................................................................................... 121 

Figures and Tables 

Figure 1. Temporal relationship of pre-disability evaluation and occurrence 

 of work disability ........................................................................................ 38 

Table 1. Results of title-and-abstract screening and full-text article review ............... 13 

Table 2. Included full-text articles by research question ............................................. 14 

Table 3. Data supporting the validity of MRI components of the McDonald criteria. 39 

Table 4. Studies validating the McDonald criteria ...................................................... 41 

Table 5. Kappa statistics for multiple raters using Poser and McDonald criteria........ 42 

Table 6. Relapse rate outcomes from placebo-controlled RCTs of disease- 

 modifying therapies ....................................................................................... 43 

Table 7. Improvements in physical function (EDSS) in placebo-controlled RCTs 

 of disease-modifying therapies...................................................................... 44 

Table 8. Randomized controlled trials of symptomatic treatments for spasticity........ 45 

Table 9. Randomized controlled trials of rehabilitation interventions......................... 49 

Table 10. Randomized controlled trials of treatments for depression ........................... 51 

Table 11. Randomized controlled trials of treatments for fatigue ................................. 52 

Table 12. Randomized controlled trials of treatments for voiding dysfunction ............ 53 

Table 13. Included studies by type of measure used and type of function considered 

 (physical, mental, other) ................................................................................ 54 

Table 14. Studies by Rozin et al. measuring ability to work among individuals 

 with MS.......................................................................................................... 55 

 Table 15. Cross-sectional studies examining current employment status and EDSS 

 level among individuals with MS .................................................................. 57 

Table 16. Cognitive function and work status among individuals with MS.................. 58 

Table 17. Job type/characteristics and current work status among individuals 

 with MS.......................................................................................................... 60 

Table 18. Self-report on why individuals with MS continued or terminated 

viii
 employment.................................................................................................... 62 

 Table 19. Conditions/situations impeding or enhancing performance of 

 work/chores.................................................................................................... 64 

Appendixes and Evidence Tables are provided electronically at 

http://www.ahrq.gov/clinic/epcindex.htm

ix
Introduction

The Social Security Administration (SSA)

operates the world’s largest and most stringent

disability program, processing more than 3.5

million claims each year, with multiple sclerosis

(MS) representing the third most common

neurological diagnosis cited as the cause for

disability.

1 The purpose of this project, nominated

by SSA and contracted through the Agency for

Healthcare Research and Quality (AHRQ), is to

determine whether current medical knowledge

supports the SSA’s stated policies regarding MS.

In January 2003, the Duke Evidence-based

Practice Center began work on this 13-month

task to review evidence from the medical

literature for use in updating SSA’s listing of

impairments for multiple sclerosis (MS) and for

revising its disability policy (if indicated).

Research Questions

The seven major research questions addressed

during this review are as follows:

Question 1a: What is the reliability of new

McDonald criteria (incorporating supplementary

information from radiologic and laboratory studies

including magnetic resonance imaging [MRI],

visual evoked potential [VEP], and cerebrospinal

fluid [CSF] analyses) compared with long-term

follow-up diagnosis of clinically definite MS

according to the Poser criteria? 

Question 1b: What is the inter-rater reliability of

diagnosis of MS according to Poser or McDonald

criteria among neurologists or between neurologists

and non-neurologist physicians?

Question 2: What clinical indicators, including

particularly time-course of impairments, predict

physical or mental impairment at 12 months? 

Question 3a: Among patients with MS, do

current disease-modifying treatments result in longterm improvements in physical or mental outcomes

compared to placebo or usual care?

Question 3b: Among patients with MS, do

treatments aimed at symptom management result in

improvements in physical or mental outcomes

compared to usual care? 

Question 4: Among individuals with MS, what

physical, mental, laboratory, or radiographic findings

have been associated with inability to work? 

Question 5: Among individuals with MS, how

does elevated temperature or other environmental

factors impair the capacity to work? 

Key Terms and Definitions

Knowledge of the terms used in the SSA

disability evaluation process, components of that

process, and Medical Listing criteria related to

MS is critical to the reader’s understanding of this

report. To assist in the preparation of the report,

SSA provided explanations of terms and processes

as currently defined by SSA regulations and

rulings. The terms cited below, as well as other

terms and processes used by SSA for disability

determination, are defined and described in the

SSA publication, Disability Evaluation Under

Social Security 2003.

2

The statutory definition of “Disability” is “the

inability to engage in any substantial gainful

activity by reason of a medically determinable

physical or mental impairment(s) which can be

expected to result in death or which has lasted or

can be expected to last for a continuous period of

not less than 12 months.” This definition differs

from the clinically used definition of the World

Health Organization’s International Classification

of Impairments, Disabilities and Handicaps,

3 which

defines disability as “any restriction or lack of

Evidence Report/Technology Assessment

Number 100

Criteria to Determine Disability Related to 

Multiple Sclerosis

Summary

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES • Public Health Service

Agency for Healthcare Research and Quality
2

ability to perform an activity in a manner or within the range

considered normal for a human being.” While much of the

medical literature uses the latter, broader definition, the reader

must be aware that the goals of this report relate to the

statutory definition.

The following terms are defined by current (2003) SSA

regulations:

• “Claimant” is anyone who has filed a disability claim.

• “Substantial Gainful Activity” is the ability to earn an

average of $800 per month.

• “Medically Determinable Impairment” is a physical or

mental impairment that results from anatomical,

physiological, or psychological abnormalities which can be

shown by medically acceptable clinical and laboratory

diagnostic techniques.

• “Evidentiary Requirements” for disability determination are

described by SSA regulation. An acceptable medical source

must report signs, symptoms, and laboratory findings

diagnostic of an impairment. Although a claimant’s

reported signs and symptoms are not sufficient to meet the

evidentiary requirements for establishing the presence of a

medically determinable impairment, all available evidence

including the claimant’s report of symptoms is used to

evaluate the impact of any documented impairment(s) on

the claimant’s ability to carry out work tasks. 

• “Severe Impairment” is defined by the agency as any

“impairment that more than minimally limits the

claimant’s ability to do basic work activities.”

The regulations include a Listing of Impairments for each

body system that define disability. Often referred to as the

“medical listings,” this list allows quick disability

determinations to be made on the basis of medical criteria

alone. The SSA publication, Disability Evaluation Under Social

Security 2003,

2 under the neurological category of

impairments, includes Listing 11.09.

11.09 Multiple Sclerosis with:

A. Disorganization of motor function as described in 11.04; or

B. Visual or mental impairment as described under the criteria

in 2.02, 2.03, 2.04, or 12.02: or

C. Significant, reproducible fatigue of motor function with

substantial muscle weakness on repetitive activity,

demonstrated on physical examination, resulting from

neurological dysfunction in areas of the central nervous system

known to be pathologically involved by the multiple sclerosis

process.

Full details on the Medical Listing for multiple sclerosis,

including the imbedded references to sections 2, 11, and 12,

are available in the above-cited SSA publication.2

“Residual Functional Capacity” is assessed when a claimant

is determined to have a “severe” impairment that does not meet

or equal the intent of the medical listings. Physical capacity

(lifting, carrying, walking, standing, sitting, pedaling, and so

on) and mental capacity (cognitive and behavioral, thought

processing, concentration, pace, behavior) are assessed in

determining residual functional capacity.

To adjudicate claims by individuals with MS for disability

benefits, SSA must determine whether the claims file includes

information from an acceptable medical source that documents

the signs, symptoms, and laboratory findings that are diagnostic

of a physical or mental impairment. SSA adjudicators also

determine whether the impairment would be expected to more

than minimally interfere with the claimant’s capacity to carry

out basic work activities for at least 12 consecutive months or

end in death. If a severe impairment is identified, the

adjudicator determines whether the medical findings meet or

equal an impairment in the medical listings. If the

documented impairment does not meet or equal a listed

impairment, the adjudicator must determine the claimant’s

residual functional capacity and consider vocational factors

prior to making a final disability determination. 

Methods

A systematic and comprehensive search of the medical

literature was conducted and was followed by a thorough

review and evaluation of the literature determined to be

relevant to the major research questions.

Literature Sources

The primary sources of literature were MEDLINE® (1966-

April 2003), CINAHL® (1983-April 2003), Cochrane

Database of Systematic Reviews, and Web of Science. Searches

of these databases were supplemented by reviews of reference

lists contained in all included articles and in relevant review

articles and meta-analyses.

Search Strategies

Searches were limited to the English language and to human

subjects. For efficacy-of-treatment topics, the searches were also

limited to studies with randomized controlled trial designs. In

all, there were five major searches: 

1. Search 1 was a general search targeting MS and

employment issues that merged search terms for multiple

sclerosis, transverse myelitis, and optic neuritis with

employment terms such as disability evaluation, work

capacity evaluation, employment, and activities of daily living.

No study designs were excluded.

2. Search 2 was targeted to studies on the reliability of

diagnostic criteria for MS. Major search terms employed

were multiple sclerosis (exploded), multiple sclerosis/di

(limited to diagnostic articles), text word options for poser

and mcdonald, and exploded terms reproducibility of results/
or observer variation/ or psychometrics, along with the text

word reliability. No study designs were excluded.

3. Search 3 focused on treatment of fatigue for MS and

specified several drugs used in the treatment of MS-related

fatigue. No study designs were excluded.

4. Search 4 looked for a wide range of symptomatic therapies

(other than fatigue) and disease-modifying therapies. A

wide selection of treatments was specified, and the search

was limited to randomized controlled trial designs.

5. Search 5 was focused on the predictive value of the

McDonald diagnostic criteria, specifically on their use of

additional paraclinical diagnostic methods (MRI, VEP, and

CSF) and on studies reporting sensitivity, specificity, and

reproducibility.

All searches, including narrowly focused sub-searches,

yielded 1,487 potentially relevant citations.

Abstract and Full-text Screening Criteria

For each question, we developed fairly detailed instructions

and decision rules for the screeners’ reference. There were very

broad inclusion requirements for abstracts: MS study subjects

and potential relevance to any of the five questions. For the

full-text screening, screeners were asked to record their

include/exclude decision, research question assignment, and, if

appropriate, exclusion criteria that detailed insufficiencies in

study design and clinical substance requirements.

The titles and abstracts of the 1,487 articles were reviewed

against the inclusion/exclusion criteria by at least two of five

clinical investigators. The full text of each article passing the

title-and-abstract screening was retrieved from the library for

further review.

At the full-text review stage, each article was independently

evaluated by two investigators, who forwarded their decisions

to the task order manager for recording and comparison. If

indicated, reviewers were asked to reconcile differences of

opinion and return a reconciled final decision. If reviewers had

difficulty reaching agreement, or submitted indecisive codes,

the principal investigator was the arbiter.

Approximately 50 percent of the articles were included after

the abstract screening and full-text article review stages.

Data Abstraction and Development of

Evidence Tables

Data from articles included after full-text screening were

abstracted directly into an evidence table template, which

served as a data abstraction form. The study’s writer/editor

began the process with a partial abstraction of each included

article. The partial abstraction included descriptions of the

study design, interventions, number of subjects at the start of

the study, and types of outcomes data to be collected. The

partial abstraction form was forwarded to a clinician for

completion and then returned to the writer/editor, who

checked it for completeness and consistency of information and

forwarded it to a second clinician for over-reading. The overreader returned the table to the writer/editor for a final check of

the completeness of the content, editing, and formatting. 

At the end of the data abstraction stage and the very close

scrutiny of each article, 168 articles were included. 

Results and Discussion

The primary goal of this review was to examine the evidence

in the medical literature for data that can guide policy in

determining disability in MS patients. Although the literature

in general (and certain studies in particular) suffers from

limitations, reasonably strong conclusions can still be drawn for

most of the seven research questions.

Reliability of Criteria for Diagnosing MS

This topic encompassed two questions: 

Question 1a: What is the reliability of new McDonald criteria

(incorporating supplementary information from radiologic and

laboratory studies including MRI, VEP, and CSF analyses)

compared with long-term follow-up diagnosis of clinically definite

MS according to the Poser criteria? 

Question 1b: What is the inter-rater reliability of diagnosis of

MS according to Poser or McDonald criteria among neurologists or

between neurologists and non-neurologist physicians.

Analytic approach. Regarding Question 1a, the most

important difference between the Poser criteria4 and the new

McDonald criteria5 is the addition of MRI findings to the

diagnosis of MS, in lieu of the presence of a second attack.

Our approach to this question was to identify studies in two

categories: (1) those that specifically compared the new

McDonald criteria to long-term diagnosis of clinically definite

MS according to the Poser criteria; and (2) those that provided

data on the accuracy of various MRI techniques, VEP analyses,

and CSF analyses as supplements to clinical diagnosis of MS.

For Question 1b, the relevant diagnostic criteria were the

Poser and McDonald criteria plus any other clinical, laboratory,

neurological exam, MRI, VEP, CSF, or other data supporting

the MS diagnosis. Results had to describe data on agreement

or disagreement on the MS diagnosis between evaluating

physicians. Agreement statistics could include kappa scores,

sensitivity and specificity rates, or other data of the type that

could be used to complete a two-by-two table.

Results. The validity of the McDonald criteria is wellsupported by two types of evidence: (1) follow-up studies of

patients with clinically isolated syndrome (CIS) diagnosed

according to the McDonald criteria and (2) studies that

correlate specific MRI findings (components of the McDonald

criteria) with clinical diagnosis. First, two studies6,7 show that

between 73 and 94 percent of patients presenting with CIS

who go on to develop clinically definite MS over 1 to 4 years of

follow up could be diagnosed with MS according to the

McDonald criteria (but would have been undiagnosed under

3
4

previous Poser criteria). Furthermore, the specificity of the

McDonald criteria is reasonably high, ranging from 83 to 87

percent. Second, many studies8-16 support the MRI component

of the McDonald criteria by showing a strong and consistent

association between the number of T2 lesions on MRI and the

subsequent development of clinically definite MS among

patients with CIS or optic neuritis.

Two studies17,18 examined the inter-rater reliability of

neurologist-physicians in diagnosing MS according to the Poser

criteria; one of these18 also examined inter-rater reliability in

diagnosing MS according to the McDonald criteria. We found

no data examining inter-rater reliability among non-neurologist

clinicians. Overall, there was substantial agreement between

observers in classifying MS. Poorer agreement was observed in

determining whether a patient had one or more “attacks” of

MS and in interpretation of MRI. 

Discussion. From the studies identified in the review, the

McDonald criteria appear to have substantial evidence for

validity and offer the obvious potential advantage of resulting

in an earlier diagnosis of MS than the Poser criteria permit.

The McDonald criteria have been criticized for their

complexity in comparison with previous criteria; however, we

found data that demonstrate that these criteria yield a good

overall diagnostic reliability, at least as good as the previous

Poser criteria. However, data about reliability are available only

for neurologists specializing in MS; adoption of the new criteria

by clinicians with less expertise could result in deterioration of

reliability. Further research on the inter-rater reliability of these

criteria in broader clinical settings would be helpful to

determine the quality of MS diagnosis.

Prediction of Physical or Mental Impairment

at 12 Months

The research question for this topic was What clinical

indicators, including particularly time-course of impairments,

predict physical or mental impairment at 12 months?

Analytic approach. There were four main categories of

clinical predictors of particular interest to the analysis: (1)

clinical characteristics such as exacerbation rates, disease type,

age at disease onset, sex, degree of remission after relapse, and

type and number of neurological symptoms; (2) imaging

studies, particularly MRI; (3) laboratory test results such as

apolipoprotein E (APOE) «4 allele and intrathecal

immunoglobulin-G (IgM) synthesis; and (4) self-reported

health status using validated scales.

Our evaluation was limited to those studies with a time

course of 12 months (SSA’s statutory limit), a timeframe which

treating physicians would not ordinarily consider an important

decision point. The course of MS has typically been studied

over time horizons of many years. 

Results. We found relatively little data describing changes in

neurological or other impairments over 9 to 24 months;

however, we used the data that were available to approximate

the 12-month time horizon dictated by statutory requirements.

Clinical characteristics have been the best studied, with four

reports providing evidence for this review.19-22 Brain23,24 and

spinal cord25 MRI have not been shown to be promising.

Suggestive evidence is available for laboratory markers26-29 and

self-reported quality of life,30 but these indicators will need

further study to establish their reliability and utility. While

clinical features do not individually provide reliable guidance

on prognosis, multivariate predictive models based on relatively

easy-to-obtain features may have better performance; such

models have not, however, been validated. 

Discussion. The ability to predict the future course of MS

has been an active area of research; however, most studies

examining disease course do so over relatively long time periods

(5 to 20 years). The limited predictive ability of some

multivariate models has not been validated in populations other

than those in which the models were developed; thus, their

value for predicting disability has yet to be determined.

Disease-modifying Therapies and Long-term

Improvement

Research Question 1a was targeted to current diseasemodifying therapies: Among patients with MS, do current

disease-modifying treatments result in long-term improvements in

physical or mental outcomes compared to placebo or usual care?

Analytic approach. Interventions of interest were all

current (2003) disease-modifying immunomodulatory and

immunosuppressive treatments. Outcomes of interest were

absolute improvements that might result in an individual who

is unable to work becoming able to work. The following

domains were considered: physical functioning (primarily

Expanded Disability Status Score [EDSS]), relapse frequency,

cognitive functioning, quality of life, and adverse events.

Results. Most of the data suggest that few patients improve

on disease-modifying therapy. Those few who do improve

generally do so only in the range of 1.0 point on the EDSS.

We found no data regarding improvement in work ability and

no data that would correlate a 1.0-point improvement in EDSS

with improvement in work ability. The significance of a 1.0-

point EDSS improvement varies depending on baseline EDSS

score (because the scale is non-linear), but the improvement

data available are not generally stratified according to baseline

EDSS score. With regard to work ability, the significance of

the available data on clinical improvement is unclear. We

found no data that quantified individual patient improvement

with regard to cognitive function or quality-of-life measures.

Discussion. Our review does not support a conclusion that

the current therapies are likely to result in substantial

improvement in a significant proportion of patients with MS.

This finding is consistent with expert opinion and

demonstrated by the design inherent in current clinical trials,

that is, the use of lack of decline in EDSS scores as the primary
outcome measure. Current therapies are generally regarded as

allowing for a modest reduction in progression of MS –

particularly in the relapsing-remitting patient population – but

are not generally expected to result in significant long-term

improvement. Recently, however, combination therapies have

begun to be used in the treatment of MS; such combinations of

current therapies or new therapies may have greater potential to

result in improvements in neurological status.

Symptom Management and Improvement 

Symptom management was the focus of Question 3b:

Among patients with MS, do treatments aimed at symptom

management result in improvements in physical or mental

outcomes compared to usual care.

Analytic approach. The effectiveness of symptomatic

therapies for spasticity, rehabilitation, urinary management,

fatigue, depression, and cognitive impairment was examined.

Relevant outcomes were analyzed within six categories: (1)

symptom-specific functional status or quality-of-life outcomes;

(2) physical functioning (primarily EDSS); (3) cognitive

functioning; (4) work or employment outcomes; (5) generic

quality-of-life outcomes; and (6) adverse events.

Results and discussion. Treatment aimed at alleviation of

symptomatic manifestations of MS, rather than at the

underlying disease, could have an important role in maximizing

functioning among people with MS. Among the six areas we

investigated, the degree of impairments and the effectiveness of

the treatments varied. We found:

• Although drugs such as baclofen, diazepam, dantrolene and

tizanidine are often used to reduce spasticity in MS, the

research evidence for a beneficial therapeutic effect is

inconsistent. Uncertain findings here, as with other

symptoms (cognitive impairment, fatigue), may be due, in

part, to measurement issues. Better measurement tools

may be required in order to confirm the clinical impression

that widely used anti-spasticity drugs such as baclofen,

tizanidine, and dantrolene are more effective than placebo.

Given current measurement techniques, it is not surprising

that active-treatment comparison studies fail to show

clinically important differences among these drugs.

• Physiotherapy interventions failed to influence impairments as

measured by EDSS. These interventions were, however,

associated with measurable changes in functional status.

Improvements in health (handicap) were observed in the

Medical Outcomes Study 36-Item Short-Form Health

Survey (SF-36) and several other measures. The

interventions employed in rehabilitation studies were

multifaceted, and it is difficult to attribute beneficial effects

to particular components of the interventions. 

• Depression treatments, including psychotherapy, behavioral

therapy, and certain drug therapies, can lead to measurable

improvements in mood, but the link to improved functional

status and, further, to ability to work was not demonstrated in

these studies per se. There are few data linking treatment of

depression to improvements in other symptoms (such as

fatigue or cognitive impairments) or other outcomes (such

as functional status or quality of life). 

• Measurement of fatigue is limited by a definition that spans

several domains, leading to difficulty with validation.

Amantadine appears to have some ability to alleviate

fatigue in MS, as demonstrated by statistically significant

differences in some outcomes in several trials;31-34 however,

the clinical significance of these effects is likely small.

Pemoline has been less often studied and shows results

suggesting some effect.33-35 There is little support for the

efficacy of 4-aminopyridine.36 Modafinil has shown

promising results in phase-II trials,37 but has not yet been

evaluated in a double-blind randomized controlled trial.

Further research on new pharmacological therapies (such as

modafinil) and development of additional data on the

validity of instruments for fatigue measurement and their

sensitivity to change would be helpful directions for future

research. 

• Studies of treatments for voiding dysfunction show clear

improvements in symptoms, but provide less clear data on how

improvements in urinary symptoms impact other areas of

health, and no data on how these symptomatic improvements

impact work ability. Desmopressin was highly effective at

reducing urine volume and also consistently effective at

reducing urinary frequency.38-42 This was shown to translate

into improvements in uninterrupted sleep hours and in

fewer episodes of incontinence. Physical treatments,

including both pelvic floor rehabilitation43 and use of a

handheld vibrator during micturition,44 were also shown to

reduce urinary symptoms compared with control. Many

interventions commonly used for urinary disorders in MS

have not been studied in randomized controlled trials of

MS patients. Commonly used interventions for which no

randomized controlled trials have been performed among

MS patients include anticholinergic and antimuscarinic

drugs, behavior modification, and intermittent or

indwelling urinary catheterization.

• None of the studied treatments for cognitive impairments has

had a consistent measurable effect on cognitive performance in

MS. Treatment of cognitive impairments has been little

studied and indirectly studied, in the sense that most data

on cognitive effects are inferred from studies aimed at

treatment of fatigue or depression. One study suggested

that fatigue symptoms do not correlate with cognitive

impairment, though they do correlate with symptoms of

depression.34 Future studies would benefit from more

precise delineation of study population based on screening

for cognitive performance deficits within a relatively

narrow and defined range; this would likely improve the

chances of finding a treatment effect and would also make

5
6

clearer the population for whom the results would be

applicable.

Association of Clinical Findings and Work

Ability

In contrast to the previous questions, Question 4 directly

linked clinical results with ability to work: Among individuals

with MS, what physical, mental, laboratory, or radiographic

findings have been associated with inability to work?

Analytic approach. The phrasing of this question

predetermined the outcome of interest as ability to work.

Findings reported as absolute and relative measures of physical

and mental/cognitive function and laboratory and radiographic

testing related to work activity were assessed. 

Results and discussion. There is a significant gap between

what is included in the literature and the type of research

evidence required to link objective clinical measures (physical,

mental, laboratory, and radiographic findings) with ability to

work. Although objective physical and cognitive measures have

been developed, their application in the occupational literature

is sparse. Furthermore, assessment of how symptoms such as

pain and fatigue impact work ability is essentially absent. The

reported findings on work ability displayed some consistency

across studies. For example, individuals who had higher EDSS

levels45,46 or low cognitive function47 were more likely to report

not working. However, the strength of association across these

studies was not clearly demonstrated, as most reported

frequencies or crude estimates of association. Several studies

had small sample sizes, which hindered researchers from

calculating risk estimates that were adjusted for potential biases

such as age, education, level of employer assistance, job type,

and desire to work. In addition, most studies considered only

physical function or cognitive function, when both can hinder

employment. 

Environmental Factors and Work Ability 

Similar to the previous question, the focus of Question 5 was

the ability to work: Among individuals with MS, how does

elevated temperature or other environmental factors impair the

capacity to work?

Analytic approach. The evidence sought for this question

was on the association of workplace environmental conditions

and demands (ambient temperature, individual’s body

temperature, heat or cold exposure) on the ability of an

individual with MS to work. Relative and absolute measures of

association were assessed.

Results. With regard to work impairment, limitation, or

disability related to temperature conditions, we found

remarkably little research that met our inclusion criteria; thus,

this question remains mostly unanswered. The one included

report confirmed that some MS patients perceive that excessive

heat impedes their work capacity.

48

Discussion. The evidence provides no basis for

generalizations such as maximum appropriate working

temperature levels unique to MS patient populations. It is

unlikely that medical data in Social Security Disability

Insurance (SSDI) application files in the current era will

include objective diagnostic test results identifying MS patients

who respond adversely to heat challenges. However, subjective

patient reports may describe such associations with or without

clinician comment or correlation with objective clinical status

measures. Although not necessarily founded on randomized

controlled trial data, current clinical impression seems to hold

that ambient and/or exercise-induced body temperature effects

may bear a relationship to MS symptom status in some

patients, perhaps more so than is thought to be the case for

chronic disease states in general.

Future Research

Future research about work ability among individuals with

MS can shed a great deal of light on factors that foster or

hinder employment. Our full report,49 particularly the evidence

reported on association of clinical findings and work ability,

highlights significant evidence and information gaps

concerning 

• Patterns of MS patient reports regarding functional

limitations. 

• Information commonly collected in medical encounters

with MS patients (and therefore available to SSA). 

• Knowledge about the impact on performance of specific

work tasks of commonly objectified parameters such as

coordination, strength, and vision, and especially of factors

such as fatigue or cognitive dysfunction, which are either

difficult to measure or are less commonly assessed in detail.

• Effective research methods for categorizing job or task

demands in such a way as to isolate those demands that are

likely to be “critical” for an SSDI applicant with MS.

In the context of these gaps, it may be productive to pursue

research approaches that simultaneously address four domains: 

1. Subjective reports (this domain is not sufficient alone for

SSDI determination purposes).

2. Objective clinical data (ideally of the sort commonly

encountered in medical records).

3. In-depth objective measures (which may be available and

not widely applied clinically. but which may be used with

subsets of subjects to explore correlation with other

domains).

4. Work status measures (ideally longitudinal, with

stratifications based on work demands).

Such an approach may apply to thermal sensitivity as well,

with some additional specification and focus. Parallel

assessment of concomitant ambient temperature, physical
exertion, and core body temperature would address key relevant

physiological exposure factors. 

Outcome measures could include the domains outlined

above, for example: 

• Self-perceived well-being and level of symptoms such as

fatigue. 

• Clinical parameters such as walking speed or muscle

strength.

• In-depth measures such as potentially associated

biomarkers or physiological parameters.

• Work status measures, including absenteeism and disability

benefits use.

Availability of the Full Report

The full evidence report from which this summary was taken

was prepared for the Agency for Healthcare Research and

Quality (AHRQ) by the Duke Evidence-based Practice Center,

under Contract No. 290-02-0025. It is expected to be available

in May 2004. At that time, printed copies may be obtained free

of charge from the AHRQ Publications Clearinghouse by

calling 800-358-9295. Requesters should ask for Evidence

Report/Technology Assessment No. 100, Criteria to Determine

Disability Related to Multiple Sclerosis. In addition, Internet

users will be able to access the report and this summary online

through AHRQ’s Web site at www.ahrq.gov.

Suggested Citation

McCrory DC, Pompeii LA, Skeen MB, Moon SD, Gray

RN, Kolimaga JT, Matchar DB. Criteria to Determine

Disability Related to Multiple Sclerosis. Summary, Evidence

Report/Technology Assessment No. 100. (Prepared by the

Duke Evidence-based Practice Center, under Contract No.

290-02-0025.) AHRQ Publication No. 04-E019-1. Rockville,

MD: Agency for Healthcare Research and Quality. May 2004.

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23. Koziol JA, Wagner S, Sobel DF, et al. Predictive value of lesions for

relapses in relapsing-remitting multiple sclerosis. Am J Neuroradiol

2001;22(2):284-91.

24. Rovaris M, Comi G, Ladkani D, et al. Short-term correlations

between clinical and MR imaging findings in relapsing-remitting

multiple sclerosis. Am J Neuroradiol 2003;24(1):75-81.

25. Stevenson VL, Leary SM, Losseff NA, et al. Spinal cord atrophy and

disability in MS: a longitudinal study. Neurology 1998;51(1):234-8.

26. Chapman J, Sylantiev C, Nisipeanu P, et al. Preliminary observations

on APOE epsilon4 allele and progression of disability in multiple

sclerosis. Arch Neurol 1999;56(12):1484-7.

27. Trotter JL, Clifford DB, McInnis JE, et al. Correlation of

immunological studies and disease progression in chronic progressive

multiple sclerosis. Ann Neurol 1989;25(2):172-8.

28. Villar LM, Masjuan J, González-Porqué P, et al. Intrathecal IgM

synthesis predicts the onset of new relapses and a worse disease course

in MS. Neurology 2002;59(4):555-9.

29. Fuhr P, Borggrefe-Chappuis A, Schindler C, et al. Visual and motor

evoked potentials in the course of multiple sclerosis. Brain

2001;124(Pt 11):2162-8.

30. Nortvedt MW, Riise T, Myhr KM, et al. Quality of life as a predictor

for change in disability in MS. Neurology 2000;55(1):51-4.

31. Canadian MS Research Group. A randomized controlled trial of

amantadine in fatigue associated with multiple sclerosis. Can J Neurol

Sci 1987;14(3):273-8.

32. Cohen RA, Fisher M. Amantadine treatment of fatigue associated

with multiple sclerosis. Arch Neurol 1989;46(6):676-80.

33. Krupp LB, Coyle PK, Doscher C, et al. Fatigue therapy in multiple

sclerosis: results of a double-blind, randomized, parallel trial of

amantadine, pemoline, and placebo. Neurology 1995;45(11):1956-61.

34. Geisler MW, Sliwinski M, Coyle PK, et al. The effects of amantadine

and pemoline on cognitive functioning in multiple sclerosis. Arch

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35. Weinshenker BG, Penman M, Bass B, et al. A double-blind,

randomized, crossover trial of pemoline in fatigue associated with

multiple sclerosis. Neurology 1992;42(8):1468-71.

36. Rossini PM, Pasqualetti P, Pozzilli C, et al. Fatigue in progressive

multiple sclerosis: results of a randomized, double-blind, placebocontrolled, crossover trial of oral 4-aminopyridine. Mult Scler

2001;7(6):354-8.

37. Rammohan KW, Rosenberg JH, Lynn DJ, et al. Efficacy and safety of

modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: a

two centre phase 2 study. J Neurol Neurosurg Psych 2002;72(2):179-

83.

38. Fredrikson S. Nasal spray desmopressin treatment of bladder

dysfunction in patients with multiple sclerosis. Acta Neurol Scand

1996;94(1):31-4.

39. Hilton P, Hertogs K, Stanton SL. The use of desmopressin (DDAVP)

for nocturia in women with multiple sclerosis. J Neurol Neurosurg

Psych 1983;46(9):854-5.

40. Hoverd PA, Fowler CJ. Desmopressin in the treatment of daytime

urinary frequency in patients with multiple sclerosis. J Neurol

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41. Kinn AC, Larsson PO. Desmopressin: a new principle for

symptomatic treatment of urgency and incontinence in patients with

multiple sclerosis. Scand J Urol Nephrol 1990;24(2):109-12.

42. Valiquette G, Herbert J, Maede-D'Alisera P. Desmopressin in the

management of nocturia in patients with multiple sclerosis. A doubleblind, crossover trial. Arch Neurol 1996;53(12):1270-5.

43. Vahtera T, Haaranen M, Viramo-Koskela AL, et al. Pelvic floor

rehabilitation is effective in patients with multiple sclerosis. Clin

Rehab 1997;11(3):211-9.

44. Prasad RS, Smith SJ, Wright H. Lower abdominal pressure versus

external bladder stimulation to aid bladder emptying in multiple

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45. Hammond SR, McLeod JG, Macaskill P, et al. Multiple sclerosis in

Australia: socioeconomic factors. J Neurol Neurosurg Psych

1996;61(3):311-3.

46. LaRocca N, Kalb R, Kendall P, et al. The role of disease and

demographic factors in the employment of patients with multiple

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47. Rao SM, Leo GJ, Ellington L, et al. Cognitive dysfunction in multiple

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48. Gulick EE, Yam M, Touw MM. Work performance by persons with

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49. McCrory DC, Pompeii LA, Skeen MB, et al. Criteria to Determine

Disability Related to Multiple Sclerosis, Duke Evidence-based Practice

Center, Contract #290-02-0025, to be completed. 2004.

www.ahrq.gov

AHRQ Pub. No. 04-E019-1

May 2004

ISSN 1530-440X
Evidence Report 
3

Note: Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gov/clinic/epcindex.htm. 

Chapter 1. Introduction 

Purpose 

 The purpose of this project, nominated by the Social Security Administration (SSA) and 

contracted through the Agency for Healthcare Research and Quality (AHRQ), was to determine 

whether current medical knowledge supports the SSA’s stated policies regarding MS. In January 

2003, the Duke Evidence-based Practice Center began work on this 13-month task to review 

evidence from the medical literature for use in updating SSA’s listing of impairments for 

multiple sclerosis (MS) and for revising its disability policy (if indicated).

 

Background 

The Social Security Administration runs the world’s largest disability program and processes 

more than 3.5 million claims each year. Multiple sclerosis is the third most common 

neurological diagnosis cited as the cause for disability. SSA uses the most stringent criteria of 

any disability program in the world to define disability.1

Knowledge of the terms used in the SSA disability evaluation process, components of that 

process, and Medical Listing criteria related to MS is critical to the reader’s understanding of this 

report. To assist in the preparation of the report, SSA provided explanations of terms and 

processes as currently defined by SSA regulations and rulings. The terms cited below, as well as 

other terms and processes used by SSA for disability determination, are defined and described in 

the SSA publication, Disability Evaluation Under Social Security 2003.2

 The statutory definition of “Disability” is: The inability to engage in any substantial gainful 

activity by reason of a medically determinable physical or mental impairment(s) which can be 

expected to result in death or which has lasted or can be expected to last for a continuous period 

of not less than 12 months. This definition differs from the clinically used definition of the 

World Health Organization’s International Classification of Impairments, Disabilities and 

Handicaps (1980),3

 which defines disability as “any restriction or lack of ability to perform an 

activity in a manner or within the range considered normal for a human being.” While much of 

the medical literature uses the latter, broader definition, the reader must be aware that the goals 

of this report relate to the statutory definition. 

The following terms are defined by current (2003) SSA regulations: 

“Claimant” is anyone who has filed a disability claim. 

“Substantial Gainful Activity” is the ability to earn an average of $800 per month. 

“Medically Determinable Impairment” is a physical or mental impairment that results from 

anatomical, physiological, or psychological abnormalities which can be shown by medically 

acceptable clinical and laboratory diagnostic techniques. 

“Evidentiary Requirements” for disability determination are described by SSA regulation. 

An acceptable medical source must report signs, symptoms, and laboratory findings diagnostic of 

an impairment. Although a claimant’s reported signs and symptoms are not sufficient to meet 

the evidentiary requirements for establishing the presence of a medically determinable 

impairment, all available evidence including the claimant’s report of symptoms is used to 
evaluate the impact of any documented impairment(s) on the claimant’s ability to carry out work 

tasks. 

“Severe Impairment” is defined by the agency as any “impairment that more than minimally 

limits the claimant’s ability to do basic work activities.” 

The regulations include a Listing of Impairments for each body system that define disability. 

Often referred to as the “medical listings,” this list allows quick disability determinations to be 

made on the basis of medical criteria alone. The SSA publication, Disability Evaluation Under 

Social Security 2003,2

 under the neurological category of impairments, includes Listing 11.09. 

11.09 Multiple Sclerosis with: 

A. Disorganization of motor function as described in 11.04; or 

B. Visual or mental impairment as described under the criteria in 2.02, 2.03, 2.04, or 

12.02: or 

C. Significant, reproducible fatigue of motor function with substantial muscle weakness on 

repetitive activity, demonstrated on physical examination, resulting from neurological 

dysfunction in areas of the central nervous system known to be pathologically involved 

by the multiple sclerosis process.

All pages pertinent to the Medical Listing for multiple sclerosis, including the imbedded 

references to sections 2, 11, and 12, are found in Appendix A. 

“Residual Functional Capacity” is assessed when a claimant is determined to have a “severe” 

impairment that does not meet or equal the intent of the medical listings. Physical capacity 

(lifting, carrying, walking, standing, sitting, pedaling, etc.) and mental capacity (cognitive and 

behavioral, thought processing, concentration, pace, behavior) are assessed in determining 

residual functional capacity. 

In order to adjudicate claims by individuals with MS for disability benefits, SSA must

determine whether the claims file includes information from an acceptable medical source that 

documents the signs, symptoms, and laboratory findings that are diagnostic of a physical or 

mental impairment. SSA adjudicators also determine whether the impairment would be expected 

to more than minimally interfere with the claimant’s capacity to carry out basic work activities 

for at least 12 consecutive months or end in death. If a severe impairment is identified, the 

adjudicator determines whether the medical findings meet or equal an impairment in the medical 

listings. If the documented impairment does not meet or equal a listed impairment, the 

adjudicator must determine the claimant’s residual functional capacity and consider vocational 

factors prior to making a final disability determination. 

Research Questions 

This evidence report covers five major topic areas framed within seven research questions, 

all of which are targeted to the adult population with MS. Our primary goal was to identify, 

review, and evaluate the published literature to answer the research questions; our secondary 

goal was to identify areas where no evidence exists or where the evidence has important 

limitations and then describe the type of data that would be needed to more fully address the 

question. 

The questions are listed below by topic area, along with a brief description of our analytical 

approach, including interventions and outcomes of interest. 

4
Reliability of MS Diagnostic Criteria 

Question 1a. What is the reliability of new McDonald criteria (incorporating supplementary 

information from radiologic and laboratory studies including magnetic resonance imaging 

[MRI], visual evoked potential [VEP], and cerebrospinal fluid [CSF] analyses) compared with 

long-term follow-up diagnosis of clinically definite MS according to the Poser criteria?

The major difference between the Poser criteria4 and the new McDonald criteria5 is the

addition of MRI findings. Our approach to this question was to identify studies in two 

categories: (1) those that specifically compared the new McDonald criteria with the reference 

standard of long-term diagnosis of clinically definite MS according to Poser criteria; and (2) 

those that provided data on the accuracy of various MRI techniques, CSF, and VEP (paraclinical 

diagnostic techniques incorporated into the criteria) with regard to the diagnosis of MS and thus 

supported their use as a supplement to clinical diagnosis. 

In reporting results, the focus was on both relative measures (e.g., Hazard ratios) and 

absolute rates (e.g., percentages of patients with or without positive CSF who met Poser criteria 

at long-term follow up), with a primary focus on the latter. 

Question 1b. What is the inter-rater reliability of diagnosis of MS according to Poser or 

McDonald criteria among neurologists or between neurologists and non-neurologist physicians? 

The relevant diagnostic criteria were the Poser and new McDonald criteria plus any other 

clinical, laboratory, neurological exam, MRI, CSF, VEP, or other data supporting the MS 

diagnosis. Results had to describe data on agreement or disagreement on the MS diagnosis 

between evaluating physicians. Agreement statistics could include kappa scores, sensitivity and 

specificity rates, or other data of the type that could be used in completing a two-by-two table. 

Predictors of Physical and Mental Impairments at 12 Months 

Question 2. What clinical indicators, including particularly time-course of impairments, 

predict physical or mental impairment at 12 months?

There were four main categories of clinical predictors of particular interest to the analysis: 

(1) clinical characteristics such as exacerbation rates, disease type, age at disease onset, sex, 

degree of remission after relapse, and type and number of neurological symptoms; (2) imaging 

studies, particularly MRI; (3) laboratory test results such as apolipoprotein E (APOE) ε4 allele 

and intrathecal immunoglobulin-M (IgM) synthesis; and (4) self-reported health status using 

validated scales. 

The evaluation of studies for this question was limited to those with a time course of 12 

months (SSA’s statutory limit), a timeframe which treating physicians would not ordinarily 

consider an important decision point. For this disease, the course has typically been studied over 

time horizons of many years. 

Effect of Treatment and Symptom Management on Disease Course 

Question 3a. Among patients with MS, do current disease-modifying treatments result in 

long-term improvements in physical or mental outcomes compared to placebo or usual care?

Interventions of interest for this question were all current (2003) disease-modifying 

immunomodulatory treatments (interferons and glatiramer acetate) and immunosuppressive 

5
treatments (e.g., azathioprine, mitoxantrone, cyclophosphamide, intravenous [IV] 

immunoglobulin-G [IgG]). 

Outcomes of interest were physical functioning (primarily Expanded Disability Status Scale 

[EDSS] scores), proportion of patients with “improvement,” relapse frequency, cognitive 

functioning, quality of life, and adverse events. 

Question 3b. Among patients with MS, do treatments aimed at symptom management result 

in improvements in physical or mental outcomes compared to usual care?

The effectiveness of symptomatic therapies for spasticity, rehabilitation, urinary 

management, fatigue, depression, and cognitive impairment was evaluated. Relevant outcomes 

were analyzed within six categories: (1) symptom-specific functional status or quality-of-life 

outcomes; (2) physical functioning (primarily EDSS); (3) cognitive functioning; (4) work or 

employment outcomes; (5) generic quality-of-life outcomes; and (6) adverse events. 

The analysis of studies relevant to Questions 3a and 3b was complicated by issues of

definition, particularly for outcomes reporting “improvement,” “long-term improvement,” and 

“relapse rates.” Our reporting of the results and subsequent analysis are presented within SSA’s 

regulatory definition of “disability,” which considers physical or mental impairments that can be 

expected to result in death or which have lasted or can be expected to last for a continuous period 

of not less than 12 months. 

Association of Clinical Findings with Work Ability

Question 4. Among individuals with MS, what physical, mental, laboratory, or radiographic 

findings have been associated with inability to work?

The phrasing of this question predetermined the outcome of interest as ability to work. 

Findings reported as absolute and relative measures of physical and mental/cognition function 

and laboratory and radiographic testing related to work activity were assessed. 

Environmental Factors and Work Ability

Question 5. Among individuals with MS, how does elevated temperature or other 

environmental factors impair the capacity to work?

This question was interpreted as the association of workplace environmental conditions and 

demands (specifically, ambient temperature, individual’s body temperature, or exposure to heat 

or cold) on the ability of an individual with MS to work. Relative and absolute measures of 

association were assessed. 

Limitations of Report 

In requesting this evidence report, SSA sought evidence from the medical and scientific 

literature to determine whether current medical knowledge supports SSA’s stated policies 

regarding MS. Seven specific questions were framed within five topic areas. The information 

compiled in this report may enable SSA, for example: (1) to improve consistency of disability 

claims by applying more objective criteria, but only if the criteria are valid; (2) to change the 

population eligible for disability through a change in the diagnostic criteria for MS; (3) to 

influence changes in treatment that might reduce the number of people permanently disabled by 

6
MS; and (4) beyond motor and cognitive impairments, to consider how other significant 

symptoms, such as fatigue and urinary urgency, may be incorporated into considerations of 

disability status. 

We believe the evidence presented in this report could also be used as the basis for a 

consensus conference of multidisciplinary experts on Listing of Impairments for MS that would 

employ formal consensus methods to update the current listing, as well as possibly expanding the 

disability process to include sociocultural factors that impinge upon desiring, seeking, finding, 

acquiring, and sustaining a job. 

7
9 

Note: Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gov/clinic/epcindex.htm.

Chapter 2. Methods 

The basis of this evidence report is a systematic comprehensive review and evaluation of the 

literature relevant to five topic areas proposed by the Social Security Administration. 

Literature Search and Review 

Sources 

The primary sources of literature were MEDLINE® (1966-April 2003), CINAHL® (1983-

April 2003), Cochrane Database of Systematic Reviews, and Web of Science. Searches of these 

databases were supplemented by reviews of reference lists contained in all included articles and 

in relevant review articles and meta-analyses. 

Search Strategies 

The basic search strategy used the National Library of Medicine’s Medical Subject Headings 

(MeSH) key word nomenclature developed for MEDLINE® and was adapted for use in the other 

databases. The searches were limited to the English language and to human subjects. For 

efficacy of treatment topics, the searches were also limited to studies with randomized controlled 

trial designs. The texts of the five major search strategies are given in Appendix B. In addition, 

we used Web of Science (Thompson ISI, Philadelphia, PA) to identify articles that cited the 

recent McDonald criteria from the International Panel on the Diagnosis of Multiple Sclerosis.5

The searches yielded a total of 1487 citations, whose records are maintained in a ProCite 

(Thompson ISI ResearchSoft, Berkeley, CA) database. 

Abstract and Full-text Screening Criteria 

The seven specified questions spanned several topic areas and produced a considerably large 

and varied literature, which complicated the screening process. For each question, we developed 

fairly detailed inclusion/exclusion criteria. The titles and abstracts of the 1487 articles were 

reviewed against these criteria by at least two of five clinical investigators (“title-and-abstract 

screening” stage). Where no abstract was available, the title, source, and keywords were 

screened. At this stage, articles were included if requested by one investigator. The full text of 

each article passing the title-and-abstract screening was obtained for further review. 

At the “full-text review” stage, each article was independently evaluated by two 

investigators, who forwarded their decisions to the task order manager for recording and 

comparison. If indicated, reviewers were asked to reconcile differences of opinion and return a 

reconciled final decision. If reviewers had difficulty reaching agreement, or submitted indecisive 

codes, the principal investigator was the arbiter. 

We developed detailed screening instructions for the title-and-abstract screening (Appendix 

C) and additional decision rules for the full-text screening (Appendix D). For the full-text 

screening, we also produced a summary decision sheet, on which screeners recorded their 

include/exclude decision, research question assignment, and specific exclusion criterion (if 

appropriate) for each article. 
Summaries of the results of the title-and-abstract screening and full-text review are provided 

in Tables 1 and 2. 

Data Abstraction and Development of Evidence Tables 

We determined that the data from the included articles could be abstracted directly into an 

evidence table template, which would serve as a “data abstraction form.” To facilitate the 

development of the evidence tables and to use everyone’s particular skills and time to their best 

advantage, the writer/editor began the data abstraction process with a partial abstraction of each 

article that was included at the full-text review stage. The partial abstraction/evidence table 

included descriptions of the study design, interventions, number of subjects at the start of the 

study, and the types of outcomes data to be collected; this partial abstraction was forwarded to 

the primary abstractor. The completed evidence table was returned to the writer/editor, who 

checked for completeness and consistency of information and then forwarded the table to a 

second investigator for over-reading. The over-reader returned the table to the writer/editor for 

final check of the completeness of the content, editing, and formatting. The data 

abstraction/evidence table templates for each research question are provided in Appendix E. 

Quality Assessment Criteria 

At the data abstraction stage, we evaluated each included article for factors affecting internal 

and external validity. The quality assessment criteria were incorporated into the last column of

the data abstraction/evidence table templates (Appendix E) and varied by question. The 

questions and their associated criteria and range of responses follow. 

Question 1a: What is the reliability of new McDonald criteria (incorporating supplementary 

information form radiologic and laboratory studies including magnetic resonance imaging 

[MRI], visual evoked potential [VEP], and cerebrospinal fluid [CSF] analyses) compared with 

long-term follow-up diagnosis of clinically definite multiple sclerosis (MS) according to the 

Poser criteria? The quality assessment criteria were: 

1) Patients evaluated using Poser criteria regardless of results on initial tests? 

Yes/No/Unclear 

2) Follow-up > 80%? Yes/No/Not reported (NR)/Not applicable (NA; relevant to 

retrospective cohort studies or case-control studies) 

Question 1b: What is the inter-rater reliability of diagnosis of MS according to Poser or 

McDonald criteria among neurologists or between neurologists and non-neurologist physicians? 

There were two criteria:

1) Evaluating physicians blinded to one another’s diagnosis? Yes/No/Unclear 

2) Did study sample include an appropriate spectrum of patients (not just “difficult” 

cases)? Yes/No/Unclear 

Question 2: What clinical indicators, including particularly time-course of impairments, 

predict physical or mental impairment at 12 months? The criteria were:

1) Study described as “population-based”? Yes/No 

2) Sample of patients assembled at a common point in the course of their disease? 

Yes/No/Unclear 

3) Sample of patients assembled at an early point in the course of their disease? 

Yes/No/Unclear 

10
4) Follow up > 80%? Yes/No/NR/NA (retrospective or case-control study) 

5) Outcomes assessed using a widely used scale? Yes/No 

6) Outcomes assessed in a blind fashion? Yes/No/Unclear 

7) If subgroups with different prognoses are identified: (a) was there adjustment for 

important prognostic factors? Yes/No/Unclear/NA; (b) was there independent 

validation? Yes/No/Unclear/NA 

Question 3a: Among patients with MS, do current disease-modifying treatments result in 

long-term improvements in physical or mental outcomes compared to placebo or usual care? 

AND Question 3b: Among patients with MS, do treatments aimed at symptom management 

result in improvements in physical or mental outcomes compared to usual care? The criteria 

used for each of these questions were:

1) Described as “randomized”? Yes/No

2) Method of randomization clearly described? Yes/No 

3) Concealment of allocation? Yes/No/Unclear 

4) Described as “double-blind”? Yes/No 

5) Patients blinded? Yes/No/Unclear 

6) Investigators blinded? Yes/No/Unclear 

7) Outcome assessors blinded? Yes/No/Unclear 

8) Number of withdrawals in each group stated? Yes/No 

For crossover trials only:

9) Period or carry-over effects? Yes/No/Not discussed 

10) Washout period? Yes (give duration)/No 

11) Number of patients in each sequence clearly described? Yes/No 

12) Were patients who did not complete all of the period excluded from the analysis? 

Yes/No/Unclear 

Question 4: Among individuals with MS, what physical, mental, laboratory, or radiographic 

findings have been associated with inability to work? AND Question 5: Among individuals with 

MS, how does elevated temperature or other environmental factors impair the capacity to work?

The quality assessment criteria for these two questions were:

1) Study described as “population-based”? Yes/No 

2) Follow up > 80%? Yes/No/NR/NA 

3) Work outcomes assessed using a widely used scale? Yes/No 

4) Work outcomes assessed in a blind fashion? Yes/No/Unclear 

5) If subgroups with different work ability are identified: (a) was there adjustment for 

important prognostic factors? Yes/No/Unclear/NA; (b) was there independent 

validation? Yes/No/Unclear/NA 

We did not sum the criteria into an overall quality assessment score, but rather we considered 

and reported each criterion individually. We favored this approach for several reasons: 

 Previous work has shown that numeric grading systems may not discriminate well 

between “high-quality” and “low-quality” studies, even for randomized trials.6,7

 Development and use of a new quality score would require additional work for 

validation, for which there was no time or budget allocation in the task order. 

 Identification of specific weaknesses in each study was helpful in identifying trends, 

which in turn assisted with our recommendations for future research. 

11
 Describing key design components, rather than assigning a single aggregate score, is also 

consistent with recent recommendations from an expert panel on meta-analysis of 

observational studies.8

Peer Review Process 

We employed internal and external quality-monitoring checks through every phase of the 

study to reduce bias, enhance consistency, and verify accuracy. Examples of internal monitoring

procedures include: three progressively stricter screening opportunities for each article (title-and 

abstract screening, full-text article review, data abstraction review); hands-on involvement of 

three individuals (two clinicians) in each data abstraction; agreement of at least two clinicians on 

all included studies. 

Our principle external quality-monitoring device was the peer-review process. Nominations 

for peer reviewers were solicited from several sources, including a technical advisory panel and 

interested federal agencies. The list of nominees was forwarded to the Agency for Healthcare 

Research and Quality (AHRQ) for vetting and approval. 

12
15 

Note: Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gov/clinic/epcindex.htm.

Chapter 3. Results

Diagnostic Reliability of McDonald Criteria 

Introduction 

This section addresses results for Question 1a: What is the reliability of new McDonald 

criteria (incorporating supplementary information from radiologic and laboratory studies 

including magnetic resonance imaging [MRI], visual evoked potential [VEP], and cerebrospinal 

fluid [CSF] analyses) compared with long-term follow-up diagnosis of clinically definite 

multiple sclerosis (MS) according to the Poser criteria? 

The diagnosis of MS has traditionally been based on clinical history and examination, and on 

the absence of an alternative diagnosis. Paraclinical tests such as imaging techniques,9

 evoked 

potentials,10 and CSF analyses have been used to aid diagnosis, but their precise role in formal 

diagnostic criteria for MS has been a source of debate. With the advent of MRI, which provides 

much more detailed images of the brain and spinal cord than were possible with computed 

tomography (CT), debate over the role of paraclinical tests in the diagnosis of MS has been 

renewed. 

Of the various diagnostic criteria proposed for MS, the most widely used have been those by 

Poser et al. (1983).4

 The Poser criteria focus on objective examination evidence of abnormalities 

in at least two separate areas of the central nervous system, with historical information to suggest 

at least two periods of MS involvement over time. The criteria may be summarized as follows:4

 Clinically definite MS: 

- 2 attacks and clinical evidence of 2 separate lesions; or

- 2 attacks; clinical evidence of 1 lesion and paraclinical evidence of another, separate 

lesion. 

 Laboratory-supported definite MS: 

- 2 attacks; clinical or paraclinical evidence of 1 lesion; and CSF immunologic 

abnormalities; or

- 1 attack; clinical evidence of 2 separate lesions; and CSF immunologic abnormalities; 

or

- 1 attack; clinical evidence of 1 lesion and paraclinical evidence of another, separate 

lesion; and CSF immunologic abnormalities. 

 Clinically probable MS: 

- 2 attacks and clinical evidence of 1 lesion; or

- 1 attack and clinical evidence of 2 separate lesions; or 

- 1 attack; clinical evidence of 1 lesion and paraclinical evidence of another, separate 

lesion. 

 Laboratory-supported probable MS: 

- 2 attacks and CSF immunologic abnormalities. 

In light of the growing potential of paraclinical tests – particularly MRI – to contribute to the 

diagnosis of MS, the International Panel on the Diagnosis of Multiple Sclerosis met in July 2000 

to reassess existing diagnostic criteria. The panel recommended changes to the criteria that 

(1) integrated MRI into the overall diagnostic scheme and (2) provided for the diagnosis of 

primary progressive disease.5

 The new criteria (here referred to as the McDonald criteria)5 were 
designed to be used by practicing physicians and adapted, as necessary, for clinical trials. They 

dropped the Poser categories of “clinically definite,” “laboratory-supported definite,” “clinically 

probable,” and “laboratory-supported probable” MS and proposed that the disease be diagnosed 

using the following criteria:5

 2 or more attacks; objective clinical evidence of 2 or more lesions 

- No additional data needed 

 2 or more attacks; objective clinical evidence of 1 lesion; plus

- Dissemination in space, demonstrated by: 

• MRI, or

• 2 or more MRI-detected lesions consistent with MS plus positive CSF, or

• Further clinical attack implicating a different site.

 1 attack; objective clinical evidence of 2 or more lesions; plus

- Dissemination in time (demonstrated by MRI). 

 1 attack; objective clinical evidence of 1 lesion (monosymptomatic presentation, clinically 

isolated syndrome); plus

- Dissemination in space, demonstrated by: 

• MRI, or 

• 2 or more MRI-detected lesions consistent with MS plus positive CSF, and

- Dissemination in time, demonstrated by: 

• MRI or 

• Second clinical attack. 

 Insidious neurological progression suggestive of MS; plus

- Positive CSF, and 

- Dissemination in space, demonstrated by: 

• 9 or more T2 lesions in brain, or

• 2 or more lesions in spinal cord, or

• 4-8 brain lesions plus 1 spinal cord lesion, or

• abnormal VEP associated with 4-8 brain lesions, or

• abnormal VEP with fewer than 4 brain lesions plus 1 spinal cord lesion; and

- Dissemination in time, demonstrated by: 

• MRI, or

• Continued progression for 1 year. 

The publication of the McDonald criteria has renewed the discussion of the value of 

incorporating paraclinical testing, particularly MRI, in the diagnosis of MS. The Social Security 

Administration (SSA), aware of the difficulties brought on by improper or inadequate diagnosis, 

has sought evidence from the literature regarding the value of the various diagnostic criteria. 

Question 1a seeks specific information regarding the reliability of the McDonald criteria. 

In this review, we sought to identify specifically those studies that evaluated whether patients 

diagnosed with MS according to the McDonald criteria would later meet the Poser criteria for 

clinically definite MS. We also sought articles that, although not specifically using the 

McDonald criteria, may have evaluated components of the McDonald criteria against later 

diagnosis of MS according to the Poser criteria. 

There exists a significant literature regarding the diagnostic utility of newer MRI techniques, 

such as magnetization transfer or various measures of atrophy,11-21 but we did not include such 

articles as they are not a part of currently used diagnostic criteria in general or the McDonald 

criteria specifically. 

16
Results 

Thirteen articles22-34 describing 11 different study populations met the inclusion criteria for 

this question (see Evidence Table 1a in Appendix F). Of the included articles, two27,34

specifically addressed the comparative performance of the Poser and McDonald criteria, nine22-

25,28,30-33

 examined the performance of various standard MRI techniques in addition to clinical 

diagnosis, one29 evaluated the performance of other paraclinical testing in addition to Poser 

criteria, and one26 contained data regarding the performance of the McDonald criteria, although 

it was not specifically designed to answer this question. 

Those studies that did not specifically address the relative performance of the Poser and 

McDonald criteria nevertheless provided background information regarding the improved 

diagnostic yield achieved by adding MRI and paraclinical testing to the clinical diagnosis. These 

studies generally did not utilize MRI in the same manner as the McDonald criteria, and therefore 

it is difficult to apply these results directly. For example, several studies examined the 

performance of MRI abnormalities at baseline with subsequent diagnosis of MS. As the data 

summarized in Table 3 indicate, the results of these studies document the significant predictive 

value of baseline MRI findings for the subsequent development of MS. The McDonald criteria 

utilize serial MRI studies to add to the diagnostic performance. Therefore, although these studies 

provide background information documenting the utility of MRI, they do not specifically address 

the McDonald criteria use of MRI. 

The two studies that did specifically address the performance of the McDonald criteria in 

comparison with the Poser criteria27,34

 reported remarkably similar results (Table 4). The first 

study27 evaluated 119 patients with clinically isolated syndromes at baseline and reevaluated 50 

of these patients at 3 years. MRI studies from 3 months, 1 year, and 3 years were retrospectively 

analyzed in a blinded fashion using the McDonald criteria. In this study, the diagnosis of MS 

had been made clinically (using the Poser criteria) prior to the retrospective application of the 

McDonald criteria. The second study34 followed 139 patients with clinically isolated syndromes 

prospectively for a mean of 39 months, with 86 patients followed for at least 3 years. In this 

study, the diagnosis of MS was made prospectively according to the Poser criteria and compared 

with the prospective application of the McDonald criteria. The two studies showed sensitivity of

the McDonald criteria ranging from 0.73 to 0.94, with specificity ranging from 0.83 to 0.87, 

when compared to diagnosis using the Poser criteria. 

Using the Poser criteria as the diagnostic gold standard in this way is problematic, mainly 

because the limited duration of any clinical study means that some patients may be classified as 

non-diseased at the conclusion of a study who later go on to meet the Poser criteria for MS. 

Once the Poser criteria are defined as the gold standard, other tested criteria can at best correlate 

highly with Poser diagnosis. It is possible that the McDonald criteria might perform better than 

the Poser criteria (in terms of sensitivity, ability to diagnose MS early, and/or association with 

prognosis) if both could be compared to a (hypothetical) true gold standard. The high level of 

agreement of McDonald criteria with later Poser criteria diagnosis observed in the studies 

reviewed here is not inconsistent with this possibility. 

17
Inter-rater Reliability of Diagnosis with McDonald 

and Poser Criteria

Introduction 

The preceding discussion of Question 1a was concerned with the validity of new diagnostic 

criteria for MS; this section examines the inter-rater reliability of the application of these criteria 

as posed by Question 1b: What is the inter-rater reliability of diagnosis of MS according to 

Poser or McDonald criteria among neurologists or between neurologists and non-neurologist 

physicians? High inter-rater reliability of the McDonald criteria would suggest that their use in 

clinical practice should achieve similar validity to the findings of the literature as reviewed in 

Question 1a. 

Our primary goal was to evaluate studies that provide direct analysis of inter-rater reliability 

of the McDonald or Poser criteria. We also sought studies that evaluated the inter-rater 

reliability of components of the McDonald criteria, such as MRI studies of T2 lesions or 

gadolinium-enhancing lesions. We excluded studies of inter-rater reliability of MRI techniques 

that are not utilized in the McDonald criteria, such as measurements of cerebral atrophy, 

magnetic resonance spectroscopy, and measurements of T2 lesion volume. 

Results 

Two studies met our inclusion criteria (see Evidence Table 1b in Appendix F).37,38 Both 

examined inter-rater reliability of neurologist-physicians in diagnosing MS according to the 

Poser criteria. One of the studies38 also examined inter-rater reliability for diagnosing MS 

according to the McDonald criteria. We found no data examining the inter-rater reliability 

among other clinicians. 

Ford et al. (1996)37 examined the inter-rater reliability of the Poser criteria. Overall, there 

was substantial agreement between the two observers in classifying MS (kappa = 0.65; 95 

percent confidence interval [CI], 0.52 to 0.78). There was disagreement as to whether a patient 

had one or more “attacks” of MS. Agreement was substantial for clinical evidence of separate 

lesions and was almost perfect for both paraclinical evidence and laboratory support (all kappa 

values > 0.90). The primary disagreement was in defining “attacks” of MS, and the authors 

appropriately noted that this might be due to the retrospective nature of the evaluation. 

The primary shortcomings of this study were that only two evaluators were compared, and 

diagnoses were based on retrospective analysis of data from clinical records. This process is 

significantly different from prospective diagnosis. Prospective diagnosis allows the clinician 

access to detailed information that may be inadequately recorded in the medical record, such as 

lesion location, intensity of enhancement, and overall appearance of MRI changes. Likewise the 

details of clinical exacerbations may be communicated to an examining physician making 

prospective diagnoses, but may be inadequately or incompletely recorded in the medical record. 

In general, retrospective diagnosis is frequently based on relatively less complete information as 

recorded in the medical record. 

Zipoli et al. (2003)38 specifically addressed Question 1b by examining the inter-rater 

reliability of both the Poser and McDonald criteria (see Table 5). In this study, four neurologists 

assessed all patients consecutively admitted for diagnosis to a university department of 

18
neurology from September 2001 through June 2002 who had been followed for at least 6 months. 

The mean follow up was 12.7 months. The study evaluated 41 MS patients, of whom 15 had 

relapsing-remitting MS, two had secondary progressive MS, five had primary progressive MS, 

and 19 had clinically isolated syndromes. Three additional patients who were not diagnosed 

with MS were included in the evaluation. Data were abstracted from medical records onto 

standardized forms by a non-evaluating neurologist. No diagnoses were recorded. The four 

evaluating neurologists were stated to have similar clinical experience in MS diagnosis and 

management. The study does not report any specific training of these neurologists with regard to 

the McDonald criteria or MRI analysis. The four evaluating neurologists reviewed the 

standardized forms and all MRI scans independently without discussing their findings. Eighteen 

patients had follow-up MRI scans in addition to baseline scans. 

In this study, the primary difficulty in the McDonald criteria appeared to be decreased 

agreement in MRI interpretation, specifically in those patients with high lesion loads. The 

authors commented that this study utilized neurologist evaluators rather than neuroradiologists. 

Previous studies have correlated level of radiographic training with agreement in 

interpretation.

39,40 Judging dissemination in time was of particular difficulty in those patients 

with clinically isolated symptoms. The authors suggested that neuroradiologists be encouraged 

to interpret scans in MS patients with the McDonald MRI criteria in mind, providing specific 

information regarding lesion location and timing. 

Predictors of Physical and Mental 

Impairments at 12 Months

Introduction 

This section examines the evidence pertaining to Question 2: What clinical indicators, 

including particularly time-course of impairments, predict physical or mental impairment at 12 

months? The notion here is that an individual diagnosed with MS but not yet work disabled 

could, within the follow-up period of disability evaluation, become work disabled. In 

formulating a response to this question, we considered three crucial study features: the 

assessment of possible prognostic features, the period of follow up, and the assessment of a valid 

measure of physical or mental impairment. The assessment of possible prognostic features had 

to occur between the time of diagnosis of MS and the occurrence of work disability; in most 

studies this assessment occurred at or near study entry, but this was not necessary. The 12-

month timeframe specified in this question was the major limiting criterion in the number of

studies that could be included for evaluation; to expand the pool of studies, we included any 

evaluations in which follow up occurred within a window of 9 to 24 months from study entry (or 

measurement of the purported prognostic feature). Thus, a study that related prognostic data 

available at one time with outcome data at another time 9 to 24 months later would be eligible; 

furthermore, a study might provide such data over multiple different time frames (see Figure 1). 

In all cases, the available outcome measure was the Disability Status Scale (DSS) or the 

Expanded Disability Status Scale (EDSS). For purposes of judging a level approximately 

associated with work disability, we focused on the transition from an EDSS score of less than 6 

to greater than 6. Since deficits associated with MS unrelated to acute exacerbations are not 

expected to regress, we did not include studies in which patients were already severely disabled. 

19
Results 

Twelve publications41-52 describing 11 separate studies met the inclusion criteria (see

Evidence Table 2 in Appendix F). Four main categories of predictors were analyzed in the 

included articles: (1) clinical characteristics; (2) imaging study results; (3) laboratory test 

results; and (4) self-reported status. The following discussion is organized by these categories. 

Clinical characteristics. Clinical characteristics were described in four reports42,43,45,49

describing three studies. In a 1989 study by Goodkin et al.,45 exacerbation rates and adherence 

to disease types were analyzed. A non-population-based cohort of 425 patients was followed; 

254 patients with definite MS completed the evaluations, including the following patterns of 

disease: stable (n = 80), relapsing-remitting stable (n = 155), relapsing-remitting progressive (n 

= 48), and chronic progressive (n = 142). After a follow up of 1 to 5 years (mean, 2.6 years), 

disease pattern was not found to be a stable characteristic of patients, with 44 percent of patients 

changing from stable or relapsing-remitting to progressive disease, while 40 percent of patients 

with progressive disease stabilized. Further, disease pattern did not predict change in EDSS 

scores at 2 years. 

Runmarker et al. (1994)49 followed patients with relapsing-remitting course at onset for up to 

25 years. Of 308 patients identified at the onset, 200 had sufficient data for analysis. 

Multivariate survival models were developed to predict time from onset to start of progressive

disease and time from onset to a DSS score of 6; similar models were developed for predicting 

events from the end of the fifth year of disease onward. Several factors appeared to be predictive 

in one or more of the models, including age at onset, sex, degree of remission after relapse, 

mono- or poly-regional symptoms, type of affected nerve fibers, and number of affected 

neurological systems. Patients with early onset had a low initial risk of progression, rising to a 

maximum over about 15 years; patients with a late onset had a higher initial risk, which rose for 

several years, then fell. The predictions were not validated internally or externally. 

The most recent included study, by Cottrell et al. (1999a42 and 1999b43), evaluated a 

prospective, population-based cohort of patients with primary progressive MS. The original 

cohort was followed for a mean of 23 years; this was supplemented by an additional cohort, with 

a follow-up time not reported. The probability of progressing from one DSS level to the next 

was highest initially (87 percent probability of progressing from level 1 to 2 in 1 year), relatively 

constant for patients in DSS levels 2 to 5 (probability of progression of 1 level ranging from 26 

percent to 40 percent), and lower for patients in DSS levels 6 to 9 (ranging from 2 percent to 10 

percent). Using a multivariate analysis of potential predictors of progression to DSS of 8, 

several factors were significant, including sex, age at onset, years from onset to reaching a DSS 

of 3, and number of systems involved. The model was not validated, nor was its discriminative 

ability examined. However, in univariate survival curves, the discrimination of these individual 

factors appears modest at best. 

Imaging study results. Three studies of MRI satisfied inclusion criteria, with the majority 

of exclusions attributable to lack of comparison of MRI with subsequent course. Two studies46,48

evaluated monthly MRIs on patients with relapsing-remitting disease. Koziol et al. (2001)46

studied 50 patients in the context of a trial of cladribine in an effort to identify predictors of 

exacerbation. Three potential predictors were considered: enhancing lesions in three 

consecutive monthly MRIs, new enhancing lesions in three consecutive months, and new 

hypointense lesions in three consecutive monthly images. In all cases, the sequential MRIs had 

poor sensitivity (36 percent, 31 percent, and 31 percent, respectively), but higher specificity (85 

20
percent, 89 percent, and 89 percent, respectively). As a result, the positive predictive value was 

low (approximately 25 percent for an exacerbation in the next month), but the negative

predictive value was fairly high (89 percent for each predictor). 

In a substudy of patients in a trial of glatiramer acetate, Rovaris et al. (2003)48 examined the 

univariate correlations of baseline T1 and T2 lesion volume versus change in EDSS score. 

Without adjusting for baseline EDSS (which was correlated with baseline lesion volume), 

modest Spearman rank correlation coefficients were seen in the comparison of baseline lesion 

volume to EDSS at 9 months. Absolute changes in EDSS were not reported, and the 

investigators acknowledged that the associations were not clinically strong. 

In one imaging study,50 28 patients with various disease patterns and 13 healthy control 

subjects had spinal cord images performed at the second cervical level. While changes in spinal 

cord size were noted, there was no statistically significant association noted between cord area 

and change in EDSS. 

Laboratory test results. Laboratory tests were evaluated in four included studies: one of 

apolipoprotein E (APOE) ∈4 allele,41 two of immunological markers (one in blood,51 one in 

cerebrospinal fluid52), and one of evoked potentials.44

APOE ∈4 allele, associated with impaired neuronal repair, was assessed by Chapman and 

colleagues for its ability to predict clinical progression of MS.41 Forty-seven patients with 

relapsing-remitting MS were evaluated for the presence of APOE ∈4 allele. Results indicated 

that the presence of this genotype was associated with more rapid disease progression, with mean 

increase in EDSS of 4.0 during a 2-year follow up in patients with the allele compared to a mean 

increase of 2.7 for individuals without the genotype. Notably, the APOE ∈4 allele was not 

found to be associated with other factors possibly associated with relapse, including baseline 

EDSS, prior rate of relapse, or exacerbation rate in the prior 2 years. 

Villar et al. (2002)52 examined intrathecal immunoglobulin-M (IgM) synthesis in 22 patients 

with relapsing-remitting disease to determine if its presence during early stages of the disease 

correlated with a worse prognosis. Patients were evaluated as to their time to conversion to 

clinically definite MS, number of relapses, and changes in EDSS. While half of the patients with 

intrathecal IgM synthesis progressed at least one EDSS unit after 1 year, none of the patients 

without this marker progressed in that period. Notably, relapse rate was similar in patients with 

and those without intrathecal IgM synthesis. 

Trotter et al. (1989)51 measured interleukin-2 (IL-2) levels in serum of 10 patients with 

chronic progressive MS and 12 normal controls, as well as concavalin A suppressor, mitogen 

stimulation, and phenotyping of peripheral blood mononuclear cells. Only IL-2 levels at 

baseline correlated with disability over 18 months. Though no cutoff value for elevation was 

selected a priori, a value of 40 U/mL corresponded to a sensitivity of 67 percent and specificity 

of 100 percent for the outcome of worsening one or more units in EDSS. Notably, these results 

were not examined after adjusting for other predictive features, particularly those diagnostic of 

MS. 

One study was identified that compared results from motor and visual evoked potentials at 

baseline with subsequent EDSS. Fuhr et al. (2001)44 studied 30 patients with relapsing-remitting

(n = 25) or secondary progressive (n = 5) patterns using measures of motor and visual evoked 

potentials, such as the sum of Z scores of central motor conduction time. Results of these tests at 

baseline were moderately correlated with EDSS score at 24 months (0.43, p = 0.03). No cutoff 

was defined a priori for a positive evoked potential study. However, from the data provided, a Z 

score at baseline exceeding 0 was associated with a sensitivity of 53 percent and specificity of 70 

21
percent for any worsening of EDSS at 24 months. For the population studied, the overall 

likelihood of progressing was 17/27 (63 percent); of 11 patients with a positive study, nine (82 

percent) progressed, and of 15 with a negative study, eight (53 percent) progressed. 

Self-reported status. Self-reported health status was compared to subsequent course in one 

study.47 Of 97 patients with relapsing-remitting MS, six were lost to follow up before 12 

months. Quality of life (QOL) was assessed using the Medical Outcomes Study 36-Item ShortForm Health Survey (SF-36), with results dichotomized into poor/fair versus good/very 

good/excellent. The relative risk for any worsening in EDSS at one year was 1.9 (95 percent CI, 

1.0 to 3.5). In absolute terms, having a poor or fair QOL assessment at baseline was associated 

with a 42 percent likelihood of progression to any degree, while a better QOL response was 

associated with a 23 percent chance of worsening. This association persisted with multivariate 

adjustment for baseline clinical characteristics. The association did not extend to other 

dimensions of the SF-36. Moreover, no assessment was made regarding the presence of a 

disability claim.

Disease-modifying Therapies and 

Long-term Improvement

Introduction 

In this section we report results for Question 3a: Among patients with MS, do current 

disease-modifying treatments result in long-term improvements in physical or mental outcomes 

compared to placebo or usual care? In attempting to answer this question, we were looking for 

data indicating whether individual patients improve on current disease-modifying therapy. 

Specifically, we were looking for data suggesting that disease-modifying treatments might result 

in enough clinical improvement to decrease an individual’s level of impairment to the point 

where he or she might not be disabled at some future time. 

As readers familiar with the relevant literature will recognize, most studies of the efficacy of 

disease-modifying agents assume that individual patient improvement is unlikely and do not 

consider data on improvement as part of the outcome assessment. In general, the literature 

assumes that while disease-modifying agents may be expected to reduce progression, they are 

not likely to result in improvement. This “disconnect” between the question we were asking and 

the assumptions of the clinical trial literature led us to conduct a broad search of the literature to 

examine indicators of efficacy, with a more specific examination of any available data 

delineating individual patient improvement. 

Our search strategy focused on reports that described data from randomized controlled trials 

of disease-modifying agents in patients with any degree of impairment. For the data to be 

meaningful with regard to improvement, we selected studies that included the outcome measures 

of change in physical function, cognitive function, work/employment status, and reduction in 

relapse rates where outcomes were reported over at least 12 months. We excluded studies 

evaluating therapies not currently in use. Ultimately, our focus was on those studies that 

reported data on individual patient outcomes – particularly the improvement of individual 

patients. We excluded studies that did not contain placebo controls because the demonstration of 

individual patient improvement without a comparison to control patients might only reflect 

22
improvement that is part of the natural history of MS rather than a treatment-specific 

improvement. 

Results 

Fifty-one publications53-103

 describing 34 separate trials, met our inclusion criteria (see 

Evidence Table 3a in Appendix F). The treatments evaluated included interferon beta, 

glatiramer acetate, mitoxantrone, glucocorticoids, intravenous (IV) immunoglobulin-G (IgG), 

azathioprine, cyclophosphamide, plasma exchange, methotrexate, cladribine, cyclosporine, and 

combinations of these therapies. Outcome measures were primarily group or mean changes in 

rates of relapses, changes in rates of progression on the EDSS, and occasionally changes in some

measures of cognition or quality of life. These studies are adequate to answer issues regarding 

the efficacy of therapy, but do not provide information regarding individual patient 

improvement. 

Relapse rates. Data on relapse rate outcome measures are summarized in Table 6.53,54,59,62-

65,68,72-78,82-84,86,89,92,93,95-97,100,103

 In most of these studies the baseline mean annual relapse rate 

was approximately one relapse per year. The effect of most of the therapies studied was a mean 

reduction in the range of 0.3 relapses per year; higher reductions (up to one relapse per year) 

were reported after treatment with IV IgG when baseline relapse rates were in the range of 1.5 to 

2 relapses per year. We found only one study that reported reductions in individual patient 

relapse rates. Kappos et al. (2001)79 reported that treatment with interferon beta increased the 

proportion of patients who were relapse-free or had decreased relapse rates from 45 percent 

(placebo) to 53.1 percent (treatment). In summary, the effect of treatment with any of the 

currently used therapies is a mean reduction in relapses of less than one relapse per year. The 

benefit may be higher in patients with higher baseline relapse rates, but we did not find data 

stratified in this manner. 

Physical function (EDSS). Studies reporting data on individual patient improvement in 

EDSS scores are summarized in Table 7.53,55,58,59,63-65,67,68,75-78,80,83,90,96,97,102,103 Most of these 

studies provided a definition (and in some cases more than one definition) of improvement, 

usually corresponding to at least a one-point decrease in EDSS score. Changes of half a point 

(0.5) in EDSS may not be reliable due to uncertainty regarding this degree of change and 

uncertain clinical significance. The proportion of patients meeting varied definitions of 

improvement in placebo groups ranged from 0 to 22 percent; the differences in proportions of 

patients improving ranged from -1 to 49 percent, although most fell into the range of 0 to 12 

percent. Higher EDSS change thresholds (-2 points or -3 points) resulted in lower proportions of 

patients meeting improvement definitions in one study.55

Improvement in cognitive function. Two included studies evaluated the efficacy of therapy 

with regard to cognitive function.76,78 Both studies demonstrated benefit of therapy over placebo 

but did not present data with regard to the quantitative improvement seen in individual patients. 

Improvement in quality-of-life measures. Two included studies (described in three 

publications) evaluated the efficacy of therapy with regard to quality-of-life measures.59,66,79 

Both studies demonstrated benefit of therapy over placebo in the groups studied, but did not 

present data with regard to the quantitative improvement seen in individual patients. 

23
Symptom Management and Improvement 

Introduction 

This section of the report considers Question 3b: Among patients with MS, do treatments 

aimed at symptom management result in improvements in physical or mental outcomes 

compared to usual care? Several symptomatic complaints are common among patients with 

MS. Among the most common are fatigue and voiding dysfunction. Less well recognized are 

cognitive dysfunction and pain. We assessed the effectiveness of therapies aimed at particular 

symptoms including spasticity, voiding dysfunction, fatigue, depression, and cognitive 

impairment, as well as more comprehensive treatment aimed at multiple symptoms or multiple 

areas of functional status, i.e., rehabilitation. We excluded trials of drugs that are not currently 

commercially available in the US. 

We sought randomized controlled trials reporting physical and mental health outcomes. We

excluded studies that reported data on patient preferences for treatments as the only outcome. 

We examined outcomes within six categories: (1) symptom-specific functional status or qualityof-life outcomes; (2) physical functioning (primarily EDSS); (3) cognitive functioning; (4) work 

or employment outcomes; (5) generic quality-of-life outcomes; and (6) adverse events. In 

contrast to our treatment of the previous question (Question 3a), we did not require data to be 

reported as the proportion of patients meeting a definition of symptom “improvement.” We

report all data comparing treatment and control groups on the above outcomes regardless of the 

format in which they were presented or analyzed.

Results 

We included a total of 68 articles describing 65 separate studies (see Evidence Table 3b in 

Appendix F). By topic, these included: for spasticity, 35 articles104-138 describing 32 separate 

studies; for rehabilitation, 10 articles/studies;139-148

 for depression, eight articles/studies;149-156 for 

fatigue seven articles/studies;157-163

 for voiding dysfunction, seven articles/studies;164-170 and for 

cognitive problems, one article/study.171

Spasticity. Among the 32 studies of specific treatments aimed at management of spasticity 

were randomized controlled trials (RCTs) of oral medications, intramuscular medications, and 

intrathecal medications, as well as physical treatments (magnetic stimulation and electrical 

neuromuscular stimulation). Trials of drug treatments were most common and considered the 

following agents: tizanidine, baclofen, diazepam, gabapentin, dantrolene, threonine, botulinum

toxin, cannabinoids/delta-9-tetrahydrocannabinol (delta-9-THC), progabide, and amantadine. 

Baclofen was the subject of six comparisons with placebo,105,109,117,124,129,130

 six comparisons with 

tizanidine,104,108,113,122,126,134,136 two comparisons with diazepam,106,110 and one with stretching 

exercises.105 In addition, one trial compared intrathecal baclofen with placebo.125

Tizanidine was studied in two placebo comparisons,133,137

 six comparisons with baclofen (see 

above), and one with diazepam.

127

Dantrolene was studied in one placebo comparison111 and one comparison with 

diazepam.

131,132 We found two studies each of gabapentin,107,121 progabide,119,120,128

 botulinum

toxin,114,135

 and threonine112,116 versus placebo. Delta-9-THC was tested in two trials115,138

24
against both placebo and cannabis sativa plant extract. Electrical118 and magnetic123

neuromuscular stimulation were each compared to sham stimulation. 

Study quality. All 32 trials randomly allocated patients to treatment groups, but the methods 

of randomization were clearly described for only 5/32 (16 percent). Most failed to provide 

enough information to determine whether there had been adequate concealment of the allocation 

schedule (25/32; 78 percent). In the seven studies that reported enough information for 

evaluation, there was adequate concealment in four, and inadequate concealment in three. 

Thirty of 32 trials (94 percent) were described as double-blind; patients were described as 

blinded in 29 trials, and in one trial118 it was unclear whether patients were blinded. Treating 

investigators were blinded in 28 trials; outcome assessors were blinded in 30 trials, but it was 

unclear whether they were blinded in another study.105 Most studies (27/32; 84 percent) reported 

the number of withdrawals in each treatment group. 

Twenty of the 32 studies were of crossover design; the remaining trials were of parallelgroup design. Among the crossover trials, we assessed several dimensions of quality unique to 

the crossover design. The presence of period effects or carry-over effects was not discussed in 

over half the studies (11/20; 55 percent). One trial reported having a period or carry-over effect 

and appropriately analyzed first-period data only.121 Most crossover trials (17/20; 85 percent) 

included a washout period. Thirteen (65 percent) failed to report clearly the number of patients 

assigned to each treatment sequence. In six studies it was unclear whether patients who did not 

complete both treatment periods were excluded; two studies appeared to use an inappropriate 

unpaired analysis retaining patients who did not complete the crossover in the final analysis. 

Study populations. Only 11 of the studies describe the study population in terms of EDSS 

score at baseline; mean baseline EDSS ranged from 4.7 to 7.4 in studies reporting means. The 

two studies of botulinum toxin114,135

 appeared to include the most severely impaired patients, 

with median EDSS scores above 7.5. Other study populations included mostly subjects with 

EDSS scores in the range of 5.0 to 7.0. 

Studies used a variety of outcome measures, many of which were not validated. Of the 

placebo-controlled trials, 12 of 20 (60 percent) used the Ashworth Scale or Modified Ashworth 

Scale. However, this scale was often combined with other measures135 or summed across sides 

and muscle groups to create outcome variables and statistical testing that have not been 

validated. 

Findings. Trial design and results are summarized in Table 8. Assessments of muscle tone 

were not consistently positive for most of the drug treatments, with the exception of two studies 

each of gabapentin107,121

 and progabide.119,120,128 Results of functional assessments were largely 

inconclusive; the only positive findings on functional assessments were associated with delta-9-

THC; deterioration in 9-Hole Peg Test (9-HPT) and Multiple Sclerosis Functional Composite 

(MSFC) was associated with delta-9-THC in one small study115 while a much larger study found 

improvements in 10-meter walk time

138 with delta-9-THC compared to placebo. Both studies 

reported these changes in the absence of a significant effect on objective measures of muscle 

tone. However, beneficial effects in the latter study for mobility are not easily ascribable to the 

drug’s psychoactive properties alone. 

In contrast to oral treatments, which were of uncertain effectiveness, intrathecal baclofen 

treatment showed a profound effect on muscle tone and spasms in one trial;125 however, the 

patients in this study were selected based on response to a pre-trial intrathecal dose of baclofen. 

 None of the trials comparing active drug treatments showed statistically significant 

differences in efficacy between agents, although there were some differences in tolerability. 

25
Rehabilitation. Among the 10 studies we classified as rehabilitation were RCTs of a variety 

of interventions delivered in a variety of settings. Probably the most comprehensive was a study 

of home-based management, which included not only traditional rehabilitation services but also 

nursing, education, psychological support, and social services.144 Several studies examined more 

typical rehabilitation interventions delivered in inpatient or outpatient settings.139,140,142,145 One 

study examined supervised exercise,143

 and one physiotherapy.148 Three studies used 

interventions that were probably less intense than traditional rehabilitations described as 

professionally guided self-care,141 wellness intervention (education in health behaviors and 

lifestyle change),146 and symptom management and adjustment (education and behavioral 

therapy).

147

Only one study used an active treatment comparison group, comparing inpatient 

rehabilitation to outpatient rehabilitation.139 Two other studies used control interventions 

presumed to be ineffective: a home exercise program145 and self-exercise treatment.142

Study quality. All 10 trials randomly allocated patients to treatment groups, but the methods 

of randomization were clearly described for only five (50 percent). Most failed to provide 

enough information to determine whether there had been adequate concealment of the allocation 

schedule (six; 60 percent). In the four studies that reported enough information for evaluation, 

there was adequate concealment in three and inadequate concealment in one. 

Because of the nature of the interventions, none of these studies was able to blind patients or 

therapists; however, four (40 percent) masked outcome assessors. Most studies (seven; 70 

percent) reported the number of withdrawals in each treatment group. All but one of the studies 

was parallel-group in design; one study of home physiotherapy used a crossover design.148

Study populations. Most of the studies (seven; 70 percent) described the study population in 

terms of EDSS score at baseline. Two studies had populations with notably lower mean EDSS 

scores of 3.4: the single study of supervised exercise143 and one of the more 

educational/behavioral intervention studies,147 which notably had a broad range of EDSS scores, 

from 0 to 9. In other studies, the populations were more impaired on average, with mean EDSS 

scores of 5.9 to 6.2 and medians of 5.5 to 6.5. 

Outcome measures used in these studies included measures of impairment (e.g., EDSS), 

disability (e.g., Functional Independence Measure [FIM]), and handicap (e.g., SF-36), and not 

only related to individual functions, but often used comprehensive measures of overall disability 

and handicap. 

Findings. Physiotherapy interventions failed to influence impairments as measured by EDSS 

(see Table 9). These interventions were, however, associated with measurable changes in 

functional status. Improvements in health (handicap) were observed in the SF-36 and several 

other measures. 

Depression. Among the eight studies of treatments aimed at depression were RCTs of a 

variety of interventions delivered in a variety of settings. Two placebo-controlled studies used 

drug treatments either alone155 or with a psychotherapy co-intervention.156 One study tested 

psychotherapy,149 and five trials used behavioral therapy, described as cognitive-behavioral 

therapy150,151,153,154

 or cognitive remediation.152

The two drug studies were placebo-controlled and were the only studies to employ blinding 

of patients and investigators. The remaining studies used control groups that were passive (waitlist150,151

 or no treatment152,154) or active (current events discussion group,149 support group153); 

one study used both an active and passive control group.149

26
Study quality. All eight trials randomly allocated patients to treatment groups, but the 

methods of randomization were clearly described for only two (25 percent). Six trials (75 

percent) failed to provide enough information to determine whether there had been adequate 

concealment of the allocation schedule; the other two trials did not have adequate concealment of 

allocation. Because of the nature of the interventions, none of the behavioral therapy studies was 

able to blind patients or therapists; however, neither did any of these studies mask outcome

assessors. Both studies of drug treatments were double-blind. Half of the studies failed to report 

the number of withdrawals in each treatment group. All but one of the studies were parallelgroup in design; one study of amitriptyline used a crossover design.155 Although this study did 

not report the number of patients in each sequence, it did employ a 1-week washout period and 

stated that there was no period or carry-over effect. 

Study populations. Among the eight trials, the populations studied were quite variable with 

regard to the presence of depression or depressive symptoms. Some studies selected patients 

with MS without regard to the presence of a diagnosis of depression or depressive 

symptoms;

149,150,152

 however, most studies either required a formal diagnosis of a depressive 

disorder153,156

 or required a certain score on a depression scale.151,154 One study specifically 

included patients based on the particular complaint of episodes of involuntary laughing or 

weeping.155

Findings. The included trials are summarized in Table 10. All but one of the studies 

reported statistically significant improvement in mood outcomes; Mendoza et al. (2001)152 failed 

to achieve statistical significance for changes in the Beck Depression Inventory (BDI), but the 

results did show a strong trend in favor of cognitive remediation. Treatment effects were 

similarly significant for studies of patients with depression diagnoses or those meeting minimum 

depression scale scores. 

The studies were consistent in finding that untreated control groups149-152,154

 showed no 

improvement over time. In contrast, a control group of patients receiving psychotherapy as a cointervention did show improvement.156 Two studies that used active controls (current events 

discussion group149 or support group152

) found marginal improvements in some outcomes, but 

still allowed detection of treatment effects. 

Fatigue. Among the seven studies of specific treatments aimed at management of fatigue 

associated with MS were RCTs of oral and topical medications. Amantadine was the subject of 

four placebo comparisons.157-159,161 Pemoline was evaluated in three placebo 

comparisons,159,161,163 two of which were three-arm studies including both amantadine and 

pemoline.159,161 Two more placebo comparisons evaluated 4-aminopyridine162 and transdermal 

histamine/caffeine.160

Study quality. All seven trials randomly allocated patients to treatment groups, but the 

methods of randomization were clearly described for only one.157 None provided enough 

information to determine whether there had been adequate concealment of the allocation 

schedule. All of the studies were described as double-blind, and all described the number of 

dropouts or withdrawals from each treatment group. 

Four of the trials used a crossover design.157,158,162,163 One reported a period effect and 

appropriately analyzed first-period data;157 the other three crossover studies tested for and 

reported no period or carry-over effects. One of the trials did not use a washout period.162 Two 

reported the number of patients in each sequence. 

Study populations. All studies selected patients based on complaints of persistent fatigue; 

some studies required either a threshold score on a fatigue measurement scale or a run-in period 

27
during which fatigue symptoms were demonstrated to be stable. Mean EDSS scores at baseline 

were reported for six of the seven studies (86 percent). Two studies had populations with higher 

EDSS scores than the others: Rossini et al. (2001),162 with a mean EDSS score of 6.2; and 

Gillson et al. (2002),160 with entry criteria requiring EDSS between 5.0 and 6.5. The other 

studies had less impaired populations on average, with mean EDSS scores ranging from 2.6 to 

4.3. 

Findings. Included trials are summarized in Table 11. Four studies comparing amantadine 

with placebo found statistically significant results on a few outcome measures, and statistical 

trends on others, consistent with a treatment effect. The two largest studies157,161

 found 

statistically significant treatment effects on the MS-Specific Fatigue Scale (MS-FS) or visual 

analog fatigue scores. Two of three studies comparing pemoline to placebo also reported 

statistically significant treatment effects.161,163

 One small study reported a treatment effect on the 

Modified Fatigue Impact Scale (MFIS) associated with transdermal histamine/caffeine, but no 

effects on functional measures (25-foot timed walk, 9-HPT) or cognitive performance.160 The 

single trial of 4-aminopyridine included in our review failed to show a treatment effect.162 

Voiding dysfunction. Among the seven studies of treatments for voiding dysfunction were 

five placebo-controlled trials of desmopressin nasal spray,164-167,170

 one trial of pelvic floor 

rehabilitation,169 and one trial of abdominal vibration or pressure.168 

Study quality. All seven trials randomly allocated patients to treatment groups, but none 

clearly described the methods of randomization. None provided enough information to 

determine whether there had been adequate concealment of the allocation schedule. All of the 

desmopressin studies were described as double-blind. Blinding was not possible for the 

vibration and rehabilitation studies. All but one167 of the studies described the number of 

dropouts or withdrawals from each treatment group. 

Six of the seven studies were of crossover design; one study of amitriptyline used a parallelgroup design.169 Only one of the crossover trials incorporated a washout period,168 and only one 

tested for carry-over or period effect.170

Study populations. Only two studies characterized populations in terms of EDSS, with 

means of 4.4 and 6.7. All studies recruited patients with MS and some kind of voiding 

dysfunction such as nocturia, urinary frequency, or incontinence. 

Findings. Included studies are summarized in Table 12. The five studies of desmopressin 

nasal spray all demonstrated statistically significant reductions in short term urinary frequency 

(number of voidings) during 6-hour periods after dosing. Most studies dosed at bedtime to 

control nocturia, but one study used daytime dosing to control daytime urinary frequency.166 At 

longer time intervals (24 hours) the treatments failed to show significant effects. The number of 

episodes of incontinence showed a statistical trend in one study,170 but this outcome was not 

reported in the other studies of desmopressin. 

Among the two nonpharmacological treatments, a program of pelvic floor rehabilitation 

(biofeedback and exercise) was effective in reducing incontinence episodes and nocturia;169 this 

study also showed a measurable reduction in urinary symptom-related handicap (p < 0.05). A 

small study of the use of a handheld abdominal vibrator at time of voiding succeeded in reducing 

post-void residual urine volumes and also appeared to reduce incontinence, but not urinary 

frequency.168 Interpretation of the results of this study was limited by poor reporting of the data 

and statistical analysis (no statistical tests were reported for several outcomes). 

Cognition. Studies aimed at treatment of cognitive deficits in MS are challenging to 

characterize. We did not identify a single study that (1) selected a study population with 

28
demonstrable cognitive deficits, (2) delivered a treatment (drug, behavioral, or psychological) 

aimed at improving cognitive performance, and (3) measured effects of treatment using tests of

cognitive performance. However, one trial met at least two of these criteria and merits 

discussion here.171 In addition, some of the studies aimed at treatment of depression assessed 

cognitive performance at baseline or as secondary outcomes.152 Some of the rehabilitation trials 

evaluated mood-related outcomes in addition to functional outcomes, but none evaluated 

cognitive performance as an outcome measure. Finally, two of the studies aimed at treatment of 

fatigue also evaluated effects on cognitive function.159,160

Study quality. Lincoln et al. (2002)171 describe both the method of randomization and 

adequate concealment of allocation. Because of the nature of the intervention, blinding of 

patients and therapists was not possible; however, outcome assessors were masked. The study 

reported the number of withdrawals and dropouts in each treatment group. 

Study populations. No studies selected patients based on screening for cognitive deficits at

study entry. Lincoln et al. (2002)171 enrolled MS patients without regard to cognitive 

performance for their study of a cognitive intervention; however, 78 percent of the study 

population enrolled scored greater than 1 (the recommended cut off) on the mental disability 

question from Guy’s Neurological Disability Scale (GNDS), and 95 percent either reported 

cognitive problems or showed significant impairment (score below cut off) on the Brief 

Repeatable Battery (BRB-N). Thus, while the proportion of patients with cognitive deficits may 

be elevated in this study due to selection biases, the prevalence of measurable cognitive deficits 

in other MS trials is likely also elevated. 

Findings. Lincoln et al. (2002)171 found no differences between the cognitive rehabilitation, 

assessment, and screening groups in any of the outcomes measured at 4 months (shortly after the 

end of the 6-week intervention) or at 8 months. Although the prevalence of cognitive deficits at 

baseline was relatively high, a large number of patients had self-reported cognitive deficits that 

were not detectible on GNDS or BRB-N, which may have hampered the ability to detect 

treatment effects. Furthermore, the population was heterogeneous with regard to their cognitive 

performance, which at best results in increased variance, making it more difficult to show 

statistical significance to differences between groups. 

Geisler et al.(1996)159 evaluated the effect of amantadine and pemoline on fatigue and 

cognition. Although the Symbol Digit Modalities Test (SDMT), a measure of attention and 

visuomotor search, showed a drug treatment effect (with the amantadine-treated group showing 

the greatest improvement), all other neurobehavioral outcomes failed to demonstrate a treatment 

effect. The authors acknowledge that the study did not have sufficient statistical power to detect 

small- to medium-sized treatment effects. But also, the study found no statistically significant 

correlation between fatigue symptoms and cognitive deficits either at baseline or post-treatment. 

Gillson et al. (2002)160 reported results from the Paced Auditory Serial Additions Test

(PASAT) in a trial of transdermal histamine and caffeine in a population of MS patients with 

fatigue. No significant treatment effect was detected. 

29
Association of Clinical Findings with Work Ability

Introduction 

This section summarizes findings related to Question 4: Among individuals with MS, what 

physical, mental, laboratory, or radiographic findings have been associated with inability to 

work?

Aspects surrounding ability to work are multifactorial in nature involving individual skill 

level, education level, interest in working, financial needs, domestic responsibilities, 

transportation needs, and other factors such as social norms and expectations. Functional 

limitations (physical and/or mental) associated with MS are presumably the primary 

determinants of work capacity. Adverse, intermittent, and poorly measurable symptoms such as 

fatigue and pain compound the task of determining if an individual with MS is able to work. 

Employers’ willingness or ability to provide workplace accommodations for workers who have 

limitations also impacts whether or not an individual with MS can work. 

Several different types of physical and cognitive function measures (e.g., EDSS, disease 

subtype, mobility aids) were employed within and across studies to determine work ability 

among individuals with MS. For the purpose of this review we have grouped the summary of 

study findings according to these types of measures, which are listed in Table 13. Some studies 

used various types of measures and therefore are listed and discussed in more than one section. 

Categorizing studies or specific tests into physical function versus mental/cognitive function for 

this review was somewhat challenging since some tools measure both types of function. For 

example, the EDSS focuses on the functioning of numerous systems, including mental 

functioning, but is weighted more heavily towards testing ambulation. For the purpose of this 

review, tools like this are categorized according to the dominant area of function tested, resulting 

in the categorization of EDSS under “physical function.” Tools testing multiple types of

function are discussed in greater detail below. 

Results 

A total of 22 articles

172-193

 representing 20 research studies were included in this review (see 

Evidence Table 4 in Appendix F). The majority of studies (n = 15) employed tests to measure 

physical function, while fewer studies (n = 5) measured cognitive or mental function (Table 13). 

To date, no studies have been ascertained that used laboratory or radiographic measures to 

determine work ability among individuals with MS. 

Most of the studies (n = 18) were cross-sectional in design, where work status or work ability 

was measured at a single point in time, primarily at the time of study enrollment. The other two 

studies were retrospective in design, including one case-control study193 and one retrospective 

cohort study.181 No prospective studies, where changes in physical and/or cognitive function 

over time were considered in relation to changes in work status or ability, were identified for this 

review. 

Twenty papers describing 18 studies used work status (yes/no or full-time, part-time, 

unemployed, retired, housewife) as a proxy measure for work ability among individuals with 

MS.172-189,192,193 The remaining two190,191

 attempted to incorporate several aspects of work 

ability as a study outcome: the Hyllested criteria. The remainder of this section is organized by 

30
types of measurement tools used to examine inability to work: Hyllested criteria, EDSS/DSS, 

cognitive measures, use of mobility aids, MS disease subtype, job type/characteristics, and selfreport. 

Hyllested criteria. As indicated above, only two190,191

 of the 20 included studies sought to 

determine ability to work among individuals with MS beyond the measurement of work status. 

Findings from these studies are reported separately (Table 14) from other studies that employed 

similar methods of measuring physical and mental functioning. Two cross-sectional studies 

conducted in Israel by Rozin et al. (1975191 and 1982190) used similar methods for determining 

work ability among selected groups of individuals with MS ages 17 to 50 years. Interviews were 

conducted by social workers in the study participants’ homes where demographic and 

occupational information was collected, as well as information about desire to be trained and 

employed. Subjects were evaluated by neurologists to determine degree of disability using a 

scale similar to the EDSS (described below) called the Hyllested criteria, which ranges from 0 

(no functional disability, no residual signs) to 6 (bedridden, incontinent, requires constant 

supervision), with the mid-level score of 3 defined as moderate disability with work impairment 

sufficient to require a lighter job. Using these data, study participants were categorized into one 

of three groups: (1) Group A - completely handicapped with no rehabilitation potential; 

(2) Group B - potential for vocational rehabilitation, but unemployed or currently employed, but 

needs rehabilitation services for continuation of employment; or (3) Group C - currently working 

without need of rehabilitation intervention. All Group B patients underwent additional tests to 

evaluate their functioning potential by a rehabilitation physician, occupational therapist, and 

psychologist. Study participants were also categorized into types of disability (physical, mental, 

or both); however, it is unclear how researchers measured mental disability. Furthermore, it is 

unclear if physical disability was determined strictly on the basis of the Hyllested criteria or if 

additional information was used. (The earlier study by Rozin et al. [1975]191 addresses 

additional aspects of employment by examining disability type and level by job type, discussed 

in greater detail under “Job type/characteristics,” below.) 

Group A participants who were handicapped without rehabilitation potential were more

likely to be disabled due to a decrease in physical or physical and mental function, with few 

being disabled strictly due to a decrease in mental function. Both studies190,191

 observed that 

about half of Group C (fully employed without need of vocational rehabilitation) were physically 

disabled and ranked as being either mild to moderately disabled on the Hyllested scale. Subjects 

in Group B (those who would benefit from vocational rehabilitation) were more likely to have 

moderate to severe physical disability. Although these patients had significant physical 

limitations, they were still considered to be individuals who would benefit from vocational 

rehabilitation and capable of working. 

The obvious advantages of these studies include the consideration of work ability beyond 

work status, as well as the examination of both physical and mental function among the same

sample population with regard to work ability, which most other studies did not report. 

However, a limitation of these methods is that researchers used current work status to determine 

ability to work, which could possibly bias the outcome of their evaluation. If a study participant 

was not working and expressed no desire to work, but was actually capable of performing a job, 

they may have been classified as someone who is not a candidate for vocational rehabilitation. 

Additional limitations include the omission of detailed information about how mental function 

was measured. These studies were also limited by small sample sizes, and data collected about 

education and marital status were not included as possible confounders in multivariate analyses. 

31
Because these were cross-sectional studies, the levels of physical and mental functioning were 

measured at the time of the study and not at the time when study participants ceased 

employment. The timing between impaired function and inability to work was not established. 

EDSS/DSS. Three cross-sectional studies (Table 15)174,180,188

 and one case-control study193

used the EDSS, and two cross-sectional studies183,187 used the DSS to assess ability to work 

among individuals with MS. The EDSS (and its earlier version, the DSS) is a clinical tool 

commonly used for rating neurological impairment in individuals with MS.

194 Clinicians 

determine a patient’s EDSS level by first assigning a separate grade for eight functional systems 

including pyramidal, cerebellar, bowel and bladder, cerebral, brain stem, sensory, visual, and 

other functions. A composite of grades is then used to determine an individual’s EDSS score 

ranging from 0 (normal neurological exam) to 10.0 (death due to MS).194

 The level of function 

for each of the eight systems is considered for EDSS score; however, assignment of a level is 

superseded by an individual’s ability to ambulate (e.g., free from mobility aids vs. need for 

mobility aids), possibly giving more weight to ambulation than the other seven functional 

systems. For example, individuals with MS who are able to walk without ambulatory aid would 

receive a score of 0 through 4.5, whereas a need for constant bilateral assistant (e.g., canes, 

crutches or braces) would predetermine an individual to receive a score of 6.5. Although mental 

function is factored into the EDSS scoring system as one of eight systems, it is not considered 

independently of ambulation at any EDSS level. 

As detailed in Table 15, a lower frequency of employment was consistently observed in 

groups with higher EDSS levels in all three cross-sectional studies. Unemployment among study 

participants with an EDSS ranging from 3 to 6 was reported to be approximately 42 percent,174

52 percent,180 and 72 percent,188 respectively, while employment among lower EDSS levels 

(≤ 2.5) was 37 percent, 42 percent, and 51 percent, respectively. Unemployment was most 

common among individuals with higher levels of EDSS (≥ 6.5). A case-control study193

observed that mean EDSS levels were significantly different between unemployed cases (0 = 

5.4; standard deviation [SD] = 0.1) and employed controls (0 = 4.5; SD = 0.1) with MS (p = 

0.01). This is only a 1-point difference on the EDSS scale, but 4.5 and 5.4 straddle the scale’s 

demarcation of work ability, with 4.5 defined as “able to work a full day” and 5.5 defined as 

“disability severe enough to preclude full daily activities.”194 These findings may reflect the 

timing of the neurological exam to assess EDSS, which was conducted at the outset of the study 

and not at the point when employment ceased. Physicians may not have been blinded to study 

participants’ work status at the time of the exam, possibly biasing their evaluation. 

Hammond et al. (1996)183

 conducted a large (n = 2099) cross-sectional study in Australia and 

reported that after adjusting for age, men with moderate DSS levels (4-6) were almost three 

times more likely to be unemployed (prevalence ratio [PR], 2.7; 95 percent CI, 2.1 to 3.6), and 

women were four times more likely to be unemployed (PR, 4.0; 95 percent CI, 2.7 to 5.8) 

compared to men and women (respectively) with lower DSS levels (0-3). Men and women with 

severe DSS (7-9) were also more likely to be unemployed (men PR, 17.9; 95 percent CI, 7.5 to 

41.5; women PR, 24.6; 95 percent CI, 8.0 to 76.1) when compared to this same group. The 

second study187 observed that a 1-point increase in DSS was associated with a seven percent 

decrease in the likelihood of being employed, and being male increased the probability of 

employment by 11 percent after controlling for numerous factors such as age, sex, education, 

marital status, and parenthood. 

Findings from these studies suggest that individuals with higher EDSS/DSS levels are more 

likely to report not working. The three cross-sectional studies that examined EDSS had small 

32
sample sizes such that adjustment of prevalence ratios for other aspects associated with work 

ability was not possible. Extrapolation of these findings is limited because they focus only on a 

single dimension of work ability. 

Studies by Larocca et al. (1982)187 and Hammond et al. (1996)183 included multivariate 

analyses where adjusted estimates were reported; however, no measures of cognitive impairment 

or job characteristics and responsibilities were considered. Again, these studies were crosssectional, and the assessment of EDSS during enrollment in the study failed to establish the 

timing between impaired physical function and inability to work. 

From a more global perspective, a semantic issue with EDSS deserves mention. Level 5.5 

denotes disability severe enough to preclude full daily activities. It is not clear to what degree 

clinicians equate this EDSS-based activity preclusion with being incapable of working, without 

exploring other aspects of work ability such as cognitive function and employer 

accommodations. Conversely, cognitive impairment sufficient to impair work capacity would 

not typically be reflected in the EDSS score.189

Cognitive measures. Three studies primarily examined cognitive function and work status 

among patients with MS (Table 16). Two of these172,189

 administered a battery of cognitive tests, 

while the third177 collected data on cognitive function (attention/concentration, 

planning/organizing, retrospective and prospective memory) and ambulatory assistance through a 

self-report survey. The former studies examined a broad spectrum of function including verbal 

skills, memory, visuospatial perception, problem solving, and attention and concentration. In 

addition to these tests, Beatty et al. (1995)172 also administered the Ambulation Index (which is 

highly correlated with the EDSS, r = 0.96). Ambulation, short-term memory, delay recall, age, 

and verbal ability were found to explain 49 percent of the variance in employment status. 

Patients who were still working attained significantly higher scores on most of the individual 

measures of cognitive performance and were impaired on significantly fewer cognitive domains. 

Rao et al. (1991)189 reported that cognitively impaired patients were also less likely to be 

employed compared to individuals who were cognitively intact, but information on which 

specific cognitive tests (or impairments) were associated with employment was not reported, and

level of physical function was not considered in the analyses. Self-perceived cognitive deficit 

and need for mobility assistance were also associated with unemployment, as were fewer years 

of education and age.177 However, occupational level (socioeconomic index), number of people 

living at home, and duration of illness did not impact employment status. A study by Genevie et 

al. (1987)179 also considered self-reported cognitive function in combination with physical 

function and other symptoms, but details of the types of cognitive limitations were not described 

(see Evidence Table 4 in Appendix F for details of study limitations). 

One additional study focused on self-reported expressive communication disorder, and study 

participants were asked if the communication disorder interfered with employment.173

Employment status among those with self-reported communication problems was less compared 

to the entire study sample. Methodological problems (described in Evidence Table 4 in 

Appendix F) prevented further interpretation of this study. 

Common sense suggests that impaired cognitive function has the potential to seriously 

impact work ability. However, the three studies described in Table 16 do not provide the 

evidence needed to determine the type and/or level of cognitive impairment when an individual 

with MS is no longer able to work. Unlike the studies by Rao et al. (1991)189 and Edgely et al. 

(1991),177 Beatty et al. (1995)172 provided far more detail about the specific cognitive tests that 

were associated with not working. In addition, these researchers also considered level of 

33
ambulation in combination with cognitive function and demographic characteristics. Since only 

a global measure of variance was provided it is difficult to interpret the strength of association 

between each of these domains (cognitive function, level of ambulation, demographic 

characteristics) and work ability. The 1991 study by Rao et al.189 did provide details about the 

types of tests that were administered, but used a global measure of “intact versus not intact” to 

examine work ability. The method of self-report of cognitive function used by Edgley et al. 

(1991)177 has limitations in that someone with impairment may not be able to objectively 

measure their own level of cognitive function. Finally, the temporal relationship between 

cognitive impairment and cessation of work among study participants was not captured in these 

cross-sectional studies. 

Mobility aids. The number and type of mobility aids study participants used was measured 

in two studies176,186

 as a proxy measure for degree of disability. Kornblith et al. (1986)186

developed a three-level Mobility Dysfunction Index (MDI) ranging from no assistance needed 

(Level 1), to any combination of cane, walker, leg brace, etc. (Level 2), to use of a wheel chair 

for more than half the time in- or outdoors (Level 3). A 1-point increase in MDI decreased the 

probability of males working by 24.3 percent, while it decreased the likelihood employment for 

females by 15.4 percent, leading investigators to conclude that mobility was a major determinant 

of employment, while age and duration of disease were minor. Dyke et al. (2000)176 considered 

the number of mobility aids used and reported that only 20 percent of the variance in 

employment among a sample of women was accounted for by the number of mobility aids used, 

age, and education. 

Use of certain mobility aids (e.g., wheelchair) can certainly provide a measure of degree of 

physical disability, as well as indicate the possible level to which the disease progression has 

hindered physical function, but Dyke et al. (2000)176 considered only the number of aids used. A 

limitation of using the number of mobility aids to measure degree of disability is that it most 

likely is not sensitive enough to detect changes in other aspects of disease status and mental 

function, and it certainly does not capture job requirements. Desk jobs that require only sitting 

may enable someone who uses a wheelchair, but is not cognitively impaired, to continue 

working. 

Disease subtype. Although there is great variability in the course of MS, three subtypes of 

disease are generally recognized: (1) relapsing-remitting; (2) primary progressive; and 

(3) secondary progressive.195 The terms of these subtypes have changed over time due to 

refinements made within each classification, which are reflected in the different terms used in the 

following studies. One cross-sectional study184 and one case-control study193 compared MS 

patients’ current work status with disease subtype. Both studies reported a higher frequency of 

employment among study participants with relapsing-remitting compared to primary 

progressive184 and relapsing-progressive MS.193 These findings are consistent with the greater 

degree of disability typically noted among individuals with progressive MS;196 however, the 

analyses for both of these studies were crude and did not consider other factors associated with 

ability to work, except for Jacobs et al. (1999),184 which attempted to control for age by 

restricting analyses to individuals less than 60 years of age. Furthermore, disease subtype was 

not measured until enrollment into the study. The disadvantage of using disease subtype for 

determining work ability is that the range of cognitive and/or physical function within each 

classification can vary tremendously. Furthermore, these studies do not provide the needed 

information for the measurement of physical and/or cognitive function that results in cessation of 

employment. 

34
Job type/characteristics. Six studies (Table 17) either focused primarily on job type or 

work characteristics181,192,193 or included information about occupation as a secondary aim in 

their study.183,187,191

 Although the purpose of this review was to summarize information about 

measurements of physical and/or mental function among individuals with MS associated with 

inability to work, examining job requirements provides an indirect measure of the physical 

and/or mental levels of function needed to sustain employment. 

In a case-control study conducted by Verdier-Talliefer et al. (1995)193 several job 

characteristics were examined for their relationship with unemployment among MS patients. 

After adjusting for age, sex, type of disease, and level of education, an elevated odds of 

unemployment was observed among study participants whose jobs required physical strength 

(odds ratio [OR], 7.6; 95 percent CI, 3.2 to 18.2), manual precision (OR 3.1; 95 percent CI, 1.6 

to 6.3), and frequent moves (OR, 2.5; 95 percent CI, 1.3 to 4.9). Furthermore, the odds of 

unemployment decreased when the job was a “desk job” (OR, 0.3; 95 percent CI, 0.1 to 0.5), or 

one that required sitting (OR, 0.3; 95 percent CI, 0.1 to 0.7). When all of the demographic and 

job characteristics were considered together in a multivariate model, work in the public sector

was protective against unemployment (OR, 0.4; p < 0.05), and work requiring physical strength 

increased the odds of unemployment (OR, 4.5; p < 0.001). Analyses stratified by sex revealed 

that factors associated with unemployment for men involved a rigid work schedule (OR, 17.1; 

p < 0.01), while for women unemployment was strongly associated with work requiring physical 

strength (OR, 4.5; p < 0.05). These findings are consistent with those of Scheinberg et al. 

(1980),192 who observed that currently employed (n = 51) study participants were more likely to 

hold jobs that were clerical (35.3 percent) or professional (37.2 percent) as opposed to skilled 

(13.7 percent) or unskilled (2.0 percent) labor. An early study by Rozin et al. (1975)191

categorized study participants into groups according to their level of function and ability to work, 

described in greater detail above. This study crudely assessed changes in employment from the 

time of diagnosis to the time of the study. Study participants included in Group B (unemployed, 

but had the potential for vocational rehabilitation or employed, but needed rehabilitation services 

to continue employment) were more likely to remain in clerical and professional type jobs, 

compared to those in skilled and unskilled labor. Furthermore, those in Group C (currently 

working without need of rehabilitation intervention) were able to remain in the workplace, 

although they shifted employment from labor-intensive jobs to clerical or professional. Authors 

note that of the 131 clients with working potential, only 18 percent indicated that they stopped 

work because of MS, but provided no additional information about why study participants left 

work. Again, the limitations of this study are its small sample size and the lack of consideration 

of additional factors that influence ability to work. Grønning et al. (1990)181 reported consistent 

findings that heavy work was predictive of early unemployment; however, this study had serious 

limitations with regard to how jobs were categorized into heavy versus light work (see Evidence 

Table 4 in Appendix F). 

Two studies did not focus primarily on job characteristics in the analyses, but did provide 

commentary about it. LaRocca et al. (1982)187 reported that a significant portion of the variance 

in employment status was unexplained by typical demographic characteristics such as age, 

education, and occupation, but was explained by more subjective measures of workplace 

characteristics, social support, and coping style. Unfortunately, additional information about 

workplace characteristics was not provided. Dyck et al. 2000176 commented that 17 percent of 

the women in their study reported that they quit work because they were unable to negotiate 

reduced work hours with their managers. 

35
From what we know about the possible physical and cognitive limitations associated with 

MS, as well as the resulting fatigue and other symptoms, it is not surprising that unemployment 

is more common among individuals whose jobs required physical exertion. The strength of the 

case-control study by Verdier-Talliefer et al. (1995)193 is that it considered numerous working 

conditions that increased or decreased the odds of unemployment. The remaining studies 

provided descriptive information that was parallel with findings reported by Verdier-Talliefer et 

al. (1995).193

 Unfortunately, none of these studies systematically examined whether employers’ 

willingness or ability to provide workplace accommodations or flexible work schedules fostered 

continued employment. 

Self-report. Several studies provided descriptive information about conditions or situations 

that influenced individuals with MS to cease employment (Table 18). Physical difficulty, 

ambulation problems, visual difficulties, emotional problems, and fatigue were reasons for 

ceasing employment among participants in two studies177,192

 who indicated that they left work 

because of MS. In addition, both studies reported that a significant percentage of women (37.4 

percent and 26 percent, respectively) indicated leaving for reasons other than MS, including 

marriage and/or pregnancy. Among individuals who remained at work, fatigue was reported as 

the most common symptom impeding work performance or restricting the work that could be 

done in two cross-sectional studies.176,182 An additional study not included in Table 18178

reported that 10 percent (n = 30) of study participants indicated that they quit work because of 

fatigue. Although these findings do not involve specific clinical tests to determine the presence 

or absence of cognitive or physical impairment, qualitative data like these are useful for shaping 

quantitative data analyses, as well as shaping future research. 

Environmental Factors and Work Ability 

Introduction 

This section describes the evidence pertaining to Question 5: Among individuals with MS, 

how does elevated temperature or other environmental factors impair the capacity to work? The 

precise scope of this question was defined in collaboration with the project’s technical advisory 

panel and representatives of SSA. This process led to consensus that temperature was the sole 

environmental factor that warranted investigation. We therefore focused specifically on 

evidence regarding the associations between thermal (ambient or climatic temperature)

conditions in the work environment and the work capacity, work status, or disability status of 

patients with MS. It was recognized that occupational physical activity might be a modifier of 

the effect of environmental temperature. 

The importance assigned to temperature effect in MS is based on longstanding clinical 

impressions that excessive or high heat conditions may be associated with transient worsening of

symptoms and/or function in some patients with MS.197,198

 We did not attempt to assess the 

quality of the evidence underlying such clinical impressions, nor did we investigate possible 

mechanisms whereby ambient and/or body temperature might act physiologically to affect 

MS.199-201

 We also did not examine treatment modalities based on thermal sensitivity in relation 

to Question 5; rather, randomized controlled trials of cooling garments and other temperaturelowering interventions were considered for inclusion under Question 3b (symptomatic 

treatments). 

36
A key issue for SSA disability determination in MS would seem to be assessment of reported 

functional or activity limitations due to worsening symptoms or decreases in functional capacity 

that are temporally associated with particular activity demands or the physical environments 

attendant to certain jobs. If such worsening were consistent and had significant adverse impact, 

the associated demand or situation might be considered a “critical job demand” for some jobs 

(i.e., the limiting point of a potentially significant mismatch between a person’s work capacity 

and the job requirements). Another research question of interest to SSA might be whether 

environmental temperature conditions characteristic of particular workplaces or jobs are 

associated with different rates of MS work disability. 

Results 

A single research study met the inclusion criteria for this question (see Evidence Table 5 in 

Appendix F).182 Other candidate articles were typically excluded due to a lack of data regarding 

work capacity, work status, or disability status variables. In considering some of the excluded 

interventional studies aimed at short-term reduction of individual body temperature,199,201-203

 it 

was clear that an unacceptable degree of extrapolation would be required to relate the 

conclusions of these studies to work demands or circumstances of likely relevance to SSA. 

 The single included article,182 a questionnaire survey, also has significant limitations in its 

applicability to SSA-relevant issues. It does, however, suggest that some MS patients perceive 

temperature as a factor that can either impede (high temperature) or enhance (cool temperature) 

work performance. This cross-sectional study divided 508 respondents with MS into four selfreported work status categories. Table 19 summarizes subjects’ responses to open-ended 

questions regarding impediments to and enhancers of work/chore performance. Independent 

raters coded the actual responses into several categories. Table 19 includes only temperaturerelated conditions/situations and those endorsed by all four work groups. Overall, 53 workimpeding categories were identified, with 22 of those being endorsed by at least five percent of 

respondents. For work-enhancement, 27 total categories were identified, with 17 being endorsed 

by at least five percent of respondents. 

37
Chapter 4. Discussion 

The goals of this review relate to examining the evidence in the medical literature for data 

that can guide policy for determining disability in patients with multiple sclerosis (MS). We

found at least some evidence with which to address four of the five major topic areas. Although 

the literature in general and certain studies in particular suffer from limitations, reasonably strong 

conclusions can be drawn in some areas. The evidence for each topic is summarized below and is

followed by a summation of knowledge gaps and recommendations for future research. 

Discussion of Evidence

Reliability of Criteria for Diagnosing MS (Questions 1a and 1b) 

The recently proposed McDonald criteria for diagnosing MS are well supported by two types 

of evidence. First, two studies show that between 73 and 94 percent of patients presenting with 

clinically isolated syndrome (CIS) who go on to develop clinically definite MS (CDMS) over 1-4 

years of follow up could be diagnosed with MS according to the McDonald criteria. 

Furthermore, the specificity of these criteria is reasonably high, ranging from 83 to 87 percent. 

Second, many studies support the magnetic resonance imaging (MRI) component of the 

McDonald criteria, by showing a strong and consistent association between the number of T2 

lesions on MRI and the subsequent development of CDMS among patients with CIS or optic 

neuritis. Thus the McDonald criteria appear to have substantial evidence for validity and offer 

the obvious potential advantage of resulting in an earlier diagnosis of MS than the Poser criteria 

permit. 

The McDonald criteria have been criticized for their complexity in comparison with previous 

criteria; however, we found data that demonstrate that the McDonald criteria yield a good overall 

diagnostic reliability, at least as good as the previous Poser criteria. However, widespread 

adoption of the new criteria could result in deterioration of this reliability. Barkhof et al. 

(1997)39 demonstrated that among neurologists inter-rater reliability of MRI diagnosis

significantly improves with increased level of training. Non-neurologists are unlikely to be able 

to achieve the same level of MRI agreement and are therefore unlikely to be able to maintain this 

level of agreement with the McDonald criteria as a whole. Further research on the inter-rater 

reliability of these criteria in broader clinical settings would be helpful to determine the quality 

of MS diagnosis. 

While these data may be sufficient to secure a place in clinical practice for the McDonald 

criteria, certain difficulties arise in applying these criteria retrospectively from medical record 

review for the process of determining disability. At the present time most patients have not been 

diagnosed according to the specific application of the McDonald criteria. Therefore, they may 

have medical records that do not clearly delineate the nature and timing of their specific MRI 

changes in a manner that conforms to the McDonald criteria. 

65
Predictors of Physical and Mental Impairments at 12 Months 

(Question 2) 

The ability to predict future course of MS has been an active area of MS research; however, 

most studies examining disease course do so over quite long time periods of 5 to 20 years. We

found a paucity of data describing changes in neurological or other impairments over 9-24 

months, which we used to approximate the 12-month time horizon dictated by statutory 

requirements. Clinical characteristics have been the best studied, with four reports providing 

evidence for this review. While clinical features do not individually provide reliable guidance on 

prognosis, multivariate predictive models based on relatively easy-to-obtain features may have 

better performance. However, the reliability and validity of these predictive models has not been 

evaluated and thus their value for predicting disability has yet to be determined. 

In contrast to their value in predicting development of CDMS among patient with CIS, 

imaging studies do not appear to provide especially useful prognostic data among patients with 

MS. The absence of lesions on sequential MRI studies is associated with a lower probability of

an exacerbation in the ensuing month, and long-term prediction of health outcomes needed in the 

context of disability assessments has not been shown to be possible. Somewhat more promising 

strategies for predicting outcome of MS patients is the use of laboratory markers, such as 

apolipoprotein E (APOE) ∈4 allele, interleukin-2 (IL-2) levels, or intrathecal immunoglobulin-M 

(IgM) synthesis, although the current level of evidence is best considered preliminary. These 

reports may provide the rationale for further validation studies, but are not standard practice and 

their practical impact is thus limited. 

A single study of quality-of-life measures as predictors of long-term outcome was 

suggestive, especially considering the persistence of the association after adjusting for clinical 

characteristics. In addition to the uncertain generalizability of these results, such measures could 

have substantial reliability problems in the context of disability assessment. 

Notably, no study was identified that examined the relationship between various factors and 

subsequent mental impairment. 

Disease-modifying Therapies and Long-term Improvement (Question 

3a) 

Most of the data presented suggest that few patients improve on therapy. Those few who do 

improve generally do so only in the range of 1.0 point on the Expanded Disability Status Scale 

(EDSS). We found no data regarding improvement in work ability and no data that would 

correlate a 1.0-point improvement in EDSS with improvement in work ability. The significance 

of a 1.0-point EDSS improvement varies depending on baseline EDSS score (because the scale is 

non-linear), but the improvement data available are not generally stratified according to baseline 

EDSS score. With regard to work ability, the significance of the available data on clinical 

improvement is unclear. We found no data that quantified individual patient improvement with 

regard to cognitive function or quality-of-life measures. 

In considerations regarding the determination of disability, the ability of a therapy to reduce 

mean exacerbation rates is of unclear significance. We have considered this issue out of concern 

that despite any given level of physical dysfunction, one might consider that an individual with 

frequent relapses may have impaired job performance solely on the basis of exacerbations. The 

66
data presented in Table 6 (see Chapter 3) document that with any of the current therapies, mean 

reductions in relapse rates are generally less than one relapse per year. 

The data examined in this evidence review do not support the conclusion that the current 

therapies are likely to result in substantial improvement in a significant proportion of patients 

with MS. This finding is consistent with expert opinion and demonstrated by the inherent design 

of current clinical trials, that is, the use of lack of decline in EDSS scores as the primary outcome

measure. The present state of therapy is generally regarded as allowing for modest reduction in 

progression of MS – particularly in the relapsing-remitting patient population – but is not 

generally expected to result in significant long-term improvement. The rare exception is most 

likely in patients with relapsing disease who are progressing rapidly and undergo aggressive 

immunosuppressive therapy. 

In general, the studies reviewed were not designed to answer the question we have asked. 

Indeed, individual patient improvement is not a common expectation of these trials. The authors 

believe that, despite the relative lack of data, the conclusions from the data examined do reflect 

the state of the current therapies. We believe that the data available document that individual 

patient improvement is an uncommon result of the current therapies. Further studies of currently 

available therapies would be unlikely to yield different conclusions; however, the recent trend of 

combining treatments in MS could yield different results. Combinations of currently available 

therapies and new therapies now under investigation may result in greater potential for individual 

patient improvement in neurological status. 

Symptom Management and Improvement (Question 3b) 

Treatment aimed at alleviation of symptomatic manifestations of MS, rather than the 

underlying disease, could have an important role in maximizing functioning among people with 

MS. Among the six areas we investigated, the degree of impairments and the effectiveness of 

the treatments varied. We review the conclusions and discuss the limitations and implications

for further research by sub-topic below. 

Spasticity. Although drugs such as baclofen, diazepam, dantrolene, and tizanidine are often 

used to reduce spasticity in MS, the research evidence for a beneficial therapeutic effect is 

inconsistent. This may be due, in part, to measurement issues. Spasticity is a difficult parameter 

to measure; too much muscle tone interferes with function due to spams and rigidity (resistance 

to movement); too little muscle tone can also interfere with function due to weakness. In some

patients, a certain degree of elevated muscle tone in certain muscle groups can be desirable. 

We had additional difficulty in estimating the clinical relevance of improvements that were 

reported, even when those changes were statistically significant. Many studies that dichotomized 

patients into “improved” versus “unimproved” failed to provide a definition or threshold of what 

changes represented “improvement.” Nonetheless, the relatively high baseline EDSS scores of 

patients enrolled in spasticity trials and unimpressive results of treatment suggest that antispasticity treatment is unlikely to have a clinically important impact on patients’ functional 

status, and is, thus, unlikely to impact disability determination per se. Furthermore, all of these 

drugs are limited by poor tolerability at therapeutic doses. Our findings were consistent with 

another recent systematic review.204 Better measurement tools may be required in order to 

confirm the clinical impression that widely used anti-spasticity drugs such as baclofen, 

tizanidine, and dantrolene are more effective than placebo. Given current measurement 

67
techniques, it is not surprising that active-treatment comparison studies fail to show clinically 

important differences among these drugs. 

Rehabilitation. Physiotherapy interventions failed to influence impairments as measured by 

EDSS. These interventions were, however, associated with measurable changes in functional 

status. Improvements in health (handicap) were observed in the Medical Outcomes Study 36-

Item Short-Form Health Survey (SF-36) and several other measures. It is interesting that the 

historically first randomized controlled trial (RCT) of rehabilitation was not designed to assess 

the effectiveness of the intervention, but to evaluate whether less costly outpatient rehabilitation 

was as effective as inpatient rehabilitation.139 Only more recently have trials been conducted that 

were designed to assess the value of rehabilitation compared to controls. Except for one study of 

supervised exercise,

143 the interventions employed in these studies were multifaceted, and it is 

difficult to attribute beneficial effects to particular components of the interventions. However, 

three other trials focused on non-physiotherapy interventions, which may be part of a 

rehabilitation program.

141,146,147

 Two of these studies found changes in health measures (SF-36) 

not unlike those seen in physiotherapy-based rehabilitation interventions; however, these studies 

did not include measures of impairments or function. 

Depression. Depression treatments, including psychotherapy, behavioral therapy, and 

certain drug therapies, can lead to measurable improvements in mood. There are fewer data 

linking treatment of depression to improvements in other symptoms (such as fatigue or cognitive 

impairments) or other outcomes (such as functional status or quality of life). The changes 

demonstrated in instruments designed to measure depression were not small but, still, the link to 

improved functional status and, further, to ability to work was not demonstrated in these studies 

per se. To do so would require extrapolation from studies of treatment of depression in non-MS 

populations. 

Fatigue. Amantadine appears to have some ability to alleviate fatigue in MS, as 

demonstrated in statistically significant differences in some outcomes in several trials; however, 

the clinical significance of these effects is likely small. Pemoline has been less often studied and 

shows results suggesting some effect. There is little support for the efficacy of 4-aminopyridine. 

Modafinil has shown promising results in phase-II trials,205 but has not yet been evaluated in a 

double-blind RCT. Measurement of fatigue is limited by a definition that spans several domains, 

leading to difficulty with validation. Further research on new pharmacological therapies (such as 

modafinil) and development of additional data on the validity of instruments for fatigue 

measurement and their sensitivity to change would be helpful directions for future research. 

Voiding dysfunction. Desmopressin was highly effective at reducing urine volume and also 

consistently effective at reducing urinary frequency. This was demonstrated to translate into 

improvements in uninterrupted sleep hours and in fewer episodes of incontinence. Physical 

treatments, including both pelvic floor rehabilitation and use of a handheld vibrator during 

micturition, were also shown to reduce urinary symptoms compared with control. Only studies 

of pelvic floor rehabilitation measured impact on symptom-related handicap. These studies 

showed clear improvements in symptoms, but provided less clear data on how improvements in 

urinary symptoms impact other areas of health, and no data on how these symptomatic 

improvements might impact work ability. 

Many interventions commonly used for urinary disorders in MS have not been studied in 

randomized controlled trials of MS patients. Commonly used interventions for which no RCTs 

have been performed among MS patients include anticholinergic and antimuscarinic drugs, 

68
behavior modification, and intermittent or indwelling urinary catheterization. Data supporting 

their use comes from trials in other populations or from case reports/series in MS. 

Cognitive dysfunction. None of the treatments studied has had a consistent measurable 

effect on cognitive performance in MS; however, the question has been little studied and 

indirectly studied, in the sense that most data on cognitive effects are inferred from studies aimed 

at treatment of fatigue or depression. One study suggested that fatigue symptoms do not 

correlate with cognitive impairment, although they do correlate with symptoms of depression.159 

Future studies would benefit from more precise delineation of study population based on 

screening for cognitive performance deficits within a relatively narrow and defined range; this 

would likely improve the chances of finding a treatment effect and also make clearer the 

population for whom the results would be applicable. 

Association of Clinical Findings with Work Ability (Question 4) 

Findings and limitations. There is a significant gap between what is included in the 

literature and the research evidence using objective measures for determining ability to work. 

Although objective physical and cognitive measures have been developed, their application in 

the occupational literature is sparse. Furthermore, assessment of how symptoms such as pain 

and fatigue impact work ability was essentially absent. 

In epidemiologic research we draw conclusions from the body of existing work and never 

from a single study. There are criteria that aid in the judgment of causality called the BradfordHill Criteria,206 which include strength of association, consistency of findings, temporality, doseresponse relationship, biological plausibility, coherence, and specificity. After applying several 

of these criteria to the pool of information in this review we conclude that the research findings 

presented here are insufficient to demonstrate that a causal relationship between specific physical 

and/or cognitive measures and work ability has been established. The reported findings did 

display some consistency across studies. For example, individuals who had higher EDSS levels 

or low cognitive function were more likely to report not working. However, the strength of 

association across these studies was not clearly demonstrated, as most studies reported 

frequencies or crude estimates of association. Several studies consisted of small sample sizes, 

which hindered researchers from calculating risk estimates that were adjusted for potential biases 

such as age, education, level of employer assistance, job type, and desire to work. In addition, 

most studies considered only physical function or cognitive function, when both can hinder 

employment. A dose-response relationship of selected functional measures and degree of work 

capacity was not established. Because the majority of studies were cross-sectional, a temporal 

relationship between impaired function and inability to work was not established. Impaired 

function may not have occurred until after the study participants had ceased employment. 

Although the bulk of these studies are descriptive in nature, they are useful for generating 

hypotheses for future studies to examine the causal relationship between impaired function and 

work ability. Some patterns that are noteworthy and should be considered when designing future 

studies to examine the risk of inability to work related to impaired function and adverse 

symptoms are as follows: 

 The study outcome of work ability that extended beyond the definition of work status was 

informative for determining possible vocational rehabilitation potential for moderately to 

severely disabled individuals. 

69
 As EDSS level increased, the frequency of reporting “not working” also increased. This 

same pattern was observed for the Hyllested criteria. However, there was considerable 

overlap between ability to work and EDSS level. Degree of disability or impaired physical 

function did not solely determine work ability. 

 Level of cognitive impairment resulting in work inability was not adequately determined; 

however, the combination of both physical and cognitive measures proved necessary when 

assessing ability to work. 

 Use of mobility aids and disease subtype as proxy measures for function provided very little 

information that was useful. Extrapolation of these definitions has the potential to lead to 

various interpretations, resulting in limited application of findings. 

 Individuals with jobs that required less physical exertion were more likely to report 

remaining employed. These findings supported studies that measured both physical and 

cognitive function directly. 

 The impact of fatigue on work ability was captured only through self-report. Direct 

measures of fatigue did not appear in the included studies. 

In conclusion to the findings presented here it is important to discuss a significant limitation 

of observational research as it relates to determining if an individual with MS is able to work. 

Population-based epidemiologic research is useful for determining patterns, trends, and causal 

relationships between exposures and disease outcomes among groups of individuals, but in prior 

studies207,208

 researchers have demonstrated that risk factors or combinations of risk factors 

included in a statistical model serve as poor screening tools at the individual level. In the case of 

MS, future epidemiologic studies may indicate that certain physical or cognitive function tests 

are strongly associated with inability to work; however, extrapolation of these findings for the 

purpose of predicting work ability at the individual is not possible. 

Future research. Future research about work ability among individuals with MS can shed a 

great deal of light on factors that foster or hinder employment. Work ability involves numerous 

medical and non-medical factors that have been discussed in great detail. In light of the gaps in 

the current literature, it would be advantageous to design future research endeavors to 

simultaneously address the following domains: 

1) Objective clinical data: Collect data on clinical measures, such as disease subtype, that 

the Social Security Administration (SSA) typically uses when determining disability 

among individuals with MS. Data collection should be tailored to gather information 

from medical records that SSA deems relevant to its process. 

2) Physical/cognitive/symptom measures: Objective measures of physical and cognitive 

function, as well as symptoms such as fatigue and pain. Consider the tools that have 

been well established and tested for measuring these types of impairments. As 

previously noted, the use of well-established tools in the occupational literature has 

been sparse with regard to MS. 

3) Work ability measures: The measurement of work ability should be extended beyond the 

definition of work status to include examination of skill level, education level, career

interests, willingness to work, and vocational rehabilitation potential. 

4) Occupational requirements/employer accommodations: Assess job responsibilities and 

employer’s willingness to provide accommodations in tandem with work ability 

measures. Current occupational requirements may not match with current level of 

function. 

5) Demographics: Age, sex, education level, marital status. 

70
6) Family responsibilities/support: Family demographics, income, responsibilities, number 

of children, and number of elderly parents who need care. 

7) Subjective reports from individuals with MS: Qualitative information about hindrances 

and enhancers of work, including characteristics specific to the job or workplace and 

symptoms related to MS. 

8) Subjective reports from employers: Qualitative information about how employers are 

able to provide accommodations and support for workers who have significant and/or

intermittent fatigue, pain, and other symptoms related to MS. Gather information about 

how employers accommodate workers who also have physical and/or cognitive 

limitations, as well as information about conditions or situations where they cannot 

provide accommodations. 

We suggest that a series of case-control studies be conducted, as well as a prospective cohort. 

For both these study designs, we suggest that resources already available through MS research 

centers across the country be used. A recent report by the Institute of Medicine209 describes 

certain limitations of research based in MS centers, but indicates that multisite research of this 

sort is valuable for conducting epidemiologic studies requiring a large number of patients with 

MS. Conducting a series of studies at several centers in the US could provide consistent 

evidence across numerous populations and geographic regions. Furthermore, data needed about 

employment history and disease progression may already be collected for established patients 

enrolled in ongoing studies. It is recommended that SSA collaborate with the National Multiple 

Sclerosis Society when selecting sites for this research. 

Although it would be ideal to conduct a prospective cohort study for the purpose of 

establishing a temporal relationship between impaired function and work inability, this could 

take considerable time and money. We recommend initially a series of case-control studies 

where cases (defined as individuals with MS who are no longer employed) and controls (defined 

as individuals with MS who are still employed) are compared on the numerous domains 

described above. This should provide SSA with more detailed information about the types of 

clinical measures it currently deems relevant for determining work ability. Sample size was an 

issue in almost every study included in the review. Sample sizes should be large enough to 

detect true differences between groups, especially when considering cognitive function. 

Furthermore, the sample size should be large enough so that subtype of disease can be 

appropriately considered through stratified analyses. The pattern of disease progression varies 

between disease subtypes in ways that could influence employment. For example, patients with 

relapsing-remitting MS may not be able to remain steadily employed because of the erratic and 

unpredictable nature of disease exacerbations, whereas individuals with primary progressive MS 

may have a more predictable disease course that does not intermittently interfere with work. 

Although there is significant overlap of symptoms between the current disease subtypes, ability 

to work may vary considerably between them. 

The case-control studies should be advantageous for examining the timing or sequence of 

clinical information and physical and cognitive function testing prior to cessation of 

employment. Demographic information would most likely be available as well. However, 

information surrounding employment issues, triggers for leaving work, obstacles or enhancers to 

work, and employers’ willingness to help may not be available. In order to capture this 

information, especially around the time that an individual with MS decides to leave work, we 

recommend that researchers conduct a prospective cohort study. Incident cases of MS must be 

captured and followed over time so that changes in physical and cognitive function can be 

71
examined in relation to ability to work. Ideally, incident or fairly recent cases where the 

individual is still employed should be captured for follow up. As previously indicated, it would 

be ideal for researchers to build on prospective studies that are already ongoing. Information 

needed for this study could be added to what is already being collected for other studies. 

The qualitative data collected through focus groups, personal interviews, and surveys have 

proven invaluable for guiding quantitative analyses. Information gathered from individuals with 

MS, as well as their employers, could provide a great deal of information about the types of 

accommodations that are useful and effective. Furthermore, companies may struggle with 

providing accommodations, especially with an individual who has frequent relapses. 

Several study limitations have been highlighted in this review, as well as patterns of findings, 

which should be considered when developing future research. Future studies that consider the 

multiple factors influencing work can lead to generating unbiased risk estimates of inability to 

work among individuals with MS. In the development phase of these studies, it is imperative 

that SSA be involved in determining the types of data to be collected. Data collection should 

reflect the information that SSA deems important when making decisions about ability to work. 

Findings in the context of other literature on work and MS. Several of the studies 

included in this review reported findings or trends about their study populations that reflect what 

is already known or established in the literature about issues surrounding employment 

independent of MS and vice-versa. 

The onset of MS occurs between ages 15 to 50 years for approximately 90 percent of 

cases.210 Thus, MS strikes individuals during peak years of education, training, and employment. 

Labor market analyses by the Bureau of Labor Statistics211 reported that, in general, higher levels 

of education enhance labor force participation, and severely disabled individuals are more likely 

to participate in the labor force if they have a college degree (57 percent) compared to disabled 

individuals with less than 4 years of high school (17.3 percent), high school completion (31.2 

percent), and some college (39.1 percent).211

The incidence of disease is twice as high among women as among men.195

 MS impacts 

women not only during peak years of employment, but also during peak reproductive and 

childbearing years. Attachment to the workforce among first-time pregnant women in the US is 

influenced by several factors including age, education, years of work experience, and whether or 

not they were employed and established in their careers prior to the onset of pregnancy.212 The 

domestic responsibilities that follow pregnancy influence employment as well: compared to 

unmarried women without children, both married mothers and single mothers commit far fewer 

hours to the workforce (although the differences have declined significantly over the past two 

decades).213 Some of the studies included here concurred with these findings in that women 

reported leaving work for reasons unrelated to MS, but related to domestic responsibilities.191 It 

can be especially challenging to distinguish between the impact of MS and the responsibilities of 

childrearing among women when examining ability to work. Some studies recognized these sex 

differences by controlling for them in their analyses.183,186,187

Symptoms associated with MS vary between individuals, but can include fatigue, ataxia, 

dementia, optic neuritis, bladder urgency and incontinence, spasticity, pain, and sexual 

dysfunction.195 As reported above, fatigue was the most common reason individuals with MS 

reported ceasing employment;177 however, fatigue, like pain, is very subjective and difficult to 

measure (see discussions of Question 3b in this and previous chapters). 

The importance of employer involvement in providing accommodations for disabled 

individuals was nationally endorsed in 1990 with the enactment of the Americans with 

72
Disabilities Act (ADA). In an earlier study by Mitchell (1981)214 two-thirds of male postal 

workers with MS received work accommodations with respect to their MS related work capacity, 

which enabled them to remain at work. With the ADA in place for more than a decade, and MS 

representing the third most common neurological diagnosis that SSA receives,1

 the paucity of 

information in the literature about how employers have enabled individuals with MS to remain at 

work exists is unfortunate. 

Environmental Factors and Work Ability (Question 5) 

Current clinical wisdom about thermal sensitivity in some MS patients is based not on large 

controlled research studies but rather on a combination of many decades of clinical observations, 

case reports, small trials of thermal challenge outcomes, and reports of beneficial therapeutic 

effects of body cooling. The present report, while not directly addressing the question, provides 

no basis for rejecting such clinical observations that excessive heat can have an adverse 

temporary effect on the well-being and symptoms of some MS patients. 

With regard to work impairment, limitation, or disability related to temperature conditions, 

we found remarkably little research that met our inclusion criteria. This should probably not be 

surprising. The difficulties of conducting population-based research on work capacity in patients 

with MS are reflected in the discussion of Question 4. Given this reality, researching 

temperature as an independent determinant of functional capacity would be particularly 

challenging. 

There remain important questions about what proportion of MS patient populations may be 

thermo-sensitive, to what degree, and why?197,200

 As to temperature sensitivity significant 

enough to impede work, this report found only one includable report.182 This study has 

significant limitations in its generalizabililty to a Social Security Disability Insurance (SSDI) 

applicant pool due to a number of issues, including the fact that the assessment of thermal 

sensitivity was completely subjective. The low percentage of respondents citing thermal factors 

in this study suggests that exposure to heat is not among major perceived critical job demands. 

Of interest, there is little or no report of thermal factors in other studies that might have 

identified perceptions of workplace temperature193 or self-reported thermal sensitivity177,185,192

 as 

variables that impede work or affect employment status. 

It is possible that most MS research has focused at a more primary symptom level (e.g., 

affective lability, numbness, speech, fatigue, cognition, ambulation, vision, incontinence) 

without addressing more subtle factors, such as temperature, that may exacerbate symptoms. 

Forced-choice questionnaires, for example, may not include an option to report thermal 

sensitivity.179

We conclude that answers to Question 5 remain mostly unknown. The evidence provides no 

basis for generalizations such as maximum appropriate working temperature levels unique to MS 

patient populations. The one included report confirmed that some MS patients perceive heat to 

impede their work capacity. It is not likely that medical data in SSDI application files in the 

current era will include objective diagnostic test results identifying MS patients who respond 

adversely to heat challenges.215 However, subjective patient reports may describe such 

associations with or without clinician comment or correlation with objective clinical status 

measures. Although not necessarily founded on randomized controlled trial data, current clinical 

impression seems to hold that ambient and/or exercise-induced body temperature effects may 

73
bear a relationship to MS symptom status in some patients, perhaps more so than is thought to be 

the case for chronic disease states in general. 

Knowledge Gaps and 

Future Research Recommendations 

This report has identified several gaps in current knowledge that can direct future research. 

Regarding diagnosis of MS, the available studies evaluating the validity and reliability of the 

recent McDonald criteria,5

 though few in number, are strong and consistent. The evidence 

reviewed suggests that diagnosis of MS using MRI data as implemented in the McDonald criteria 

has good validity compared with ultimate clinical diagnosis; further research is needed on the 

prognosis of patients diagnosed with MS using McDonald criteria, especially with regard to the 

ability of clinical or radiographic features to predict clinical outcomes. 

Regarding prognostic studies, most studies report prognosis over long periods of time, over 

which MS shows inexorable progression. Shorter-term studies demonstrate a high degree of 

variability, and few factors seem to predict near-term prognosis. Studies of prognosis are needed 

that focus on the early disease course (an inception cohort) defined by McDonald criteria; such 

studies may be more fruitful at identifying prognostic factors than previous research has been. 

Data of this sort may be most efficiently gathered in the course of disease-modifying treatment 

trials, which are also a high priority in this population. 

Regarding treatment issues, while differences in relapse rates and EDSS scores between 

control groups and groups receiving disease-modifying agents have been modest, reductions in 

disease activity as measured by MRI have been marked; the long-term significance of this 

reduction is not yet clear. Whether the failure to show differences in clinical outcomes is a 

limitation of the EDSS, the efficacy of the experimental agents, or the follow-up time is 

uncertain. Further treatment studies are needed that (1) target earlier disease (as diagnosed by 

McDonald criteria) and (2) are large enough and long enough to correlate MRI response with 

clinical response. Furthermore, while disease-modifying drug treatment trials have focused on 

physical function outcomes, this choice of outcome measure may preclude evaluating whether 

these treatments prevent or slow the development of cortical atrophy, which may correlate better 

with disability in MS. 

Regarding symptomatic treatment issues, of the six symptomatic areas we explored, several 

were well covered. Spasticity drug treatments have been well studied, although the clinical 

relevance of the major outcome measure used in these studies, the Ashworth Scale, has been 

questioned. Further research on spasticity should be directed at evaluating functional status 

outcomes rather than muscle tone outcomes; and while drug treatments may be important, 

greater attention should be directed toward physical therapy, rehabilitation, and behavioral 

approaches instead of, or in addition to, drug treatments. 

Treatment of fatigue has also focused on drug treatments, which have been largely 

unsuccessful. A new drug agent, modafinil, is currently under study, and may prove more 

useful; however, further research in non-drug approaches instead of, or in addition to, drug 

treatment may be necessary. 

Mental and psychological functioning in MS has rarely been the target in intervention trials, 

although mood and cognitive disorders have been shown to be prevalent in MS. Further 

attention is warranted toward measurement of these impairments with the goal of developing 

74
outcome measures for disease-modifying drug treatment trials or symptom-directed intervention 

trials. 

The major clinical interventions in urinary management in MS were little studied in MS 

patients specifically; it is unclear whether further research on groups of subjects with MS would 

be fruitful. 

Regarding ability to work, this report highlights significant evidence and information gaps 

concerning: 

 patterns of MS patient reports regarding functional limitations; 

 information commonly collected in medical encounters with MS patients (and therefore 

available to SSA); 

 knowledge about the impact on performance of specific work tasks of commonly objectified 

parameters such as coordination, strength, and vision, and especially of factors such as 

fatigue or cognitive dysfunction, which are either difficult to measure or are less commonly 

assessed in detail; and 

 effective research methods for categorizing job or task demands in such a way as to isolate 

those demands that are likely to be “critical” for an SSDI applicant with MS. 

In the context of these gaps, it may be productive to pursue research approaches that 

simultaneously address four domains: 

 subjective reports (this domain is not sufficient alone for SSDI determination purposes); 

 objective clinical data (ideally of the sort commonly encountered in medical records); 

 in-depth objective measures (which may be available and not widely applied clinically, but 

which may be used with subsets of subjects to explore correlation with other domains); and 

 work status measures (ideally longitudinal, with stratifications based on work demands). 

Such an approach may apply to thermal sensitivity as well, with some additional 

specification and focus. Parallel assessment of concomitant ambient temperature, physical 

exertion, and core body temperature would address key relevant physiological exposure factors. 

Outcome measures could include the domains outlined above, for example: 

 self-perceived well-being and level of symptoms such as fatigue; 

 clinical parameters such as walking speed or muscle strength; 

 in-depth measures such as potentially associated biomarkers or physiological 

parameters;199,200 and 

 work status measures, including absenteeism and disability benefits use. 

Obviously, considerable caution would be required for subject safety related to heat 

exposure.216,217 Such a research approach would be relatively complex and expensive, but might 

provide relevant information in the arenas of basic science and clinical care, and to a broad range 

of agencies, employers, and insurers dealing with MS work capacity issues. 

Generating research results of practical relevance to SSA would, in some ways, be an even 

more demanding goal. The range of potential job situations in question for SSDI determinations 

always has the potential to extend beyond the claimant’s own or previous occupation to a wide 

range of substantial gainful employment possibilities.218 Heat exposure may well be an MSrelated critical job demand in the context of various degrees of outdoor physical labor in warm

climates. However, it seems likely that less physically demanding work in temperaturecontrolled job environments would frequently be the relevant job capacity circumstance by 

which SSDI applications were ultimately determined. Therefore, it may be necessary to use a 

narrower range of exposure and outcome variables in order to address the actual questions that 

might arise in the SSDI process. Such restrictions may limit a study’s power to demonstrate 

75
associations or effects. The likely value to SSA of such an effort may well be influenced by an 

awareness of the frequency of and the particular circumstances surrounding SSDI determination 

situations in which thermal sensitivity is a critical determinant of the process outcome. 

Historical SSDI information may shed light on those particular permutations of ambient 

workplace temperature and physical demands that have commonly represented a critical or 

significant question in SSDI determinations. 

76
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86
Table 1. Results of title-and-abstract screening and full-text article review

Articles identified: 1487 

Abstracts: 

 Included 739 

 Excluded 748 

Full-text articles: 

 Included 168 

 Excluded 571 

13
Table 2. Included full-text articles by research question 

Question 1a (diagnostic reliability of McDonald criteria) 13 

Question 1b (inter-rater reliability of diagnosis with McDonald and 

Poser criteria)

2 

Question 2 (predictors of physical and mental impairments at 12 

months)

12 

Question 3a (disease-modifying therapies and long-term 

improvement)

51 

Question 3b (symptom management and improvement) 68

Question 4 (association of clinical findings with work ability) 22

Question 5 (environmental factors and work ability) 1

Total 168* 

* Note: One article was included for both Question 4 and Question 5

14
Table 3. Data supporting the validity of MRI components of the McDonald criteria 

Study Diagnosis Time to

diagnosis

of CDMS 

Paraclinical 

test(s) 

Findings

associated with

CDMS 

Proportion

developing

CDMS 

SN SP

Barkhof et al. 

199722 CIS Median

follow up 

(with

range): 

9 mo (1-

48 mo) for 

patients 

with

CDMS 

(n = 33); 

39 mo 

(23-96

mo) for 

patients 

without

CDMS 

(n = 41) 

MRI No. of T2 lesions 

≥ 9 

No. of abnormal 

MRI criteria:* 

0 

1 

2 

3 

4 

Specific MRI 

criteria: 

Final model 

Paty et al. 

198835

Fazekas et al. 

198836

24/30 (80%) 

16% 

11% 

54% 

75% 

87% 

73% 

82% 

88% 

88% 

80% 

78% 

54% 

54% 

Brex et al. 

200123 CIS 1-year

follow up 

(n = 68) 

MRI T2 lesions

Enhancing 

lesions 

T2 lesion at 

baseline and 

new T2 lesion 

Enhancing 

lesion at 

baseline and 

new enhancing

lesion 

16/48 (33%) 

11/21 (52%) 

15/27 (56%) 

7/10 (70%) 

89% 

61% 

83% 

39% 

36% 

80% 

76% 

94% 

CHAMPS 

Study Group 

200224

CIS 18-month

follow up 

(n = 190) 

MRI No. of T2

lesions: 

2-4 

5-8 

9-12 

13-21

22-34

> 35 

No. of enhancing 

lesions: 

0 

1 

> 1

> 2

20% 

15% 

33% 

33% 

26% 

20% 

23% 

33% 

43% 

52% 

Comi et al. 

200125 CIS 2 years

(n = 241) 

MRI No. of T2

lesions: 

0-8 

> 8

NR 

(OR, 3.64; 

95% CI, 1.3 

to 10.2; p =

0.014) 

39
Table 3. Data supporting the validity of MRI components of the McDonald criteria (continued) 

Study Diagnosis Time to

diagnosis

of CDMS 

Paraclinical 

test(s) 

Findings

associated with

CDMS 

Proportion

developing

CDMS 

SN SP

Filippi et al. 

199428 CIS Mean

follow up, 

63 months 

(n = 89) 

MRI Initial MRI

normal 

Initial lesion load 

> 1.23 cm3

Initial MRI 

abnormal, but 

lesion load 

< 1.23 cm3

2/32 (6%) 

19/21 (90%) 

17/31 (55%) 

Morrissey et 

al. 199330 CIS 5-year

follow up 

(n = 89) 

MRI No. of lesions: 

0 

1 

2-3 

4-10 

> 11 

2 (6%) 

1 (17%) 

12 (67%) 

12 (92%) 

16 (80%) 

Optic Neuritis 

Study Group 

200132

Optic 

Neuritis 

5-year 

follow up 

(n = 388) 

MRI No. of lesions: 

0 

1 

2 

> 3

16% 

44% 

26% 

51% 

O’Riordan et 

al. 199831 CIS 10-year

follow up 

(n = 81) 

MRI No. of

asymptomatic 

lesions at 

baseline MRI: 

0 

1 

2-3 

4-10 

> 10 

3/27 (11%) 

1/3 (33%) 

14/16 (87%) 

13/15 (87%) 

17/20 (85%) 

SastreGarriga et al. 

200333

CIS 

(brainstem 

syndrome) 

12-month 

follow up 

(n = 51) 

MRI 

CSF 

EPs 

Abnormal MRI

Abnormal CSFOCB 

Abnormal EPs

Specific MRI 

criteria: 

Paty et al. 

198835

Fazekas et al. 

198836

Barkhof et al. 

199722

17/46 (37%) 

11/25 (44%) 

10/29 (34%) 

16/32 (50%) 

16/33 (48%) 

14/27 (52%) 

94% 

100% 

89% 

89% 

78% 

42% 

42% 

52% 

48% 

61% 

*Abnormal MRI criteria: ≥ 1 gadolinium-enhancing lesions, ≥ 1 juxtacortical lesions, ≥ 3 periventricular lesions, and ≥

1 infratentorial lesions. 

Abbreviations: CDMS = clinically definite multiple sclerosis; CI = confidence interval; CIS = clinically isolated 

syndrome; CSF = cerebrospinal fluid; EPs = evoked potentials; mo = month(s); MRI = magnetic resonance imaging; 

No. = Number; OCB = oligoclonal bands; OR = odds ratio; SN = sensitivity; SP = specificity 

40
Table 4. Studies validating the McDonald criteria

Study Diagnosis Time from 

onset of 

symptoms 

Time to 

diagnosis

of CDMS 

Sensitivity Specificity PPV NPV Accuracy

3 months 

(n = 79) 

Dalton et al. 1 year 0.73 0.87 0.58 0.93 0.84 

200227 CIS 

1 year 

(n = 50) 

3 years 0.94 0.83 0.77 0.96 0.87 

Tintoré et al. 

200334 CIS 1 year 

(n = 86) 

49 months 

(mean 

follow up) 

0.74 0.86 NR NR 0.80 

Abbreviations: CDMS = clinically definite multiple sclerosis; CIS = clinically isolated syndrome; NPV = negative 

predictive value (predictive value of a negative test result); NR = not reported; PPV = positive predictive value 

(predictive value of a positive test result)

41
Table 5. Kappa statistics for multiple raters using Poser and McDonald criteria 

Poser criteria McDonald criteria 

Diagnosis of MS (all categories): 0.57 Diagnosis of MS (all categories): 0.57 

 Clinically definite MS: 0.39 MS: 0.57 

 Clinically probable MS: 0.37 Possible MS: 0.49 

Dissemination in time: 0.69 - 

Dissemination in space: 0.46 - 

Abbreviation: MS = multiple sclerosis 

42
Table 6. Relapse rate outcomes from placebo-controlled RCTs of disease-modifying therapies 

Study Therapy Relapse rate

parameter 

Active Placebo Difference P-value

Achiron et al. 199853 IV IgG ARR:

 Baseline 

 Year 1 

 Year 2 

1.85 

0.75 

0.42 

1.55 

1.80 

1.42 

0.30 

1.05 

1.0 

0.34 

0.0002 

0.0009 

Fazekas et al. 1997a63

Fazekas et al. 1997b64 IV IgG ARR: 

 Year 1 

 Year 2 

0.49 

0.42 

1.30 

0.83 

0.81 

0.41 

0.011 

0.006 

Cohen et al. 200259 IFNβ-1a ARR 0.20 0.30 0.10 0.008

Jacobs et al. 199676

Rudick et al. 199797

Fischer et al. 200065

Jacobs et al. 200075

Rudick et al. 200096

IFNβ-1a ARR 0.67 0.82 0.15 0.04

SPECTRIMS Study Group 

2001100 IFNβ-1a ARR 0.50 0.71 0.21 0.001

European Study Group on 

Interferon beta-1b in 

Secondary Progressive

MS 199862

IFNβ-1b ARR 0.44 0.64 0.20 0.0002

IFNB Multiple Sclerosis 

Study Group 199372

IFNB Study Group 199573

IFNB Study Group 199674

Pliskin et al. 199692

IFNβ-1b ARR:

 Year 1 

 Year 2 

 Year 3 

 Year 4 

 Year 5 

0.96 

0.85 

0.66 

0.67 

0.57 

1.44 

1.18 

0.92 

0.88 

0.81 

0.48 

0.33 

0.26 

0.21 

0.24 

PRISMS Study Group 

199893

Liu et al. 199982

Liu et al. 200284

Patten et al. 200189

IFNβ-1a Relapse rate,

not annualized, 

~ 2 years 

1.73 2.56 0.83

Bastianello et al. 199454 Mitoxantrone Mean RR 0.54 1.67 1.13 0.014

Millefiorini et al. 199786 Mitoxantrone No. of relapses 0.89 2.62 1.73 0.0002

Johnson et al. 199578

Weinstein et al. 1999103

Liu et al. 200083

Johnson et al. 199877

Glatiramer ARR 0.59 0.84 0.25 NR

Goodkin et al. 199168 Azathioprine ARR:

 Year 1 

 Year 2 

0.74 

0.30 

1.17 

0.79 

0.43 

0.49 

0.16 

0.05 

Romine et al. 199995 Cladribine Relapse rates,

annualized (?)

0.77 1.67 0.90 NR

Abbreviations: ARR = annual relapse rate; IFNβ-1a = interferon β-1a; IFNβ-1b = interferon β-1b; IV IgG = 

intravenous immunoglobulin-G; No. = Number; NR = not reported; RCTs = randomized controlled trials; RR = relapse 

rate 

43
Table 7. Improvements in physical function (EDSS) in placebo-controlled RCTs of disease-modifying 

therapies 

Study Therapy Definition(s) of

improvement 

(change in EDSS) 

Active Placebo Difference

Achiron et al. 199853 IV IgG -1.0 point over 2 years 31% 14% 17% 

Fazekas et al. 

1997a63

Fazekas et al. 

1997b64

IV IgG -1.0 point over 2 years 31% 14% 16% 

Cohen et al. 200259 IFNβ-1a Improvement not defined 7.5% 7.3% 0.2% (NS)

Jacobs et al. 199676

Rudick et al. 199797

Fischer et al. 200065

Jacobs et al. 200075

Rudick et al. 200096

IFNβ-1a -1.0 point (not sustained) 

-0.5 point (not sustained) 

-1.0 point (sustained) 

-0.5 point (sustained) 

19.3% 

15.7% 

18.2% 

25.5% 

11.5% 

11.5% 

8.9% 

16.1% 

8.2% 

4.2% 

9.7% 

9.4% 

Patti et al. 199990 nIFNβ -0.5 or -1.0 point: 

 Relapsing-remitting 

 Secondary progressive 

52% 

40% 

3% 

5% 

49% 

35% 

Johnson et al. 199578

Weinstein et al. 

1999103

Liu et al. 200083

Johnson et al. 199877

Glatiramer -1.0 point:

 2-year trial 

 Extension trial 

24.8% 

27.2% 

15.2% 

15.0% 

9.6% 

12.2% 

Bornstein et al.

198755 Glatiramer -1.0 point over 2 years 

-2.0 points over 2 years 

-3.0 points over 2 years 

20.0% 

12.0% 

0 

8.7% 

0 

4.4% 

11.4% 

12.0% 

-4.4% 

Ghezzi et al. 198967 Azathioprine Improvement not defined: 

 Relapsing 

 Relapsing-progressive

16% 

5% 

0 

7% 

16% (NS) 

-2% (NS) 

Goodkin et al. 199168 Azathioprine Improvement on EDSS or 

9HPT 22.2% 20% 2.2% 

van de Wyngaert et 

al. 2001102 Mitoxantrone Improvement not defined 35% 22% 13% (NS) 

Canadian 

Cooperative Multiple

Sclerosis Study

Group 199158

Cyclophosphamide -1.0 point sustained for: 

 1 year 

 2 year 

 Final 

6% 

6% 

4% 

2% 

0 

2% 

4% 

6% 

2% 

Canadian 

Cooperative Multiple

Sclerosis Study

Group 199158

Plasma 

exchange

-1.0 point sustained for: 

 1 year 

 2 year 

 Final 

8% 

3% 

2% 

2% 

0 

2% 

6% 

3% 

0 

Khatri et al. 198580 Plasma

exchange

> 1.0 point at 11 months: 

 ≥ 3 points 

 2 points 

 1 point 

10% 

13% 

13% 

0 

3% 

14% 

10% 

10% 

-1% 

Abbreviations: 9-HPT = 9-Hole Peg Test; EDSS = Expanded Disability Status Scale; IFNβ-1a = interferon β-1a; IV 

IgG = intravenous immunoglobulin-G; nIFNβ = natural interferon-β; NS = not statistically significant; RCTs =

randomized controlled trials 

44
Table 8. Randomized controlled trials of symptomatic treatments for spasticity

Treatment Study Baseline

EDSS 

No. of 

patients 

started

(completed) 

Outcomes/Results 

Baclofen PO (to 80 mg/d) 

vs. 

Placebo 

Crossover

Feldman

et al. 

1978109

NR 33 Spasm frequency (p < 0.05) 

Resistance to movement (p < 0.05) 

Clonus (knee) (p < 0.001) 

Ambulation (p = NS) 

Transfer activity (p = NS) 

Spastic limb pain (p = NS) 

Use of spastic limb (p = NS) 

Functional assessment (Barthel) (p = NS) 

Baclofen PO (to 80 mg/d) 

vs. 

Placebo 

Sachais et 

al. 1977129 NR 166 (106) Flexor spasm severity (p < 0.02) 

Ankle clonus (p = NS) 

ADL (p = NS) 

Overall disability (p = NS) 

Baclofen PO (to 45 mg/d) 

vs. 

Placebo 

Crossover 

Ørsnes et 

al. 2000124 5.0 

(median) 

3.5-6.0 

(range) 

14 Voluntary power (0-5 scale) (p = NS) 

Ashworth Scale (p = 0.33) 

Tendon reflexes (p = 0.14) 

EDSS & Ambulation Index (p = NS) 

NRS (p = NS) 

MSIS (p = NS)

Baclofen PO (to 80 mg/d) 

vs. 

Placebo 

Levine et 

al. 1977117 NR 19 (18) Ashworth Scale (p = NS) 

Baclofen PO (to 60 mg/d) 

vs. 

Placebo 

Crossover 

Sawa et 

al. 1979130 NR 21 (18) Muscle tone (p = NR) 

Baclofen PO (to 20 mg/d) 

vs. 

Stretching exercises +

baclofen 

vs. 

Stretching exercises 

vs. 

Placebo 

Crossover

Brar et al. 

1991105 NR 38 (30) Spasticity: Cybex flexion scores (p < 0.05; 

baclofen and combination vs. placebo) 

Ashworth Scale (p = 0.1; combination vs. 

placebo) 

Self-rated questionnaire of functional 

abilities (p = NR) 

Baclofen intrathecal 

vs. 

Placebo 

Crossover 

Penn et al. 

1989125 NR 20 (10 MS) Ashworth Scale (p < 0.0001) 

Spasm score (p < 0.0005) 

Tizanidine PO (to 36 

mg/d) 

vs. 

Placebo 

Smith et 

al. 1994133 NR 257 (159) Ashworth Scale (p = 0.46) 

Spasm response (p = 0.03) 

Clonus response (p = NS) 

Tizanidine PO (to 36 

mg/d) 

vs. 

Placebo 

UK 

Tizanidine

Trial 

Group 

1994137

NR 187 (155) Ashworth Scale (p < 0.004) 

Spasm frequency (p = NS) 

Muscle strength (p = NS) 

EDSS (p = NS) 

Tendon reflexes

Intermediate motor skills (p = NS) 

Upper limb function (p = NS) 

Impact on physical therapy (p = NS) 

Impact on nursing care (p = 0.09) 

45
Table 8. Randomized controlled trials of symptomatic treatments for spasticity (continued) 

Treatment Study Baseline

EDSS 

No. of 

patients 

started

(completed) 

Outcomes/Results 

Gabapentin PO 2700 mg 

vs. 

Placebo 

Crossover

Cutter et 

al. 2000107 6.0-9.0 

(range) 

22 (21) Spasm frequency scale (p = 0.0001) 

Spasm severity scale (p = NS) 

Interference with function scale (p = 0.02) 

Painful spasm scale (p = NS) 

Global assessment scale (p = 0.003) 

Modified Ashworth Scale (p = 0.0005) 

EDSS (p = NS) 

Gabapentin PO 400 mg 

vs. 

Placebo 

Crossover 

Mueller et 

al. 1997121 NR 15 Visual Faces Scale rating of pain and 

spasticity (p = 0.008) 

Ashworth Scale (p = 0.007) 

Clonus (p = 0.1) 

Reflex withdrawal to pain (p = NS) 

EDSS (p = 0.03) 

Dantrolene PO (to 350 

mg/d) 

vs. 

Placebo 

Crossover 

Gambi et 

al. 1983111 NR 24 (22) Hip flexor movement (p = NS) 

Spasticity scale (p < 0.05) 

Muscular strength (p = NS) 

Clonus (p = NS) 

Knee and ankle tendon reflexes scale (p =

NS) 

Delta-9-THC 

vs. 

Cannabis sativa extract 

vs. 

Placebo 

Zajicek et 

al. 

2003138

NR 630 (611) Muscle tone (p=0.4) 

Pain (p=0.003; favoring active treatments) 

Subjective spasticity (p=0.01) 

10-meter walk (p=0.015; favoring delta-9-

THC) 

Delta-9-THC 

vs. 

Cannabis sativa extract 

vs. 

Placebo 

Crossover 

Killestein 

et al. 

2002115

6.2 ± 1.2 

(mean ±

SD) 

16 MSFC score (p = 0.09; favoring placebo) 

9-HPT (p = 0.02; favoring placebo) 

EDSS (p = NS) 

Muscle tone (p = NS) 

SF-36 mental health subscale (p = 0.02) 

and psychological status domain (p = 0.02) 

Other parameters (p = NS) 

Progabide PO (to 45 

mg/kg/d) 

vs. 

Placebo 

Crossover 

Rudick et 

al. 1987128 6.3 ± 1.7 

(mean ±

SD) 

32 (25) Ashworth Scale (p < 0.01) 

EDSS (p = NS) 

8-meter walk (p = 0.62) 

Spasm frequency (p = 0.28) 

Reflex scores (p = 0.20) 

Strength (p = 0.77) 

Various functional tasks (p = NS) 

Progabide PO (14.3-32.7 

mg/kg/d) 

vs. 

Placebo 

Crossover 

Mondrup 

et al. 

1984119,120

NR 17 (14) Spasticity (0-4 scale) (p < 0.01) 

Spasms (p < 0.01) 

Reflex response (p < 0.01, patellar; p = NS, 

Achilles) 

Flexor reflexes (p = NS) 

Muscle strength (p = NS) 

Spasm frequency (p < 0.05) 

Spasm pain (p = NS) 

46
Table 8. Randomized controlled trials of symptomatic treatments for spasticity (continued) 

Treatment Study Baseline

EDSS 

No. of 

patients 

started

(completed) 

Outcomes/Results 

Botulinum toxin IM 

vs. 

Placebo 

Hyman et 

al. 2000114 7.5 

(median

[estimated

]) 

74 (60) Hip abduction (p = NS) 

Modified Ashworth Scale (p = NS) 

Spasm frequency (p = NS) 

Hygiene assessment (p = NR) 

Botulinum toxin IM 

vs. 

Placebo 

Crossover 

Snow et 

al. 1990135 8.0-9.5 

(range) 

10 (9) Spasticity score (Ashworth Scale + spasm 

frequency) (p = 0.009) 

Hygiene score (p = 0.02) 

Threonine PO (7.5 g/d) 

vs. 

Placebo 

Crossover 

Hauser et 

al. 1992112 4.7 ± 1.5 

(mean ±

SD) 

26 (21) Spasticity (clinician scale) (p = 0.04) 

Spasticity (patient scale) (p = 0.18) 

Threonine PO 6 g/d 

vs. 

Placebo 

Crossover 

Lee et al. 

1993116 7.4 

(mean) 

2-9 

(range) 

41 (33) Spasticity score (based on Ashworth) (p =

NR) 

Barthel Index (p = NS) 

EDSS (p = NS) 

Electrical neuromuscular 

stimulation 

vs. 

Sham stimulation 

Livesley

1992118 NR 40 (39) Spasticity, active movement, and function 

(p = NS) 

Subjective evaluation (p = NR) 

Magnetic stimulation 

vs. 

Sham stimulation 

Nielsen et 

al. 1996123 NR 38 Ashworth Scale (p = NR) 

Tendon reflexes (p = NR) 

Patient’s self-score for ease of daily

activities (p = NS) 

Tizanidine PO (to 32 

mg/d) 

vs. 

Baclofen PO (to 80 mg/d) 

Crossover 

Bass et al. 

1988104

Rice 

1989126

NR 66 (48) Spasticity (6-point ordinal scale) (p = NS) 

Strength (7-point ordinal scale) (p = NS) 

EDSS (p = NS) 

Pedersen functional disability scale (p =

NR) 

Overall evaluation (patient, clinician) (p =

NR) 

Tizanidine PO (to 36 

mg/d) 

vs. 

Baclofen PO (to 80 mg/d) 

Smolenski 

et al. 

1981134

NR 21 Muscle strength (p = NR) 

Ashworth Scale (p = NR) 

Spasms scale (p = NR) 

Tizanidine PO (to 24 

mg/d) 

vs. 

Baclofen PO (to 60 mg/d) 

Eyssette 

et al. 

1988108

NR 100 Flexor spasms (p = NS) 

Muscle tone (p = NS) 

Tizanidine PO (to 24 

mg/d) 

vs. 

Baclofen PO (to 60 mg/d) 

Crossover 

Hoogstraten et 

al. 1988113

6.1 ± 0.8 

(mean ±

SD) 

16 (11) Ashworth Scale (p = NS) 

EDSS (p = NS) 

Functional systems (p = NS) 

Isometric strength (p = NS) 

Tizanidine PO (to 16 

mg/d) 

vs. 

Baclofen PO (to 40 mg/d) 

Crossover 

Newman

et al. 

1982122

NR 36 (26) Ashworth Scale (p = NS) 

EDSS (p = NS) 

Pedersen functional disability scale (p =

NS) 

47
Table 8. Randomized controlled trials of symptomatic treatments for spasticity (continued) 

Treatment Study Baseline

EDSS 

No. of 

patients 

started

(completed) 

Outcomes/Results 

Tizanidine PO (to 35 

mg/d) 

vs. 

Baclofen PO (to 90 mg/d) 

Stien et al. 

1987136 NR 40 (38) Ashworth Scale (p = NS) 

EDSS (p = NS) 

Pedersen functional disability scale (p =

NS) 

Overall evaluation (p = NS) 

Tizanidine PO (to 18 

mg/d) 

vs. 

Diazepam PO (to 22.5 

mg/d) 

Rinne

1980127 NR 30 (26) Ashworth Scale (p = NS) 

Baclofen PO (30-60 mg/d) 

vs. 

Diazepam PO (15-30

mg/d) 

Crossover 

Cartlidge 

et al. 

1974106

NR 40 (34) Ashworth Scale (p = NS) 

Subjective impression (p = NS) 

Baclofen PO (30-120 

mg/d) 

vs. 

Diazepam PO (10-40

mg/d) 

Crossover 

From et al. 

1975110 NR 17 Ashworth Scale (p = NR) 

Spasms (p = NS) 

Clonus (p = NS) 

Urine retention, incontinence (p = NR) 

Walking (p = NR) 

Dantrolene PO (25 or 75 

mg, 4 times per day) 

vs. 

Diazepam PO (to 2 or 5 

mg, 4 times per day) 

Crossover 

Schmidt et 

al. 

1975131,132

5.5 

(mean) 

46 (42) 10- item exam evaluating spasticity, clonus, 

hyperreflexia, muscle stiffness, cramping 

(p = NR) 

Subjective evaluation (p = NR) 

Abbreviations: 9-HPT = 9-Hole Peg Test; ADL = activities of daily living; d = day(s); EDSS = Expanded Disability 

Status Scale; g = gram(s); IM = intramuscular; kg = kilogram(s); mg = milligram(s); MRD = Minimal Record of 

Disability; MS = multiple sclerosis; MSFC = Multiple Sclerosis Functional Composite; MSIS = MS-Impairment Scale; 

No. = Number; NR = not reported; NRS = Neurologic Rating Scale; NS = not statistically significant; PO = per os (by

mouth); SD = standard deviation; SF-36 = Medical Outcomes Study 36-Item Short-Form Health Survey; THC =

tetrahydrocannabinol 

48
Table 9. Randomized controlled trials of rehabilitation interventions 

Treatment Study Baseline

EDSS 

No. of 

patients 

started

(completed) 

Outcomes/Results 

Inpatient rehab (3 mo) 

vs. 

Outpatient rehab 

Francabandera

et al. 1988139 NR 84 (73) ISS (p < 0.05) 

Need for home assistance (p = 0.17) 

Inpatient rehab (20 d) 

vs. 

Wait-list control 

Freeman et al. 

1997140 6.5 (median) 

5-9 (range) 

70 (66) EDSS (p = NS) 

FIM motor score (p < 0.001) 

LHS (p = 0.01)

Inpatient rehab (3 wk) 

vs. 

Home exercise program 

Solari et al. 

1999145 5.5 (median) 

3-7 (range) 

50 (45) FIM (p < 0.01) 

EDSS (p = NS) 

SF-36 (p = NS) 

Outpatient rehab (6 wk) 

vs. 

Self-exercise treatment 

Patti et al. 

2002142 6.2 (mean) 

4-8 (range) 

111 (106) Fatigue Impact Scale (p < 0.001) 

EDSS (p = NS) 

SET (p < 0.001) 

BDI (p < 0.001) 

SF-36 (p < 0.05 on all subscales) 

Home PT (8 wk) 

vs. 

Outpatient PT

vs. 

No PT

Crossover 

Wiles et al. 

2001148 6.0 (median) 

4-6.5 (range) 

42 (40) Rivermead mobility index (p < 0.001, 

each active treatment vs. control) 

Balance time (p = 0.004; p = 0.001) 

Walk A (p < 0.003; p = 0.002)

9-HPT (p = 0.01; p = 0.08) 

Global mobility (p < 0.001; p < 0.001) 

Supervised exercise (15 

wk)

vs. 

No treatment 

Petajan et al. 

1996143 3.4 ± 1.0 

(mean ± SD) 

54 (46) FSS (p = NS) 

SIP physical dimension subscale (p <

0.05) 

EDSS (p = NS) 

ISS (p = NS) 

VO2max (p < 0.01) 

POMS (p = NS) 

Home-based 

management (rehab, 

nursing, education, 

psychological support, 

social services) 

vs. 

Usual care 

Pozzilli et al. 

2002144 5.9 ± 1.5 

(mean ± SD) 

201 (188) FSS (p = NS) 

FIM (p = NS) 

SF-36 (p < 0.05 for bodily pain, 

general health, social function and 

emotional role subscales, and physical

and mental component scores) 

EDSS (p = NS) 

MMSE (p = NS) 

STAXI (p = NS) 

STAI (p = NS) 

CDQ (p = 0.11) 

Professionally guided 

self-care 

vs. 

No treatment 

O’Hara et al. 

2002141 NR 183 (169) SDDR subscale O (p = 0.6) 

SDDR subscale E (p = 0.04) 

SF-36 (p < 0.05 on mental health and 

vitality subscales) 

Education in health 

behaviors and lifestyle 

change 

vs. 

Usual care 

Stuifbergen et 

al. 2003146 NR 142 (113) SF-36 (p < 0.05 for bodily pain and 

mental health subscales) 

Self-efficacy (p < 0.01) 

Barriers scale (p = NS) 

PRQ (p = NS) 

HPLP-II (p < 0.01) 

49
Table 9. Randomized controlled trials of rehabilitation interventions (continued) 

Treatment Study Baseline

EDSS 

No. of 

patients 

started

(completed) 

Outcomes/Results 

Multifaceted outpatient 

intervention 

(educational, 

behavioral) 

vs. 

Usual care 

Wassem et al. 

2003147 3.4 (mean) 

0-9 (range) 

27 (16) Fatigue (p = 0.09) 

Sleep disturbance (p = 0.07) 

Pain (p = NS) 

Sum of symptom severity (p = 0.03) 

SEAB (p = 0.55) 

PAIS-SR (p = 0.72) 

Abbreviations: 9-HPT = 9-Hole Peg Test; BDI = Beck Depression Inventory; CDQ = Clinical Depression 

Questionnaire; d = day(s); EDSS = Expanded Disability Status Scale; FIM = Functional Independence Measure; FSS 

= Fatigue Severity Scale; HPLP-II = Health Promoting Lifestyle Profile-II; ISS = Incapacity Status Scale; LHS = 

London Handicap Scale; MMSE = Mini Mental State Examination; mo = month(s); No. = Number; NR = not reported; 

NS = not statistically significant; PAIS-SR = Psychosocial Adjustment to Illness Scale-Self-Report; POMS = Profile of 

Mood States; PRQ = Personal Resources Questionnaire; PT = physiotherapy; SD = standard deviation; SDDR =

Standard Day Dependency Record; SEAB = Self-Efficacy for Adjustment Behaviors Scale; SET = Tempelaar Social

Experience Checklist; SF-36 = Medical Outcomes Study 36-Item Short-Form Health Survey; SIP = Sickness Impact 

Profile; STAI = State-Trait Anxiety Inventory; STAXI = State-Trait Anger Expression Inventory; VO2max = maximum 

oxygen consumption with exercise; wk = wk(s)

50
Table 10. Randomized controlled trials of treatments for depression 

Treatment Study Baseline

EDSS 

No. of 

patients 

started 

(completed) 

Outcomes/Results 

Psychotherapy 

vs. 

Active control (current 

events discussion group) 

vs. 

Passive control (no 

treatment) 

Crawford et 

al. 1985149 NR 32 MMPI Depression-30 scale (p = 0.025) 

IECS (p = 0.005) 

ASQ (p = NS) 

SES (p = NS) 

CBT

vs. 

Wait-list control 

Larcombe et 

al. 1984151 NR 21 (19) BDI (p < 0.01) 

HRSD (p < 0.01) 

Significant-Other Rating Scale (p <

0.01) 

Worst mood (p < 0.05) 

Best mood (p = NS) 

Average mood (p = NS) 

CBT + relaxation 

vs. 

Wait-list control 

Foley et al. 

1987150 6 (mean) 

1-8 (range) 

41 (36) BDI (p < 0.05) 

STAI-S (p < 0.05) 

STAI-T (p = NS) 

Hassles Scale (p < 0.05) 

PFC (p < 0.05) 

Cognitive remediation 

(CBT + memory aids) 

vs. 

Active control (support 

group) 

Mendoza et 

al. 2001152 NR 20 BDI (p = NS) 

CBT

vs. 

Support group (SEG) 

vs. 

Sertraline (200 mg/d) 

Mohr et al. 

2001153 2.4 (mean) 

0-8 (range) 

63 (52) BDI CBT vs. SEG (p = 0.003) 

Sertraline vs. SEG (p = 0.05) 

CBT vs. sertraline (p = NS) 

HRSD CBT vs. SEG (p = 0.02) 

Sertraline vs. SEG (p = 0.45) 

CBT vs. sertraline (p = 0.13) 

CBT (telephoneadministered) 

vs. 

Control (usual care) 

Mohr et al. 

2000154 NR 32 (23) POMS Depression-Dejection scale 

(p < 0.003, completers; p < 0.01, ITT

population) 

Amitriptyline 

vs. 

Placebo 

Schiffer et 

al. 1985155 NR 17 (12) Improvement in number of episodes of 

pathological laughing or crying; BDI; 

HRSD (p = 0.011) 

Desipramine +

psychotherapy

vs. 

Placebo + psychotherapy 

Schiffer et 

al. 1990156 4.6 (mean) 32 (28) Clinical improvement in psychosocial 

function (p = 0.05) 

BDI (p = 0.16) 

HRSD (p = 0.02) 

Abbreviations: ASQ = Anxiety Scale Questionnaire; BDI = Beck Depression Inventory; CBT = cognitive behavioral 

therapy; d = day; EDSS = Expanded Disability Status Scale; HRSD = Hamilton Rating Scale for Depression; IECS = 

Internal-External Control Scale; ITT = intention-to-treat; mg = milligram(s); MMPI = Minnesota Multiphasic Personality

Inventory; No. = Number; NR = not reported; NS = not statistically significant; PFC = Problem-Focused Coping score 

from Ways of Coping Checklist; SEG = supportive-expressive group therapy; SES = Self-Esteem Scale; PFC = 

Problem-Focused Coping score from the Ways of Coping Checklist; POMS = Profile of Mood States; STAI-S = StateTrait Anxiety Inventory-State; STAI-T = State-Trait Anxiety Inventory-Trait

51
Table 11. Randomized controlled trials of treatments for fatigue

Treatment Study Baseline

EDSS 

(Mean ± SD) 

No. of 

patients 

started 

(completed) 

Outcomes/Results 

Amantadine (100 mg 

twice per day x 3 wk) 

vs. 

Placebo 

Canadian MS 

Research Group 

1987157

4.3 ± 1.9 115 (109) Change in VAS fatigue score (p = NS) 

Most affected activity VAS (p < 0.05) 

ADL total score (p = 0.09) 

Amantadine (100 mg 

twice per day x 4 wk) 

vs. 

Placebo 

Cohen et al. 

1989158 4.0 ± 1.4 29 (22) Fatigue score (p = 0.58) 

Amantadine (100 mg 

twice per day x 6 wk) 

vs. 

Pemoline 

vs. 

Placebo 

Krupp et al. 

1995161 2.9 ± 0.9 119 (93) MS-FS A vs. placebo (p = 0.04) 

P vs. placebo (p = 0.4) 

FSS A vs. placebo (p = NS) 

P vs. placebo (p = 0.8) 

Amantadine (100 mg 

twice per day x 6 wk) 

vs. 

Pemoline 

vs. 

Placebo 

Geisler et al. 

1996159 2.6 ± 0.7 45 SDMT A vs. placebo (p < 0.05) 

P vs. placebo (p = NR) 

Digit Span (p = NS) 

Selective Reminding Test (p = NS) 

Benton Visual Retention Test (p = NS) 

Finger Tapping Test (p = NS) 

Pemoline 

vs. 

Placebo 

Weinshenker et

al. 1992163 3.6 ± 2.0 46 (41) EDSS (p = NS) 

Fatigue VAS (p = NS) 

Fatigue 4-point scale (p = 0.06) 

Transdermal 

histamine/caffeine 

vs. 

Placebo 

Gillson et al. 

2002160 NR 29 (26) MFIS (p < 0.02) 

25-foot timed walk (p =NS) 

9-HPT (p = NS) 

PASAT (p = NS) 

4-aminopyridine 

vs. 

Placebo 

Rossini et al. 

2001162 6.2 ± 0.8 54 (49) FSS (p = 0.19) 

EDSS (p = NS) 

Abbreviations: 9-HPT = 9-Hole Peg Test; ADL = activities of daily living; EDSS = Extended Disability Status Scale; 

FSS = Fatigue Severity Scale; MFIS = Modified Fatigue Impact Scale; mg = milligram(s); MS = multiple sclerosis; 

MS-FS = MS-Specific Fatigue Scale; No. = Number; NR = not reported; NS = not statistically significant; PASAT = 

Paced Auditory Serial Addition Test; SD = standard deviation; SDMT = Symbol Digit Modalities Test; VAS = visual 

analog scale; wk = week(s)

52
Table 12. Randomized controlled trials of treatments for voiding dysfunction 

Treatment Study Baseline

EDSS 

No. of 

patients 

started

(completed) 

Outcomes/Results 

Desmopressin nasal 

spray (20 mcg/d) 

vs. 

Placebo nasal spray 

Fredrikson 

1996164 NR 27 (22) No. of voidings in 6 hr (p < 0.05) 

No. of voidings in 24 hr (p = NS) 

Desmopressin nasal 

spray (20 mcg/d) 

vs. 

Placebo nasal spray 

Hilton et 

al. 1983165 NR 16 Subjective benefit in nocturia (p < 0.01) 

Daytime urinary frequency (p = NS) 

Nighttime urinary frequency (p < 0.001) 

Desmopressin nasal 

spray (20 mcg/d) 

vs. 

Placebo nasal spray 

Hoverd et 

al. 1998166 NR 28 (24) Daytime urinary frequency (p = 0.008) 

Nighttime urinary frequency (p = 0.26) 

Urine volume in 6 hr (p = 0.006) 

Urine volume in 24 hr (p = 0.052) 

Desmopressin nasal 

spray

vs. 

Placebo nasal spray 

Kinn et al. 

1990167 NR 13 (12) No. of voidings in 6 hr (p < 0.05) 

No. of voidings in 24 hr (p = NS) 

Urine volume in 6 hr (p < 0.05) 

Desmopressin nasal 

spray (10 mcg/d) 

vs. 

Placebo nasal spray 

Valiquette 

et al. 

1996170

6.7 (mean) 

2.5-8.5 (range)

17 (11) Nights with nocturia (p < 0.01)

Incontinence (p = 0.08) 

Frequency of nocturia (p < 0.01) 

Uninterrupted sleep hours (p < 0.01) 

Abdominal vibration 

vs. 

Abdominal pressure 

vs. 

No treatment 

Prasad et 

al. 2003168 NR 30 (28) No. of patients with no incontinence in 72

hr (p = NR) 

No. of voidings in 72 hr (p = NR) 

Post-void residual volume: 

 Vibration vs. placebo (p = 0.002) 

 Vibration vs. pressure (p = 0.059) 

Pelvic floor 

rehabilitation

(biofeedback +

exercise) 

vs. 

No treatment 

Vahtera et 

al. 1997169 4.4 (mean) 

1-6.5 (range) 

80 Incontinence (p < 0.05) 

Nocturia (p < 0.05) 

Frequency of UTIs (p = NS) 

Urinary symptom-related handicap (p < 

0.05) 

Abbreviations: d = day(s); EDSS = Extended Disability Status Scale; hr = hour(s); mcg = microgram(s); No. =

Number; NR = not reported; NS = not statistically significant; UTIs = urinary tract infections

53
Table 13. Included studies by type of measure used and type of function considered (physical, mental, other) 

Type of measure used Type(s) of function considered Study

Hyllested criteria, etc. Physical and mental Rozin et al. 1975191

Rozin et al. 1982190

Expanded Disability Status Scale 

(EDSS) and Disability Status Scale 

(DSS) 

Physical Canadian Burden of Illness Study 

Group 1998a174

Grima et al. 2000180

Hammond et al. 1996183

LaRocca et al. 1982187

Miller et al. 2000188

Verdier-Taillefer et al. 1995193

Mobility aids Physical Dyck et al. 2000176

Kornblith et al. 1986186

Job characteristics Physical, mental, symptoms Dyck et al. 2000176

Grønning et al. 1990181

LaRocca et al. 1982187

Rozin et al. 1975191

Scheinberg et al. 1980192

Verdier-Taillefer et al. 1995193

Cognitive function Mental/cognitive and physical Beatty et al. 1995172

Beukelman et al. 1985173

Edgley et al. 1991177

Genevie et al. 1987179

Rao et al. 1991189

Disease subtype – Jacobs et al. 1999184

Verdier-Taillefer et al. 1995193

Self-report Physical, mental, symptoms Dyck et al. 2000176

Edgley et al. 1991177

Freal et al. 1984178

Gulick et al. 1989182

Scheinberg et al. 1980192

54
Table 14. Studies by Rozin et al.190,191 measuring ability to work among individuals with MS 

Rozin et al. 1975191 Rozin et al. 1982190 (Series I and II combined) 

1) Study participants (n = 172) initially grouped: 

n = 41 – Group A: Completely handicapped with no 

rehabilitation potential 

n = 37 – Group B: Potential for vocational rehabilitation, 

but unemployed or currently employed, but needs 

rehabilitation services for continuation of employment 

n = 94 – Group C: Currently working, holding previous 

jobs, or changed jobs without intervention of

rehabilitation

2) Type of MS disability by group: 

No disability:

NR – Group A 

NR – Group B 

50% – Group C 

Physical disability due to MS: 

39% – Group A 

81% – Group B 

41% – Group C 

Physical and mental disability due to MS: 

56% – Group A 

19% – Group B 

 3% – Group C 

Mental disability due to MS: 

NR – Group A 

NR – Group B 

1% – Group C

Other causes of disability not connected with MS: 

5% – Group A 

NR – Group B 

5% – Group C

 

1) Study participants (n = 299) initially grouped: 

n = 71 – Group A: Completely handicapped with no 

rehabilitation potential 

n = 53 – Group B: Potential for vocational rehabilitation, 

but unemployed or currently employed, but needs 

rehabilitation services for continuation of employment 

n = 175 – Group C: Currently working, holding previous 

jobs, or changed jobs without intervention of

rehabilitation

2) Type of MS disability by group: 

No disability:

NR – Group A 

 3% – Group B

29% – Group C 

Physical disability due to MS: 

59% – Group A 

75% – Group B 

61% – Group C 

Physical and mental disability due to MS: 

30% – Group A 

11% – Group B 

 6% – Group C 

Mental disability due to MS: 

1% – Group A 

2% – Group B 

1% – Group C

Other causes of disability not connected with MS: 

7% – Group A 

2% – Group B 

1% – Group C

MS and other causes of disability:

3% – Group A 

7% – Group B 

2% – Group C

55
Table 14. Studies by Rozin et al.190,191 measuring ability to work among individuals with MS (continued) 

Rozin et al. 1975191 Rozin et al. 1982190 (Series I and II combined) 

3) Hyllested criteria of disability:

Group A (no rehabilitation potential) (n = 41) 

0% – Mild (0-2)

0% – Moderate (3-4) 

100% – Severe (5-6) 

Group B (vocational rehabilitation needed among 

unemployed and employed) (n = 37) 

0% – Mild (0-2)

57% – Moderate (3-4) 

43% – Severe (5-6) 

Group C (working) (n = 94) 

70% – Mild (0-2) 

30% – Moderate (3-4) 

0% – Severe (5-6) 

3) Hyllested criteria of disability:

Group A (no rehabilitation potential) (n = 71) 

15% – Mild (0-2) 

38% – Moderate (3-4) 

46% – Severe (5-6) 

Group B (vocational rehabilitation needed among 

unemployed and employed) (n = 53) 

36% – Mild (0-2) 

51% – Moderate (3-4) 

13% – Severe (5-6) 

Group C (working) (n = 175) 

74% – Mild (0-2) 

25% – Moderate (3-4) 

0.6% – Severe (5-6) 

Abbreviations: MS = multiple sclerosis; NR = not reported

56
Table 15. Cross-sectional studies examining current employment status and EDSS level among individuals 

with MS

Canadian Burden of Illness Study

Group 1998a174 Grima et al. 2000180 Miller et al. 2000188

EDSS ≤ 2.5 (n = 62): 

37% - Full-time

13% - Part-time 

29% - Unemployed 

13% - Other 

EDSS 1-2 (n = 78): 

44% - Full-time

14% - Part-time 

15% - Not working due to MS

27% - Not working, other reasons 

EDSS 0-3.0 (n = 113): 

42.0% - Full-time 

20.5% - Part-time 

37.5% - None 

 

EDSS 3-6: (n =68) 

28% - Full-time

10% - Part-time 

44% - Unemployed 

18% - Other 

EDSS 3-6: (n = 75) 

15% - Full-time

 8% - Part-time 

51% - Not working due to MS

13% - Not working, other reasons 

 4% - NR 

EDSS 3.5-6.5 (n = 131) 

15.4% - Full-time 

10.0% - Part-time 

74.6% - None 

EDSS ≥ 6.5: (n = 68) 

 4% - Full-time 

 6% - Part-time 

57% - Unemployed 

32% - Other 

– EDSS 7.0-8.5 (n = 56) 

8.9% - Full-time 

5.4% - Part-time 

85.7% - None 

Abbreviations: EDSS = Expanded Disability Status Scale; MS = multiple sclerosis; NR = not reported 

57
Table 16. Cognitive function and work status among individuals with MS 

Study, 

number of 

subjects 

Cognitive function measures Primary findings 

Beatty et al. 

1995172

N = 102 

38 employed

64 retired 

Categories: 

 Verbal ability (SILS Vocabulary Test) 

 Naming (Boston Naming Test) 

 Visuospatial (Perception-LOT)

 Attention/Concentration (Digit Span) 

 Information processing (Speed, SDMT, 

FAS) 

 Category fluency

 Memory (STM–Correct, NMT-Delay, SRTTotal, SRT-Delay Recall, SRT-Delay 

Recognition) 

 Problem solving/abstraction (SILSAbstraction, SILS-Conceptual Quotient, 

WCST-Categories, WCST-% Perseverative 

Responses) 

 Ambulatory Index (score 1-6) (highly 

correlated with EDSS: r = 0.96) 

 Beck Depression Index 

Significant differences between workers and 

non-workers were observed on all measures 

except Digit Span, LOT, and WCST-% 

Perseverative Response 

49% of the variance in employment status was 

explained by walking ability, age, two measures 

of memory, and one test of verbal fluency 

Partial R2

 Ambulation index: 0.25 

 STM (short term memory): 0.13 

 SRT (delay recall/memory): 0.04 

 Age (29-62 years): 0.03 

 FAS (verbal ability/letter fluency): 0.03 

Edgley et al. 

1991177

N = 602 

PDQ score – sum of 4 subscales: 

1. attention/concentration 

2. planning/organizing 

3. retrospective memory

4. prospective memory

(each subscale ranked 0-4: 

0 = never 

1 = rarely

2 = sometimes

3 = often 

4 = almost always) 

Mobility assistance: 

1. no ambulatory problems 

2. a bit unsteady

3. need cane/brace 

4. wheelchair 

5. can’t walk 

PDQ score (mean [SD]): 

Unemployed: 1.6 (0.7) 

Employed: 1.4 (0.7) 

p < 0.001 

Mobility assistance (mean [SD]): 

Unemployed: 3.1 (1.2) 

Employed: 2.2 (1.0) 

p < 0.001 

“A significant multivariate main effect for 

employment status was obtained. Compared to 

individuals who were employed, unemployed

individuals had more mobility problems 

(indicated above), obtained higher scores on

the self-report PDQ (indicated above), had 

fewer years of education. Occupational level, 

number of people living at home and illness 

duration did not impact employment status.” 

Rao et al. 

1991189

N = 100 

52 intact 

48 impaired

A battery of 36 tests were used to evaluate the 

following: 

Dementia Screen (MMS) 

Verbal Intelligence (WAIS-R) 

Memory Immediate 

Memory Recent 

Memory Remote 

Abstract Reasoning 

Attention/Concentration

Language 

Visuospatial Perception 

100 MS patients were grouped as being either 

intact or impaired 

From the Environmental Status Scale (ESS), 

one of seven domains – Actual Work Status – 

was compared to cognitive impairment (yes/no) 

Mean score of ESS scale (range 0-4) for Actual 

Work Status was lower (approximately 1.8) for 

cognitively impaired versus intact 

(approximately 2.8; p < 0.01) 

58
Table 16. Cognitive function and work status among individuals with MS (continued) 

Abbreviations: EDSS = Expanded Disability Status Scale; ESS = Environmental Status Scale; FAS = letter fluency

test (saying as many words as possible that begin with F, A, and S, 60 seconds each); LOT = Line Orientation Test; 

MMS = Mini-Mental State; MS = multiple sclerosis; N = number of subjects; NMT = New Map Test; PDQ = Perceived 

Deficit Questionnaire; SD = standard deviation; SDMT = Symbol Digit Modalities Test; SILS = Shipley Institute of 

Living Scale; SRT = Selective Reminding Test; STM = Short Term Memory Test; WCST = Wisconsin Card Sorting 

Test; WAIS-R = Wechsler Adult Intelligence Scale-Revised

59
Table 17. Job type/characteristics and current work status among individuals with MS 

Study Findings

Grønning et al. 1990181 Univariate analyses of time to unemployment: 

Non-remittent MS vs. remittent (p < 0.001) 

Heavy vs. light work (p < 0.01)

Male vs. female (p < 0.05) 

Age > 30 at onset (p < 0.01) 

Multivariate analyses, when disease subtype was not considered, occupation (heavy 

work) and age (> 30 years) were predictive of early unemployment 

Hammond et al. 1996183 “Authors noted that trade and farm workers were less likely to be in paid employment 

than professional or clerical workers as their level of disability increased.” 

(Researchers provided no data to support this statement.) 

LaRocca et al. 1982187 84% of variability in employment status was unexplained by age, sex, education, 

marital status, occupation, and parenthood 

However, variability in employment status was explained by factors such as premorbid 

personality, coping style, characteristics of the workplace, and social support systems. 

Authors suggested that these findings contribute to the probability of a patient with MS 

staying at work. (Researchers provided no data to support this statement.) 

Scheinberg et al. 1980192 Job category of currently employed subjects (n = 51): 

35.3% - Clerical 

23.5% - Professional 

13.7% - Semi-professional 

13.7% - Skilled labor 

 7.8% - Managerial 

 2.0% - Unskilled labor 

 3.9% - Other 

Verdier-Taillefer et al. 

1995193 Job characteristics and odds of unemployment (odds ratio [95% CI]): 

Desk job - 0.3 (0.1 to 0.5) 

Sitting position - 0.3 (0.1 to 0.7) 

Possibility of obtaining specific arrangements - 0.4 (0.2 to 0.8) 

Travel time > 30 minutes - 1.7 (0.9 to 3.2) 

Daily work > 8 hours - 2.6 (1.2 to 5.7) 

Accessibility problems - 1.9 (0.9 to 4.0) 

Work requirements and odds of unemployment (odds ratio [95% CI]): 

Close attention - 0.9 (0.4 to 1.8) 

Good memory - 0.7 (0.3 to 1.5) 

Physical strength - 7.6 (3.2 to 18.2) 

Manual precision - 3.1 (1.6 to 6.3) 

Rigid work schedule - 2.2 (1.1 to 4.6) 

Decision making - 1.7 (0.7 to 3.4) 

Frequent moves - 2.5 (1.3 to 4.9) 

60
Table 17. Job type/characteristics and current work status among individuals with MS (continued) 

Study Findings

Study participants were initially grouped into A, B, or C (described below), followed by

examination of changes in work status/job type

Changes in work status are from onset of MS to time of study in 1971; work type by

predetermined work groups 

Rozin et al. 1975191

Group A (n = 41): 

Completely handicapped with no 

rehabilitation potential 

Unskilled labor:

18% – onset of MS 

 0% – at time of study

Skilled, semiskilled, service: 

27% – onset of MS 

0% – at time of study

Clerical, professional, student: 

37% – onset of MS 

0% – at time of study

Housewives: 

2% – onset of MS 

0% – at time of study

Not working: 

6% – onset of MS 

100% – at time of study

Group C (n = 94): 

Currently working, holding 

previous jobs, or changed jobs

without intervention of 

rehabilitation

Unskilled labor:

22% – onset of MS 

8% – at time of study

Skilled, semiskilled, service: 

18% – onset of MS 

17% – at time of study

Clerical, professional, student: 

40% – onset of MS 

37% – at time of study

Housewives: 

12% – onset of MS 

38% – at time of study

Not working: 

8% – onset of MS 

0% – at time of study

Group B (n = 37): 

Potential for vocational rehabilitation, but 

unemployed or currently employed, but needs 

rehabilitation services for continuation of 

employment 

Unskilled labor:

28% – onset of MS 

3% – at time of study

Skilled, semiskilled, service: 

31% – onset of MS 

3% – at time of study

Clerical, professional, student: 

31% – onset of MS 

21% – at time of study

Housewives: 

5% – onset of MS 

8% – at time of study

Not working: 

5% – onset of MS 

65% – at time of study

Authors note that “of the 131 clients with working 

potential (groups B and C), only 18% stopped 

working because of MS” 

Abbreviations: CI = confidence interval; MS = multiple sclerosis

61
Table 18. Self-report on why individuals with MS continued or terminated employment 

Study Findings

Dyck et al. 2000176 Factors contributing to maintaining employment – 44% of currently employed

women were limited in the kind and amount of work they could do because of MS 

including: 

NR - fatigue “most common” 

16% - difficulty with standing and stairs 

15% - walking 

12% - writing 

11% - memory/concentration 

17% no longer working indicated “inability to negotiate reduced work hours” with 

their manager as reason for quitting work 

Edgley et al. 1991177 Study participants who indicated that they quit working because of MS symptoms 

were asked an open-ended question about types of symptoms (n = 313; 78% of 

sample) 

41% - Ambulation problems 

39% - Fatigue 

12% - Memory problems 

10% - Emotional problems 

12% - Visual difficulties 

 6% - Coordination problems

 2% - Pain 

 1% - Incontinence 

22% left for reasons unrelated to MS. Women (26%) were significantly more likely 

than men (11%) to cite reasons unrelated to MS as the primary cause of 

unemployment (χ2

 = 9.3, P < 0.01) 

Gulick et al. 1989182 Ranked comparison of conditions/situations that impede work performance (data on 

housewives and retired participants not described here): 

Fatigue:

Employed: 50%

Unemployed: 25% 

Walking: 

Employed: 12%

Unemployed: NR 

Standing: 

Employed: 8%

Unemployed: 12% 

Numbness: 

Employed: 8%

Unemployed: 5% 

Tremors: 

Employed: NR

Unemployed: 10% 

Use of wheelchair: 

Employed: NR

Unemployed: 10% 

Restricted mobility:

Employed: NR

Unemployed: 9% 

Stiffness: 

Employed: 5%

Unemployed: NR 

62
Table 18. Self-report on why individuals with MS continued or terminated employment (continued)

Study Findings

Scheinberg et al. 1980192 Among those having left employment, the most common reason for leaving among 

multiple reasons given by 182 subjects (categories not mutually exclusive): 

52.7% - Physical difficulty 

15.9% - Visual difficulty 

12.1% - Transportation difficulty 

 9.3% - Fatigue 

 1.3% - Emotional difficulty 

37.4% - Other (mainly marriage and/or pregnancy) 

Abbreviations: MS = multiple sclerosis; NR = not reported

63
Table 19. Conditions/situations impeding or enhancing performance of work/chores

Employed outside

home

Homemaker Unemployed Retired 

Conditions/situations impeding performance of work/chores (% of respondents citing) 

Fatigue 50% 51% 25% 25%

Balance 

10% 16% 11% 19%

Vision 12% 9% 11% 7%

High temperature 

7% 6% - -

Conditions/situations enhancing performance of work/chores (% of respondents citing)

Intermittent rest 21% 22% 12% 19%

Assistance with tasks 18% 22% 22% 11%

Adaptive aids 16% 18% 12% 26%

Self-pacing 13% 11% 12% 13%

Cool temperature - 8% - 6%

Positive attitude 6% 5% 5% 6%

64
Figure 1. Temporal relationship of pre-disability evaluation and occurrence of work disability

Onset 

of

symptoms

Diagnosis

Of

MS

Disability measure 

(e.g., EDSS)

Work disability

9-24 months

Work disability

9-24 months

EDSS = 6

Work disability

9-24 months

The experiences of three individuals over a 9- to 24-month time frame are depicted. Variability in the point at which 

an individual becomes unable to work is shown by the variable position of the arrow labeled “work disability.” 

Variability in the time of assessment of prognostic data is depicted by variation in the position of the left-pointing 

arrow. Variability in the duration of follow up is depicted by variation in the position of the right-pointing arrow. 

Abbreviations: EDSS = Expanded Disability Status Scale; MS = multiple sclerosis. 

38
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93
Listing of Excluded Studies 

All excluded articles listed below were reviewed in their full-text versions. Following each 

reference, in italics, is the primary reason for exclusion and the question (Q) for which the article 

was considered. If no Q is indicated, then the article was excluded a priori from the study for the 

reason given. Reasons for exclusion pertain only to the usefulness of articles for this study and 

are not intended as criticisms of the articles per se. “DA” indicates exclusion at the data 

abstraction stage. For reference, the questions are: 

Question 1a: What is the reliability of new McDonald criteria (incorporating supplementary 

information form radiologic and laboratory studies including MRI, VEP, and CSF analyses) 

compared with long-term follow-up diagnosis of clinically definite MS according to the Poser 

criteria? 

Question 1b: What is the inter-rater reliability of diagnosis of MS according to Poser 

or McDonald criteria among neurologists or between neurologists and non-neurologist 

physicians? 

Question 2: What clinical indicators, including particularly time-course of 

impairments, predict physical or mental impairment at 12 months?

Question 3a: Among patients with MS, do current disease-modifying treatments 

result in long-term improvements in physical or mental outcomes compared to placebo or 

usual care?

Question 3b: Among patients with MS, do treatments aimed at symptom management result 

in improvements in physical or mental outcomes compared to usual care?

Question 4: Among individuals with MS, what physical, mental, laboratory, or radiographic 

findings have been associated with inability to work? 

Question 5: Among individuals with MS, how does elevated temperature or other 

environmental factors impair the capacity to work? 

********** 

Abel NA, Smith RA. Intrathecal baclofen for treatment of 

intractable spinal spasticity. Arch Phys Med Rehab 

1994;75(1):54-8. Exclude-Q3-no results for placebo 

patients

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hyperintense lesions on magnetic resonance imaging in 

secondary-progressive MS patients. Eur Neurol 

1999;42(1):52-63. Exclude-Q2-no predictor with outcome

Albrecht H, Wotzel C, Erasmus LP, et al. Day-to-day

variability of maximum walking distance in MS patients 

can mislead to relevant changes in the Expanded Disability 

Status Scale (EDSS): average walking speed is a more 

constant parameter. Mult Scler 2001;7(2):105-9. ExcludeQ2-no long-term follow up

Allanson J, Bass C, Wade DT. Characteristics of patients 

with persistent severe disability and medically unexplained 

neurological symptoms: a pilot study. J Neurol Neurosurg 

Psych 2002;73(3):307-9. Exclude-no MS patients specified

Allen K, Blascovich J. The value of service dogs for people 

with severe ambulatory disabilities. A randomized 

controlled trial. JAMA 1996;275(13):1001-6. Exclude-no 

MS patients specified

Alusi SH, Worthington J, Glickman S, et al. A study of 

tremor in multiple sclerosis. Brain 2001;124(Pt 4):720-30. 

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three different ways of assessing tremor in multiple 

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Exclude-Q2-no long-term follow up

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reliability in assessing functional systems and disability on

the Kurtzke scale in multiple sclerosis. Arch Neurol 

1988;45(7):746-8. Exclude-Q2-background

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1999;5(4):216-9. Exclude-not relevant to study questions

Amato MP, Ponziani G. A prospective study on the 

95
prognosis of multiple sclerosis. Neurol Sci 2000;21(4 Suppl

2):S831-8. Exclude-Q2-wrong timeframe

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multiple sclerosis: the impact of depression, fatigue and

disability. Mult Scler 2001;7(5):340-4. Exclude-Q2-no 

long-term follow up

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studies in patients with definite multiple sclerosis. Clinical

relevance. Arch Neurol 1984;41(11):1197-202. ExcludeQ2-no analysis of predictors

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that is progressive from the time of onset: clinical 

characteristics and progression of disability. Arch Neurol 

1999;56(9):1138-42. Exclude-Q2-wrong timeframe

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and evoked potential (VEP and median nerve SEP) 

evolution in patients with MS and potentially related 

conditions. Acta Neurol Scand 1991;84(2):139-45. 

Exclude-Q2-no physical or mental outcome reported

Antel JP, Freedman MS, Brodovsky S, et al. Activated 

suppressor cell function in severely disabled patients with

multiple sclerosis. Ann Neurol 1989;25(2):204-7. ExcludeQ2-no long-term follow up

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prevalence, severity and impact in a clinic sample of 

multiple sclerosis patients. Pain 1994;58(1):89-93. 

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approaches in the treatment of ataxic multiple sclerosis: a

pilot study. Neurorehab Neural Repair 2001;15(3):203-

11.Exclude-Q3-no long-term symptom management

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2002;58(8):S23-S31. Exclude-review-background 

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80.Exclude-not relevant to study questions

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screening batteries to detect cognitive impairment in 

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AUSTIMS Research Group. Interferon-alpha and transfer

factor in the treatment of multiple sclerosis: a double-blind,

placebo-controlled trial. J Neurol Neurosurg Psych 

1989;52(5):566-74.Exclude-Q3-not current therapy

Baker DG. Multiple sclerosis and thermoregulatory

dysfunction. J Appl Physiol 2002;92(5):1779-80. ExcludeDA-Q5-review article 

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atrophy is associated with physical disability in multiple

sclerosis: semiquantitative magnetic resonance imaging and

relationship to clinical findings. J Neuroimag 

2001;11(2):129-36. Exclude-Q2-no long-term follow up

Balcer LJ. Clinical outcome measures for research in 

multiple sclerosis [review]. J Neuro-Ophthalmol 

2001;21(4):296-301. Exclude-Q2-no long-term follow up

Barkhof F. MRI in multiple sclerosis: correlation with 

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2002;15(3):239-45. Exclude-Q2-no long-term follow up

Barkhof F, Filippi M, van Waesberghe JH, et al. 

Interobserver agreement for diagnostic MRI criteria in 

suspected multiple sclerosis. Neuroradiology

1999;41(5):347-50. Exclude-Q1b-no Poser or McDonald 

criteria

Barkhof F, Filippi M, van Waesberghe JH, et al. Improving 

interobserver variation in reporting gadolinium-enhanced

MRI lesions in multiple sclerosis. Neurology 

1997;49(6):1682-8. Exclude-Q1b-no Poser or McDonald 

criteria 

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triad of gadolinium-DTPA MRI, EDSS, and CSF-MBP in 

relapsing multiple sclerosis patients treated with high-dose 

intravenous methylprednisolone. Neurology 1992;42(1):63-

7. Exclude-Q3-not RCT

Barnes D, Hughes RA, Morris RW, et al. Randomised trial 

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relapses of multiple sclerosis. Lancet 1997;349(9056):902-

6. Exclude-Q3-wrong timeframe

Basmajian JV. Lioresal (baclofen) treatment of spasticity in 

multiple sclerosis. Am J Phys Med 1975;54(4):175-7. 

Exclude-DA-Q3-data poorly described

Basmajian JV, Shankardass K, Russell D. Ketazolam once 

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Phys Med Rehab 1986;67(8):556-7. Exclude-DA-Q3-

outcomes poorly described

Basmajian JV, Shankardass K, Russell D, et al. Ketazolam 

treatment for spasticity: double-blind study of a new drug. 

Arch Phys Med Rehab 1984;65(11):698-701. Exclude-DAQ3-limited results reported for MS patients 

96
Basmajian JV, Yucel V. Effects of a GABA--derivative 

(BA-34647) on spasticity. Preliminary report of a doubleblind cross-over study. Am J Phys Med 1974;53(5):223-8. 

Exclude-DA-Q3-no separate results reported for MS 

patients

Basso MR, Beason-Hazen S, Lynn J, et al. Screening for 

cognitive dysfunction in multiple sclerosis. Arch Neurol 

1996;53(10):980-4. Exclude-Q2-no long-term follow up 

Battaglia MA, Serpero P, Bordo G, et al. Evaluation of the 

minimal record of disability in multiple sclerosis patients in

Genoa. Acta Neurol Scand Suppl 1984;101:92-9. ExcludeQ2-no long-term follow up

Bauer HJ, Krtsch U, Schipper R, et al. Disability rating 

with the IFMSS scales. Acta Neurol Scand Suppl 

1984;101:145-52. Exclude-Q2-no long-term follow up

Baumhefner RW, Tourtellotte WW, Syndulko K, et al. 

Quantitative multiple sclerosis plaque assessment with 

magnetic resonance imaging. Its correlation with clinical

parameters, evoked potentials, and intra-blood-brain barrier 

IgG synthesis. Arch Neurol 1990;47(1):19-26. Exclude-Q2-

no long-term follow up

Becker KG. APOE genotype is a major predictor of longterm progression of disability in MS. Neurology

2001;57(11):2148-9. Exclude-Q2-no long-term follow up

Beenakker EA, Oparina TI, Hartgring A, et al. Cooling 

garment treatment in MS: clinical improvement and 

decrease in leukocyte NO production. Neurology. 

2001;57(5):892-4. Exclude-DA-Q3-no specific symptom 

targeted 

Benedict RH, Shapiro A, Priore R, et al. 

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cognitively-impaired multiple sclerosis patients. Mult Scler 

2000;6(6):391-6. Exclude-DA-Q3-no comparison to usual 

care

Benesova Y, Niedermayerova I. New approach to 

evaluation of clinical state in patients with multiple

sclerosis. Bratislavske Lekarske Listy 2001;102(8):370-1. 

Exclude-Q2-no long-term follow up

Berg D, Maurer M, Warmuth-Metz M, et al. The 

correlation between ventricular diameter measured by

transcranial sonography and clinical disability and 

cognitive dysfunction in patients with multiple sclerosis. 

Arch Neurol 2000;57(9):1289-92. Exclude-Q2-no longterm follow up

Bergamaschi R, Romani A, Versino M, et al. Clinical

aspects of fatigue in multiple sclerosis. Funct Neurol 

1997;12(5):247-51. Exclude-Q2-no long-term follow up

Berger JR, Sheremata WA. Persistent neurological deficit 

precipitated by hot bath test in multiple sclerosis. JAMA. 

1983;249(13):1751-3. Exclude-review-background

Bernardi S, Buttinelli C, Grasso MG, et al. Evolution and 

severity markers in 233 MS patients. Riv Neurol 

1987;57(3):197-200. Exclude-Q2-wrong timeframe

Beutler E, Sipe J, Romine J, et al. Treatment of multiple

sclerosis and other autoimmune diseases with cladribine. 

Sem Hematol 1996;33(1 Suppl 1):45-52. Exclude-DA-Q3-

incomplete data

Bever CT Jr. The current status of studies of

aminopyridines in patients with multiple sclerosis [review].

Ann Neurol 1994;36(Suppl):S118-21. Exclude-reviewbackground

Bever CT Jr, Anderson PA, Leslie J, et al. Treatment with 

oral 3,4 diaminopyridine improves leg strength in multiple

sclerosis patients: results of a randomized, double-blind, 

placebo-controlled, crossover trial. Neurology

1996;47(6):1457-62. Exclude-Q3-no long-term symptom 

management

Bever CT Jr, Leslie J, Camenga DL, et al. Preliminary trial 

of 3,4-diaminopyridine in patients with multiple sclerosis. 

Ann Neurol 1990;27(4):421-7. Exclude-Q3-not RCT

Bever CT Jr, Young D, Anderson PA, et al. The effects of 

4-aminopyridine in multiple sclerosis patients: results of a 

randomized, placebo-controlled, double-blind,

concentration-controlled, crossover trial. Neurology

1994;44(6):1054-9. Exclude-Q3-wrong timeframe

Bjuro T, Fugl-Meyer AR, Grimby G, et al. Domestic work 

in patients with neuromuscular handicap. Scand J Rehab

Med Suppl 1978;6:193-6. Exclude-Q4-no findings relevant 

to question

Blake DJ, Bodine C. An overview of assistive technology

for persons with multiple sclerosis. J Rehab Res Develop

2002;39(2):299-312. Exclude-not relevant to study 

questions 

Blinkenberg M, Jensen CV, Holm S, et al. A longitudinal 

study of cerebral glucose metabolism, MRI, and disability 

in patients with MS. Neurology 1999;53(1):149-53. 

Exclude-Q2-wrong timeframe

Boggild M, Ford H. Multiple sclerosis. Clin Evid

2002;(7):1195-207. Exclude-review-background Q3

Bourdette DN, Prochazka AV, Mitchell W, et al. Health

care costs of veterans with multiple sclerosis: implications 

for the rehabilitation of MS. VA Multiple Sclerosis 

Rehabilitation Study Group. Arch Phys Med Rehab 

1993;74(1):26-31. Exclude-Q2-no long-term follow up

Bowen J, Gibbons L, Gianas A, et al. Self-administered

Expanded Disability Status Scale with functional system

scores correlates well with a physician-administered test.

97
Mult Scler 2001;7(3):201-6. Exclude-Q2-no long-term 

follow up. 

Branas P, Jordan R, Fry-Smith A, et al. Treatments for 

fatigue in multiple sclerosis: a rapid and systematic review. 

Health Technol Assess (Winchester, England) 

2000;4(27):1-61. Exclude-review-background.

Brassat D, Azais-Vuillemin C, YaouanquestionJ, et al. 

Familial factors influence disability in MS multiplex 

families. French Multiple Sclerosis Genetics Group. 

Neurology 1999;52(8):1632-6. Exclude-Q2-no long-term 

follow up

Brassington JC, Marsh NV. Neuropsychological aspects of 

multiple sclerosis [review]. Neuropsychol Rev

1998;8(2):43-77. Exclude-review-background Q2

Breitbart W, Rosenfeld B, Kaim M, et al. A randomized,

double-blind, placebo-controlled trial of psychostimulants 

for the treatment of fatigue in ambulatory patients with 

human immunodeficiency virus disease. Arch Intern Med 

2001;161(3):411-20. Exclude-no MS patients

Brex PA, Ciccarelli O, O'Riordan JI, et al. A longitudinal 

study of abnormalities on MRI and disability from multiple 

sclerosis. New Engl J Med 2002;346(3):158-64. ExcludeQ2-wrong timeframe

Brochet B, Guinot P, Orgogozo JM, et al. Double blind 

placebo controlled multicentre study of ginkgolide B in 

treatment of acute exacerbations of multiple sclerosis. The

Ginkgolide Study Group in multiple sclerosis. J Neurol 

Neurosurg Psych 1995;58(3):360-2. Exclude-Q2-wrong 

timeframe

Brown JR. Recent studies in multiple sclerosis: inferences 

on rehabilitation and employability. Mayo Clinic Proc

1969;44(10):758-65. Exclude-not relevant to study question 

Brown JR. Problems in evaluating new treatments for 

multiple sclerosis. Neurology 1980;30(7):8-11. Exclude-not 

relevant to study question 

Brown MG, Murray TJ, Sketris IS, et al. Cost-effectiveness 

of interferon beta-1b in slowing multiple sclerosis disability

progression. First estimates. Internat J Technol Assess 

Health Care 2000;16(3):751-67. Exclude-not relevant to 

study question

Brusaferri F, Candelise L. Steroids for multiple sclerosis 

and optic neuritis: a meta-analysis of randomized 

controlled clinical trials. J Neurol 2000;247(6):435-42. 

Exclude-DA-Q3-meta-analysis 

Bryant D, Chiaravalloti ND, DeLuca J. Objective 

measurement of cognitive fatigue in multiple sclerosis. 

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119
List of Acronyms/Abbreviations 

9-HPT 9-Hole Peg Test 

ADA Americans with Disabilities Act 

AHRQ Agency for Healthcare Research and Quality 

APOE apolipoprotein E 

BDI Beck Depression Inventory 

BRB-N Brief Repeatable Battery 

CI confidence interval 

CIS clinically isolated syndrome 

CSF cerebrospinal fluid 

CDMS clinically definite multiple sclerosis 

CT computed tomography 

Delta-9-THC delta-9-tetrahydrocannabinol 

DSS Disability Status Scale 

EDSS Expanded Disability Status Scale 

EPC Evidence-based Practice Center 

FIM Functional Independence Measure 

GNDS Guy’s Neurological Disability Scale 

IgG immunoglobulin-G 

IgM immunoglobulin-M 

IL-2 interleukin-2 

IV intravenous 

MDI Mobility Dysfunction Index 

MeSH Medical Subject Headings

MFIS Modified Fatigue Impact Scale 

MRI magnetic resonance imaging 

MS multiple sclerosis 

MSFC Multiple Sclerosis Functional Composite 

MS-FS MS-Specific Fatigue Scale 

NA not applicable 

NR not reported 

PASAT Paced Auditory Serial Addition Test 

PR prevalence ratio 

OR odds ratio 

QOL quality of life 

RCT randomized controlled trial 

SD standard deviation 

SDMT Symbol Digit Modalities Test 

SF-36 Medical Outcomes Study 36-Item Short-Form Health Survey 

SSA Social Security Administration 

SSDI Social Security Disability Insurance 

VEP visual evoked potential 

121
APPENDIXES 

to 

“Criteria to Determine Disability Related to Multiple Sclerosis” 

Prepared by the Duke Evidence-based Practice Center 

(Contract #290-02-0025) 
1

Appendix A. Excerpts from: Social Security 

Administration Office of Disability. Disability 

Evaluation Under Social Security, 2003. SSA Pub. No. 

64-039. Social Security Administration: Baltimore, MD. 

Section below has been excerpted from: 

Social Security Administration Office of Disability. Disability Evaluation Under Social 

Security, 2003. SSA Pub. No. 64-039. Social Security Administration: Baltimore, MD, pp. 92-

99.

11.00 Neurological 

A. Epilepsy. In epilepsy, regardless of etiology, degree of impairment will be determined according to 

type, frequency, duration, and sequelae of seizures. At least one detailed description of a typical 

seizure is required. Such description includes the presence or absence of aura, tongue bites, 

sphincter control, injuries associated with the attack, and postictal phenomena. The reporting 

physician should indicate the extent to which 

description of seizures reflects his own observations and the source of ancillary information. 

Testimony of persons other than the claimant is essential for description of type and frequency of 

seizures if professional observation is not available. 

Under 11.02 and 11.03, the criteria can be applied only if the impairment persists despite the fact that 

the individual is following prescribed antiepileptic treatment. Adherence to prescribed antiepileptic 

therapy can ordinarily be determined from objective clinical findings in the report of the physician 

currently providing treatment for epilepsy. Determination of blood levels of phenytoin sodium or 

other antiepileptic drugs may serve to indicate whether the prescribed medication is being taken. When 

seizures are occurring at the frequency stated in 11.02 or 11.03, evaluation of the severity of the 

impairment must include consideration of the serum drug levels. Should serum drug levels appear 

therapeutically inadequate, consideration should be given as to whether this is caused by individual 

idiosyncrasy in absorption or metabolism of the drug. Blood drug levels should be evaluated in 

conjunction with all other evidence to determine the extent of compliance. When the reported blood 

drug levels are low, therefore, the information obtained from the treating source should include the 

physician's statement as to why the levels are low and the results of any relevant diagnostic studies 

concerning the blood levels. Where adequate seizure control is obtained only with unusually large 

doses, the possibility of impairment resulting from the side effects of this medication must also be 

assessed. Where documentation shows that use of alcohol or drugs affects adherence to prescribed 

therapy or may play a part in the precipitation of seizures, this must also be considered in the 

overall assessment of impairment level. 

B. Brain tumors. The diagnosis of malignant brain tumors must be established, and the persistence 

of the tumor should be evaluated, under the criteria described in 13.00 B and C for neoplastic disease. 

In histologically malignant tumors, the pathological diagnosis alone will be the decisive 

criterion for severity and expected duration (see I 1.05A). For other tumors of the brain, the 
2

severity and duration of the impairment will be determined on the basis of symptoms, signs, and 

pertinent laboratory findings (11.05B). 

C. Persistent disorganization of motor function in the form of paresis or paralysis, tremor or other 

involuntary movements, ataxia and sensory disturbances (any or all of which may be due to cerebral, 

cerebellar, brain stem, spinal cord, or peripheral nerve dysfunction) which occur singly or in various 

combinations, frequently provides the sole or partial basis for decision in cases of neurological 

impairment. The assessment of impairment depends on the degree of interference with 

locomotion and/or interference with the use of fingers, hands and arms. 

D. In conditions which are episodic in character, such as multiple sclerosis or myasthenia 

gravis, consideration should be given to frequency and duration of exacerbations, length of 

remissions, and permanent residuals. 

E. Multiple sclerosis. The major criteria for evaluating impairment caused by multiple sclerosis are 

discussed in Listing 11.09. Paragraph A provides criteria for evaluating disorganization of motor 

function and gives reference to 11.0413 (11.04B then refers to 11.000). Paragraph B provides 

references to other listings for evaluating visual or mental impairments caused by multiple sclerosis. 

Paragraph C provides criteria for evaluating the impairment of individuals who do not have muscle 

weakness or other significant disorganization of motor function at rest, but who do develop 

muscle weakness on activity as a result of fatigue. 

Use of the criteria in 11.09C is dependent upon (1) documenting a diagnosis of multiple sclerosis, (2) 

obtaining a description of fatigue considered to be characteristic of multiple sclerosis, and (3) 

obtaining evidence that the system has actually become fatigued. The evaluation of the magnitude 

of the impairment must consider the degree of exercise and the severity of the resulting muscle 

weakness. 

The criteria in 11.09C deal with motor abnormalities which occur on activity. If the disorganization of 

motor function is present at rest, paragraph A must be used, taking into account any further increase 

in muscle weakness resulting from activity. 

Sensory abnormalities may occur, particularly involving central visual acuity. The decrease in 

visual acuity may occur after brief attempts at activity involving near vision, such as reading. This 

decrease in visual acuity may not persist when the specific activity is terminated, as with rest, 

but is predictably reproduced with resumption of the activity. The impairment of central visual 

acuity in these cases should be evaluated under the criteria in Listing 2.02, taking into account the fact 

that the decrease in visual acuity will wax and wane. 

Clarification of the evidence regarding central nervous system dysfunction responsible for the 

symptoms may require supporting technical evidence of functional impairment such as evoked 

response tests during exercise. 

F. Traumatic brain injury (TBI). The guidelines for evaluating impairments caused by cerebral 

trauma are contained in 11.18. Listing 11.18 states that cerebral trauma is to be evaluated under 

11.02, 11.03, 11.04, and 12.02, as applicable. 
3

TBI may result in neurological and mental impairments with a wide variety of posttraumatic 

symptoms and signs. The rate and extent of recovery can be highly variable and the long-term 

outcome may be difficult to predict in the first few months post-injury. Generally, the neurological 

impairment (s) will stabilize more rapidly than any mental impairment (s). Sometimes a mental 

impairment may appear to improve immediately following TBI and then worsen, or, conversely, it 

may appear much worse initially but improve after a few months. Therefore, the mental findings 

immediately following TBI may not reflect the actual severity of your mental impairment (s). The 

actual severity of a mental impairment may not become apparent until 6 months post-injury. 

In some cases, evidence of a profound neurological impairment is sufficient to permit a finding of 

disability within 3 months post-injury. If a finding of disability within 3 months post-injury is not 

possible based on any neurological impairment (s), we will defer adjudication of the claim until 

we obtain evidence of your neurological or mental impairments at least 3 months,

 post-injury. If a 

finding of disability still is not possible at that time, we will again defer adjudication of the claim 

until we obtain evidence at least 6 months post-injury. At that time, we will fully evaluate any 

neurological and mental impairments and adjudicate the claim. 

11.01 Category of Impairments, Neurological 

11.02 Epilepsy - convulsive epilepsy (grand mal or psychomotor), documented by detailed 

description of a typical seizure pattern, including all associated phenomena; 

occurring more frequently than once a month, in spite of at least 3 months of 

prescribed treatment. With: 

A. Daytime episodes (loss of consciousness and convulsive seizures) or 

B. Nocturnal episodes manifesting residuals which interfere significantly with activity during 

the day. 

11.03 Epilepsy -- nonconvulsive epilepsy (petit mal, psychomotor, or focal) documented 

by detailed description of a typical seizure pattern, including all associated 

phenomena, occurring more frequently than once weekly, in spite of at least 3 

months of prescribed treatment. With alteration of awareness or loss of 

consciousness and transient postictal manifestations of unconventional behavior or 

significant interference with activity during the day. 

11.04 Central nervous system vascular accident. With one of the following more than 3 months 

post-vascular accident: 

A. Sensory or motor aphasia resulting in ineffective speech or communication; 

or 

B. Significant and persistent disorganization of motor function in two extremities, 

resulting in sustained disturbance of gross and dexterous movements, or gait and station (see 

11.000). 
11.05 Brain tumors 

A. Malignant gliomas (astrocytoma - grades III and IV, glioblastoma multiforme), 

medulloblastoma, ependymoblastoma, or primary sarcoma; or 

B. Astrocytoma (grades I and II), meningioma, pituitary tumors, oligodendroglioma, 

ependymoma, clivus chordoma, and benign tumors. Evaluate under 11.02, 11.03, 11.04A or B, or 

12.02. 

11.06 Parkinsonian syndrome with the following signs: Significant rigidity, bradykinesia, or 

tremor in two extremities, which, singly or in combination, result in sustained disturbance of 

gross and dexterous movements, or gait and station. 

11.07 Cerebral palsy. With: A. IQ of 70 

or less; or

B. Abnormal behavior patterns, such as destructiveness or emotional instability; or 

C. Significant interference in communication due to speech, hearing, or visual defect; or 

D. Disorganization of motor function as described in 11.04B. 

11.08 Spinal cord or nerve root lesions, due to any cause with disorganization of 

motor function as described in 11.04B. 

11.09 Multiple sclerosis. With: 

A. Disorganization of motor function as described in 11.04B; or 

B. Visual or mental impairment as described under the criteria in 2.02, 2.03, 2.04, or 12.02; 

or 

C. Significant, reproducible fatigue of motor function with substantial muscle weakness on

repetitive activity, demonstrated on physical examination, resulting from neurological dysfunction

in areas of the central nervous system known to be pathologically involved by the multiple sclerosis

process. 

11.10 Amyotrophic lateral sclerosis. With: 

A. Significant bulbar signs; or

B. Disorganization of motor function as described in 11.04B. 11.11 Anterior 

poliomyelitis. With: 

4
5

A. Persistent difficulty with swallowing or breathing; or B. Unintelligible 

speech; or 

C. Disorganization of motor function as described in 11.04B. 11.12 

Myasthenia gravis. With: 

A. Significant difficulty with speaking, swallowing, or breathing while on prescribed therapy; 

or 

B. Significant motor weakness of muscles of extremities on repetitive activity against 

resistance while on prescribed therapy. 

11.13 Muscular dystrophy with disorganization of motor function as described in 

11.04B. 

11.14 Peripheral neuropathies. With disorganization of motor function as described in 11.04B, 

in spite of prescribed treatment. 

11.15 (Reserved) 

11.16 Subacute combined cord degeneration (pernicious anemia) with disorganization of 

motor function as described in 11.04B or 11.15B, not significantly improved by 

prescribed treatment. 

11.17 Degenerative disease not listed elsewhere, such as Huntington's chorea, 

Friedreich's ataxia, and spino-cerebellar degeneration. With: 

A. Disorganization of motor function as described in I 1.04B; or B. Chronic brain 

syndrome. Evaluate under 12.02. 

11.18 Cerebral trauma. 

Evaluate under the provisions of 11.02, 11.03, 11.04, and 12.02, as applicable. 

11.19 Syringomyelia. With: 

A. Significant bulbar signs; or 

B. Disorganization of motor function as described in 11.04B. 12.00 
6

Section below has been excerpted from: 

Social Security Administration Office of Disability. Disability Evaluation Under Social 

Security, 2003. SSA Pub. No. 64-039. Social Security Administration: Baltimore, MD, pp. 39-

40.

2.01 Category of Impairments, Special Senses and Speech 

2.02 Impairment of Visual Acuity. Remaining vision in the better eye after best correction 

is 20/200 or less. 

2.03 Contraction of Peripheral Visual Fields in the Better Eye. 

A. To 100 or less from the point of fixation; or 

B. So the widest diameter subtends an angle no greater than 20 degrees; or C. To 20 percent 

or less visual field efficiency. 

2.04 Loss of visual efficiency. The visual efficiency of the better eye after best correction is 20 

percent or less. (The percent of remaining visual efficiency is equal to the product of the percent of 

remaining visual acuity efficiency and the percent of remaining visual field efficiency.) 

2.05 (Reserved) 

2.06 Total Bilateral Ophthalmoplegia. 

2.07 Disturbance of Labyrinthine- Vestibular Function (Including Meniere's disease), 

characterized by a history of frequent attacks of balance disturbance, tinnitus, and progressive 

loss of hearing. With both A and B 

A. Disturbed function of vestibular labyrinth demonstrated by caloric or other vestibular 

tests; and 

B. Hearing loss established by audiometry. 
7

Section below has been excerpted from: 

Social Security Administration Office of Disability. Disability Evaluation Under Social 

Security, 2003. SSA Pub. No. 64-039. Social Security Administration: Baltimore, MD, pp. 

112-114

12.01 Category of Impairments - Mental 

12.02 Organic Mental Disorders: Psychological or behavioral abnormalities associated with a 

dysfunction of the brain. History and physical examination or laboratory tests demonstrate 

the presence of a specific organic factor judged to be etiologically related to the abnormal 

mental state and loss of previously acquired functional abilities. 

The required level of severity for these disorders is met when the requirements in both A and B are 

satisfied, or when the requirements in C are satisfied. 

A. Demonstration of a loss of specific cognitive abilities or affective changes and the 

medically documented persistence of at least one of the following: 

1. Disorientation to time and place; or 

2. Memory impairment, either short-term (inability to learn new information), intermediate, or 

long-term (inability to remember information that was known sometime in the past); or 

3. Perceptual or thinking disturbances (e.g., hallucinations, delusions); or 4. Change in 

personality; or 

5. Disturbance in mood; or 

6. Emotional lability (e.g., explosive temper outbursts, sudden crying, etc.) and impairment in 

impulse control; or 

7. Loss of measured intellectual ability of at least 15 I.Q. points from premorbid levels or 

overall impairment index clearly within the severely impaired range on neuropsychological 

testing, e.g., Luria-Nebraska, Halstead-Reitan, etc; 

AND 

B. Resulting in at least two of the following: 

1. Marked restriction of activities of daily living; or 

2. Marked difficulties in maintaining social functioning; or 

3. Marked difficulties in maintaining concentration, persistence, or pace; or 4. Repeated episodes 
8

of decompensation, each of extended duration; OR 

C. Medically documented history of a chronic organic mental disorder of at least 2 years' duration that 

has caused more than a minimal limitation of ability to do basic work activities, with symptoms or 

signs currently attenuated by medication or psychosocial support, and one of the following: 

1. Repeated episodes of decompensation, each of extended duration; or 

2. A residual disease process that has resulted in such marginal adjustment that even a minimal increase 

in mental demands or change in the environment would be predicted to cause the individual to 

decompensate; or 

3. Current history of 1 or more years' inability to function outside a highly supportive living 

arrangement, with an indication of continued need for such an arrangement. 

12.03 Schizophrenic, Paranoid and Other Psychotic Disorders: Characterized by the onset of 

psychotic features with deterioration from a previous level of functioning. 

The required level of severity for these disorders is met when the requirements in both A and B are 

satisfied, or when the requirements in C are satisfied. 

A. Medically documented persistence, either continuous or intermittent, of one or more of the 

following: 

1. Delusions or hallucinations; or 

2. Catatonic or other grossly disorganized behavior; or 

3. Incoherence, loosening of associations, illogical thinking, or poverty of content of speech if 

associated with one of the following: 

a. Blunt affect; or 

b. Flat affect; or 

c. Inappropriate affect; 

OR 

4. Emotional withdrawal and/or isolation. 
Appendix B. Search Strategies 

Search Strategy #1: Employment 

Database: MEDLINE <1966 to April Week 4 2003>

--------------------------------------------------------------------------------

1. multiple sclerosis/ 

2. multiple sclerosis.tw.

3. exp myelitis, transverse/ 

4. transverse myelitis.tw.

5. optic neuritis.tw.

6. exp optic neuritis/ 

7. or/1-6 

8. disability evaluation/ or work capacity evaluation/ 

9. exp EMPLOYMENT/ 

10. "Activities of Daily Living"/ 

11. or/8-9 

12. or/8-10 

13. 7 and 11 

14. limit 13 to (human and english language)

15. 7 and 10 

16. 15 not 13 

17. limit 16 to (human and english language)

Search #2: Reliability of diagnostic criteria for MS 

Database: MEDLINE <1966 to April Week 4 2003>

--------------------------------------------------------------------------------

1 multiple sclerosis/di (4293) 

2 mcdonald.mp. (344) 

3 multiple sclerosis/ (20934) 

4 Reproducibility of Results/ or Observer Variation/ or Psychometrics/ (102929) 

5 poser.mp. (116)

6 reliability.mp. (37919) 

7 4 or 6 (126832)

8 or/1-2,5 (4705) 

9 7 and 8 (149) 

10 2 or 5 (457) 

11 10 and 3 (102)

12 or/1,11 (4350) 

13 7 and 12 (143)

14 from 13 keep 1-143 (143) 

Search #3: Effectiveness of treatment for fatigue in MS 

Database: MEDLINE <1966 to April Week 4 2003>

--------------------------------------------------------------------------------

1 multiple sclerosis.tw. (20468)

2 exp Multiple Sclerosis/ (21587)

3 Fatigue/ (8057)

4 fatigue.tw. (21592) 

5 Amantadine/ (2571) 

6 amantadine.tw. (1889) 

7 Pemoline/ (408)

8 exp Aminopyridines/ (6784) 

9 4-aminopyridine.tw. (3341) 

10 3,4-diaminopyridine.mp. (385)

11 exp Potassium Channel Blockers/ (6598) 

9
12 Antidepressive Agents/ or exp Antidepressive Agents, Tricyclic/ or Sertraline/ or Fluoxetine/ or Fluvoxamine/ or 

Paroxetine/ or exp Serotonin Uptake Inhibitors/ or ssri.mp. or exp Antidepressive Agents, Second-Generation/ (70859) 

13 Central Nervous System Stimulants/ (5345) 

14 modafinil.mp. (202) 

15 or/5-14 (90835) 

16 or/1-2 (24958) 

17 15 and 16 (189) 

18 or/3-4 (25266) 

19 18 and 16 (367) 

20 17 and 19 (45)

21 from 20 keep 1,3-4,6-7,15,19,26 (8) 

22 from 17 keep 1-189 (189) 

Search #4: Other symptom therapy and disease-modifying therapies 

Database: MEDLINE <1966 to June Week 3 2003>

--------------------------------------------------------------------------------

1 randomized controlled trials/ (29246) 

2 random allocation/ (48831) 

3 double-blind method/ (74469)

4 single-blind method/ (7355) 

5 randomized controlled trial.pt. (176910) 

6 1 or 2 or 3 or 4 or 5 (252007) 

7 animal/ (3458955) 

8 human/ (8124713) 

9 7 and 8 (776249) 

10 7 not 9 (2682706) 

11 6 not 10 (237650) 

12 clinical trial.pt. (360658) 

13 exp clinical trials/ (147492) 

14 (clin$ adj trial$).tw. (71615) 

15 ((singl$ or doubl$ or trebl$ or tripl$) adj (blind$ or mask$)).tw. (71153) 

16 placebos/ (23020) 

17 placebo$.tw. (79266) 

18 random$.tw. (263309) 

19 research design/ (37382) 

20 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 (621803) 

21 20 not 10 (578657) 

22 comparative-study/ (1052532)

23 exp evaluation studies/ (462029) 

24 follow-up studies/ (269186) 

25 prospective-studies/ (162165)

26 (control$ or prospectiv$ or volunteer$).tw. (1344071) 

27 22 or 23 or 24 or 25 or 26 (2709523) 

28 27 not 10 (2072206) 

29 21 not 11 (350750) 

30 28 not (21 or 11) (1666124) 

31 19991$.em. (119004) 

32 200$.em. (1786129) 

33 or/31-32 (1905133) 

34 Anti-Dyskinesia Agents/ or Muscle Relaxants, Central/ or Baclofen/ or MUSCLE SPASTICITY/ or spasticity.mp. or 

Spasm/ or Botulinum Toxin Type A/ or Botulinum Toxins/ (19461) 

35 Diazepam/tu [Therapeutic Use] (3612) 

36 exp DEPRESSION/dh, dt, rh, th [Diet Therapy, Drug Therapy, Rehabilitation, Therapy] (10148) 

37 exp REHABILITATION/ or exp REHABILITATION CENTERS/ or exp REHABILITATION, VOCATIONAL/ (139505) 

38 bladder, neurogenic/ or urination disorders/ or exp urinary incontinence/ or urinary retention/ (24827) 

39 or/34-38 (193826) 

40 exp multiple sclerosis/ or multiple sclerosis.mp. (25332) 

41 39 and 40 (1544) 

42 11 and 41 (111) 

43 29 and 41 (150) 

44 30 and 41 (319) 

10
45 11 and 40 and 33 (277) 

46 42 or 45 (359) 

47 limit 46 to english language (331) 

Search #5: Predictive value of McDonald diagnostic criteria and components

Database: MEDLINE <1966 to April Week 4 2003>

--------------------------------------------------------------------------------

1 multiple sclerosis/di (4293) 

2 mcdonald.mp. (344) 

3 multiple sclerosis/ (20934) 

4 2 and 3 (15) 

5 Magnetic Resonance Imaging/ (103327) 

6 3 and 5 (2359)

7 follow-up studies/ (265132) 

8 6 and 7 (182) 

9 prospective studies/ (158042)

10 6 and 9 (88) 

11 8 or 10 (246) 

12 "sensitivity and specificity"/ (98408) 

13 2 and 12 (3) 

14 12 and 1 (171)

15 or/4,11,13-14 (408) 

16 or/4,8,13-14 (352) 

17 15 not 16 (56) 

18 from 15 keep 1-408 (408) 

19 Reproducibility of Results/ or Observer Variation/ or Psychometrics/ (102929) 

20 poser.mp. (116)

21 19 and 20 (4) 

22 19 and 2 (5) 

23 19 and 1 (112)

24 Evoked Potentials, Visual/ (8416) 

25 3 and 7 and 24 (37) 

26 oligoclonal bands.mp. (535) 

27 Cerebrospinal Fluid/ (9812) 

28 3 and 7 and 27 (4) 

29 3 and 7 and 26 (15) 

30 or/15,21-23,25,28-29 (529) 

31 limit 30 to (human and english language) (465) 

32 from 31 keep 1-465 (465) 

11
Appendix C. Instructions for Title and Abstract 

Screening 

Rate each citation as “include” or “exclude” If article doesn’t meet criteria but you think it may

provide useful background data or be a useful source to identify relevant articles (e.g. a recent on 

topic review article) then mark it as “include”. 

Bear in mind the following questions and criteria. You do not need to indicate the question for

which the citation is included. 

Question 1: 

(a) What is the reliability of new McDonald criteria (incorporating supplementary 

information form radiologic and laboratory studies including MRI, VEP, and 

CSF analyses) compared with long-term follow-up diagnosis of clinically 

definite MS according to the Poser criteria? 

• Patients with suspected MS

•

•

•

Compare new McDonald criteria with clinical diagnosis (based on clinical follow-up) 

At least 20 patients 

(b) What is the inter-rater reliability of diagnosis of MS according to Poser or 

McDonald criteria among neurologists or between neurologists and nonneurologist physicians? 

Multiple physicians assess diagnosis of MS on same actual or simulated patients. 

Question 2:

What clinical indicators, including particularly time-course of impairments, predict 

physical or mental impairment at 12 months?

• Patients with suspected MS

•

•

Studies must have follow-up patients for at least 12 months and provide data in the 9-24 

month time frame (studies that provide 5-year outcomes for example, would be too distant 

from the mandated 12-month or permanent time frame for SSA disability determination). 

Ideally, studies should have large numbers of patients, a population-based incidence cohort, 

and describe the clinical course in enough detail to assess the physical and mental

abnormalities at around 12 months after baseline assessment (this does not need to be 12-

months from time of diagnosis). Pragmatically, several types of studies might be useful. 

1. Large population based cohorts that are not necessarily incidence cohorts. 

2. Smaller studies with careful longitudinal follow-up at defined time points (e.g. RCTs) 

3. Retrospective case series 

4. Case-control studies comparing patients with continued impairments at 12-months to patients 

with recovery from exacerbations. 

12
Question 3:

(a) Among patients with MS, do current disease-modifying treatments result in 

long-term improvements in physical or mental outcomes compared to placebo or 

usual care?

• Study design must be randomized controlled trial 

•

•

•

•

•

•

•

•

No restriction on study population’s degree of impairment (i.e. low EDSS ok) 

Duration of study must be at least 12 months 

Outcomes of interest would include measures of physical functioning (e.g. EDSS), cognitive 

functioning, and work/employment outcomes at 12 months or more, as well as relapse rate. 

(b) Among patient with MS, do treatments aimed at symptom management result in 

improvements in physical or mental outcomes compared to usual care? 

Symptom management includes: 

* Bladder management (but not short-term UTI) 

 * Spasticity treatment 

* Fatigue treatment eg. exercise 

 *Depression treatment 

*Comprehensive rehabilitation programs 

Study design must be randomized controlled trial 

Populations with impairments severe enough that they would clearly meet the 

current medical listing criteria (eg. EDSS≥6) may be excluded 

Outcomes of interest would include measures of physical or mental functioning

that are either generic, or specific to the symptom treated, as well as

work/employment outcomes. 

Duration of study may be less than 12 months (at least 3 weeks) 

Question 4:

Among individuals with MS, what physical, mental, laboratory, or radiographic findings 

have been associated with inability to work?

Study design may include cohort or case control studies or small series (ethnographic studies) 

and may be cross-sectional or longitudinal. 

•

•

•

•

Study must describe the association between work/employment status (by self-reported 

inability to work, work status, or by determination of disability) and certain physical or 

mental findings 

would generally use univariate or multivariable analysis to determine association between 

work ability and a variety of physical or mental findings. 

We will not be exclusive with regard to the physical or mental findings considered. 

Question 5:

Among individuals with MS, how does elevated temperature or other environmental factors 

impair the capacity to work?

Elevated temperature (heat, hot environmental temperature, work conditions that might lead 

to elevated body temperature [eg. clothing]) is the only environmental issue that is 

particularly relevant to MS. 

•

• Study must describe work/employment status (by self-reported inability to work, work status, 

or by determination of disability)

13
Appendix D. Decision Rules for Full-text Screening 

Version 3: June 5, 2003 

GENERAL:

Study relevant to at least one of 5 key research questions? 

 If yes, then include 

 If no, then exclude 

PATIENTS: 

Are most of all of the patients in this study adult (over 17 years old)? 

 If yes, then include 

 If no, then exclude 

Have some or all of the patients been diagnosed with possible, probable or definite MS? 

 If yes, then include 

 If no, then exclude 

If the study includes a mixed population (MS + other underlying disease), then include if at least one of 

the following criteria are met: 

 Reports results separately for MS population 

 Explicitly states there is no difference in outcome between MS and other population 

 MS population represents overwhelming majority (>90%) of total population 

Otherwise, exclude. 

QUESTION 1a: 

Does study describe prospective validation of McDonald criteria or equivalent (MRI, VEP, or CSF 

analyses) according to long-term follow-up diagnosis of clinically-definite MS (according to Poser 

criteria)? 

Exclude article if: 

 Not a McDonald criterion (see attached Table 3 from McDonald article) 

 Not a longitudinal study 

 No long-term diagnosis of clinically definite MS 

 Not standard MRI technology such as magnetization transfer. Note: “Standard” MRI technologies 

include increased T2 images, enhancement, or flare.

Otherwise, include. (Retrospective studies are okay if they include a McDonald criterion). 

QUESTION 1b: 

Does study describe inter-rater reliability (IRR) of MS diagnosis according to Poser or McDonald criteria 

among neurologists or between neurologists and non-neurologist physicians? 

Exclude article if: 

 Reports IRR for MRI techniques other than T2 or gadolinium enhancing. For example, volume

and magnetization transfer would be excluded. 

Otherwise, include. 

14
QUESTION 2: 

Does study describe the association of clinical indicators (signs, laboratory or other objective findings 

including clinical course, number or frequency of exacerbations) with physical/mental health impairment 

(e.g., EDSS, cognitive function, fatigue, 6-minute walk, depression scale) 9-24 months later? MUST BE 

LONGITUDINAL STUDIES; NO CROSS-SECTIONAL STUDIES. 

Exclude article if: 

 No longitudinal follow-up (e.g., cross-sectional design). 

 Time frame is too long (>24 mo) or too short (< 9 months). Article must report data for some

point in time between 9 and 24 months. 

 No candidate predictors of outcome are considered, i.e., signs, lab, or other objective findings, 

including clinical course. 

 No assessment of physical or mental health outcomes.

Otherwise, include. 

QUESTION 3: 

Does study address question of efficacy of a treatment aimed at modifying the disease or alleviating a 

symptomatic manifestation of MS? 

Exclude article if: 

 Not a RCT 

For disease modifying treatments:

Exclude article if: 

 Not a “current” treatment, e.g. other than: beta interferon (Avonex, Betaseron, Rebif), glatiramer 

acetate (Copaxone), mitoxantrone (Novantrone), glucocorticoids. 

Apply this exclusion to disease modifying treatments only.

 Wrong time-frame, that is, too long (> 24 mo) or too short (< 9 mo) 

Apply this exclusion to disease modifying treatments only.

 Outcome measure is NOT a measure of improvement in physical or mental function (e.g., 

proportion of patients with improved EDSS ≥ 1 point). NOTE: Lack of progression is not 

sufficient for this purpose. 

Otherwise, include. 

For symptom management treatments: 

Exclude article if: 

 Not a long-term symptom management treatment, such as bladder management, spasticity; 

fatigue treatment (e.g. exercise); depression treatment; comprehensive rehabilitation program. 

Short-term symptom management (e.g., UTI treatment) would be excluded. 

Otherwise, include. 

QUESTIONS 4-5: 

Does the study report direct or indirect measures of ability to work aimed at MS patients? 

 If yes, then include 

 If no, then exclude. 

15
Note: “Indirect” measures would include self-reported information such as employment status; measuring 

performance of non-work tasks (e.g., 6-min walks, ADL) does not meet our definition of “indirect” 

measures of ability to work. 

16
Appendix E. Evidence Table/Data Abstraction Templates

Question 1a: What is the reliabilit

y of ne

w M

cDonald criteria (incorporating supplementar

y information from radio

studies including MRI, VEP, and CSF analyses) compared 

with long-term follo

w-u

p diagnosis of clinically definite 

Poser criteria? 

17 

Study

Stud

y Design Patients Clinical

Presentation

A

d

ditional Data Used 

for Diagnosis

[A

bstractor please 

complete] 

Results 

[A

bstractor please complete] 

Com

[A

bst

StudyID Prospective/ 

Retrospective cohort studyCase-controlstudyDuration of follow up: Location: 

Prospective studies:Total no. at start:Dropouts: Completed: Retrospective studies: N = (

with indication 

of time point) Both types of studies: Age: 

[Essentially inclusion criteria; see left hand column of McDonald table] 

1) MRI [indicate type of MRI; type of findings reported/analyzed; and frequency of repeat scans, if any] 2) CSF [indicate ho

w test 

conducted and how“abnormal” defined] 3) VEP [indicate ho

w

test conducted and ho

w

“abnormal” defined] 

[Describe data for each predictor/test considered. Report both relative measures (Hazard ratios, etc.) and absolute rates (e.g., percentages of patients with/

without positive CSF who 

met Poser criteria at long-ter

m follow up; 

sensitivity and specificity may also be reported); focus should be primarily onabsolute rates. Bear in mind that data may be reported for more than one longterm follo

w-up time point.] 

1) 2) 3) 4) 5) 6) 

[IF ARPLEA[COMAFFEINTERwhen by aut“invesunder[Pleasfit betwadditioand spQ

UAL

PatienregardYes/NFollow (retroscontroThis aas appQuestQuestQuestQuestQuestQuestQuest
Question 1b: What is the inter-rater reliability of diagnosis of MS according to Poser or McDonald criteria among 

between neurologists and non-neurologist physicians? 

Study Study Design Patients & 

Physicians 

Patients’ Clinical Presentation

Diagnostic Criteriaand Data Available

Results 

[Abstractor please complete] 

Com

[Abst

StudyID Cross-sectional 

diagnostic test studyMulticenter/ Single-center Setting: Location: 

Patients: N = Age: Physicians: N = (broken down by specialty type)

[Essentiallyinclusion criteria; see left hand column of McDonald table] 

1) Diagnostic criteria used: Poser/McDonald/Other 2) Data available for diagnosis (clinical data, neuro exam, MRI, CSF, VEP, lab tests, other): 

[Describe data on agreement/ disagreement on MS diagnosis between evaluating physicians. If possible, report raw data needed to complete 2x2-type table, as well as agreement statistics (kappa scores, sensitivity, specificity,simple agreement, etc.).] 

[IF ARPLEA[COMAFFEINTERwhen by aut“invesunder[Pleasfit betwadditioand sp[Pleasany) aobservQUALEvaluaanotheDid stspectrcasesThis aas appQuestQuestQuestQuestQuestQuestQuest

18 
Question 2: What clinical indicators, including particularly time-course of impairments, predict physical or menta

months? 

19 

Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Possible 

Predictors Considered

Results Com

StudyID Inclusion: 

[MS dx, definite/probable,relapse frequency, EDSS] Exclusion: 

Retrospective/ Prospective; population-based/ not populationbased; cohort study (incl. RCTs)/ case series/ casecontrol studyDuration of followup: 

Prospective studies: Total no. at start (if different diagnostic categories, give subtotals by diagnosis): Completed: Dropouts: Retrospective studies: N = (with indication of timepoint) Both types of studies: Age: Baseline measures of physical and mental functioning:

1) 2) 3) 4) 5) 6) 

[Describe data for each predictor considered. Report both relative measures (Hazard ratios, etc.) and absolute rates (e.g., percentages of men and women with EDSS > 6 at 12 mo), but focus primarily onabsolute rates. Bear in mind that data may be reported for more than one time point in the 9- to 24-mo time frame of interest to us.] 1) 2) 3) 4) 5) 6) 

IF ARPLEACOMMAFFEINTERrate) – discusthemsthat stQUALStudy Yes/NSampcommdiseasSampearly pdiseasFollow 

(retrosstudy)Outcoscale?OutcoYes/NIf subgidentifa) was prognb) was Yes/NThis aas appQuestQuestQuestQuestQuestQuest
20 

Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Possible 

Predictors Considered

Results Com

Quest
Question 3a: Among patients with MS, do current disease-modifying treatments result in long-term improvements 

outcomes compared to placebo or usual care? 

21 

Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results 

[Abstractor please complete] 

Com

[Abst

StudyID Inclusion: [MS dx, 

definite/probable,relapse frequency, EDSS] Exclusion: 

RCT (parallelgroup, openlabel/doubleblind, singlecenter/ multicenter)Duration of study treatment/followup: Provider specialty:Location: 

No. of patients randomized: [if different diagnostic categories, give subtotals by diagnosis] Dropouts: Completed: Age: Baseline EDSS: Baseline relapse rate: 

1) Agent, route, dose 2) 3) 

[If outcome/data not reported, type “NR.” For each outcome, please reportquantitative data (e.g., means ± SD orproportions [numbers of patients/total]) and statistical significance (with direction of effect). Please specify time points at which outcomes measured (9-24 mo).] 1) Physical functioning (primarily EDSS): Definition of “improvement”: Proportion of patients with “improvement”: Other (non-improvement) outcomes [list outcome measures, do not report data]: 2) Relapse frequency:Definition of “relapse”: Definition of “improvement” [includes decrease in relapse rate]: Proportion of patients with “improvement”: Other (non-improvement) outcomes [report non-improvement data on relapse rates; otherwise simply list outcome measures]: 3) Cognitive functioning [describe scale/ instrument used]:Definition of “improvement”: Proportion of patients with “improvement”: Other (non-improvement) outcomes [list outcome measures, do not report data]: 4) Work or employment outcomes: Definition of “improvement”: 

[IF ARPLEA[COMAFFEINTERrate) – discusthemsthat stQUALDescrMethodescriConceYes/NDescrPatienInvestOutcoYes/NNo. of Yes/NThis aas appQuestQuestQuestQuestQuestQuestQuest
22 

Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results 

[Abstractor please complete] 

Com

[Abst

Proportion of patients with “improvement”: Other (non-improvement) outcomes [list outcome measures, do not report data]: 5) Quality of life [describe scale/ instrument used]: Definition of “improvement”: Proportion of patients with “improvement”: Other (non-improvement) outcomes [list outcome measures, do not report data]: 6) Adverse events (no. of pts reporting AEs, most common AEs [especially when significant between-group difference], and no. of dropouts due to AEs): 
Question 3b: Among patients with MS, do treatments aimed at symptom management result in improvements in p

outcomes compared to usual care?

23 

Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results 

[Abstractor please complete] 

Com

[Abst

StudyID Inclusion: [MS dx, 

definite/probable,relapse frequency, EDSS] Exclusion: 

RCT (crossover/ parallel-group, open-label/ double-blind, single-center/ multicenter)Duration of study treatment/followup: Provider specialty:Location: 

No. of patients randomized: [if different diagnostic categories, give subtotals by diagnosis] Dropouts: Completed: Age: Baseline EDSS: 

1) Agent, route, dose 2) 3) If crossover, was washout period described? 

[If outcome/data not reported, type “NR.” For each outcome, please reportquantitative data (e.g., means ± SD orproportions [numbers of patients/total]) and statistical significance (with direction of effect). Please specify time points at which outcomes measured (earlier time points acceptable).] 1) Symptom-specific functional status/ quality-of-life outcomes [describe scale/instrument used]: Definition of “improvement”: Proportion of patients with “improvement”: Other (non-improvement) outcomes [list outcome measures, do not report data]: 2) Physical functioning (primarily EDSS): Definition of “improvement”: Proportion of patients with “improvement”: Other (non-improvement) outcomes [list outcome measures, do not report data]: 3) Cognitive functioning [describe scale/ instrument used]:Definition of “improvement”: Proportion of patients with “improvement”: Other (non-improvement) outcomes [list outcome measures, do not report data]: 4) Work or employment outcomes: Definition of “improvement”: 

[IF ARPLEA[COMAFFEINTERrate) – discusthemsthat stQUALDescrMethodescriConceYes/NDescrPatienInvestOutcoYes/NNo. of Yes/NCrossPeriod Yes/NWashNo. of descriWere of the analysThis aas nec

QuestQuestQuest
24 

Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results 

[Abstractor please complete] 

Com

[Abst

Proportion of patients with “improvement”: Other (non-improvement) outcomes [list outcome measures, do not report data]: 5) Generic quality-of-life outcomes [describe scale/ instrument used]:Definition of “improvement”: Proportion of patients with “improvement”: Other (non-improvement) outcomes [list outcome measures, do not report data]: 6) Adverse events (no. of pts reporting AEs, most common AEs [especially when significant between-group difference], and no. of dropouts due to AEs): 

QuestQuestQuestQuest
Question 4: Among individuals with MS, what physical, mental, laboratory, or radiographic findings have been as

to work? 

25 

Study Selected

Inclusion/ Exclusion Criteria 

Study Design Patients Findings

Considered

[Please verify/edit as needed]

Results [Abstractor please complete] 

Com

[Abs

StudyID Inclusion: 

[MS dx, definite/ probable, relapse frequency, EDSS] Exclusion: 

Retrospective/ Prospective/ Crosssectional; populationbased/ not populationbased; cohort study(incl. RCTs)/ case series/ case-control studyLocation/recruitment: Data collection: 

N = (if different diagnostic categories, give subtotals by diagnosis) Age: Baseline measures of physical and mental functioning: Baseline work status: 

1) Physical: 2) Mental: 3) Laboratory: 4) Radiographic: 5) Other: 

[Begin by indicating how work abilitywas assessed (stating explicitlywhether the measure was direct orindirect). For each finding possibly associated with work ability, please report both relative measures of association (Hazard ratios, etc.) and absolute rates (e.g., percentages of patients with EDSS > or < 4 who reported that they are still employed), but focus primarily on absolute rates.] 1) 2) 3) 4) 5) 6) 

[IF AEXCHER[COMAFFEINTEwhen raise“inveundeQUAStudbaseFolloWork wideWork fashiIf subidenta) waprogYes/b) waYes/This as apQuesQuesQuesQuesQuesQuesQues
Question 5: Among individuals with MS, how does elevated temperature or other environmental factors impair the 

26 

Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Environmental 

Factors Considered[Abstractor please complete]

Results 

[Abstractor please complete] 

Com

[Abst

StudyID Inclusion: 

[MS dx, definite/probable,relapse frequency, EDSS] Exclusion: 

Retrospective/ Prospective; population-based/ not populationbased; cohort study (incl. RCTs)/ case series/ casecontrol study

N = (if different diagnostic categories, give subtotals by diagnosis) Age: Baseline measures of physical and mental functioning:

1) Elevated temperature: 2) Other (please specify): 

[Begin by indicating how work ability was assessed (stating explicitly whether the measure was direct or indirect). For each environmental factor possibly associated with work ability, please report both relative measures of association (Hazard ratios, etc.) and absolute rates (e.g., percentages of patients in jobs with hot vs. cool working environments who reported that they are still employed), but focus primarily on absolute rates.] 1) 2) 3) 4) 5) 6) 

IF ARPLEACOMMAFFEINTERrate) – discusthemsthat stQUALStudy Yes/NFollow (retrosstudy)Work used sWork fashioIf subgidentifa) was prognb) was Yes/NThis aas appQuestQuestQuestQuestQuestQuestQuest
Appendix F. Evidence Tables

27 

Evidence Table 1a. Diagnostic reliability of McDonald criteria Study Study Design Patients Clinical

Presentation

Additional DataUsed for Diagnosis

Results Com

Barkhof, Filippi, Miller, et al., 1997 

Prospective cohort studyDuration of follow up: Minimum of 2 yr; median followup among patients not diagnosed with MS at end of study was 39 mo (range, 23-96 mo) Location: 3 sites in Europe (1 each in The Netherlands, Italy, and UK) 

Total no. at start:91 Dropouts: 17 (7 lost to follow up; 10 given definitive diagnosis other than MS and excluded from analysis) Completed: 74 Age: NR 

Clinically isolated syndrome suggestiveof MS and not attributable to other diseases; among those completing study (n = 74), presenting symptom was optic neuritis in 40 patients, spinal cord syndrome in 22, and brainstem/ cerebellum syndrome in 12 

Baseline MRIs performedat a median of 4 wk(range, 1-20 wk) after onset of symptoms Clinically definite MS was diagnosed when clinical signs or symptoms developed in other areas of the central nervous system after a period of at least 1 month, and when other diagnoses had been excluded byappropriate clinical tests 1) MRI –not used in the diagnosis of clinicallydefinite MS 2) CSF- not used in the diagnosis of clinicallydefinite MS 3) VEP – not used in the diagnosis of clinicallydefinite MS MRIs were analyzed during a single session by consensus of twoobservers who were unaware of the clinical findings 

This study examined various MRI lesion characteristics and used regression analysis to determine the utility of each characteristic with regard to diagnosis. Because previous criteria have demonstrated significant sensitivity, but low specificity, the authors then developed a model with greater positive predictive value based on the results of regression analysis. 1) By regression analysis, the fourdichotomized MRI parameters that demonstrated the greatest diagnostic utility were presence of 1 or moregadolinium-enhancing lesions, 1 or more infratentorial lesions, 1 or morejuxtacortical lesions, and 3 or moreperiventricular lesions. The final regression model based on the presence of 3 or more of these 4 parameters demonstrated the following characteristics: 

Sensitivity – 82%

 Specificity – 78%  Accuracy – 80%  PPV – 75%  NPV – 84%

This sanalysregard prospeassesparama modmost pbecamused istudy 

perforbut seportion only scriteria gadolianalysimagestrengapproQUALPatienregardYesFollow 
28 

Evidence Table 1a. Diagnostic reliability of McDonald criteria (continued) Study Study Design Patients Clinical

Presentation

Additional DataUsed for Diagnosis

Results Com

Brex, Miszkiel, O’Riordan,et al., 2001 

Prospective cohort studyDuration of follow up: Median, 12 mo; range, 11-19 moLocation: London, UK 

Total no. at start:81 Dropouts: 13 Completed: 68 attended all 3 studyvisits and were included in analysis Age at presentation: Mean, 31; range,17-50 

Clinically isolated syndrome (defined as the occurrence of a presumed inflammatorydemyelinating event of acute onset in the CNS in a patient with no history suggestive of an earlier demyelinating episode); presenting symptom was optic neuritis in 45 patients, brain stem syndrome in 16,spinal cord syndrome in 6, and optic tract lesion in 1; age 16-50 at presentation; appropriate investigations ruled out alternative diagnoses 

Baseline MRIs performedat a median of 5 wk(range, 1-12 wk) after onset of symptoms MRI – performed as part of the initial baseline evaluation and again after 3 mo, with and without contrast enhancement Clinical assessment at 1 yr

1) Contrast enhancing lesion at baseline was the most predictive initial MRIcharacteristic with positive predictive value of 52%, specificity of 80%, and sensitivity of 61%. 2) A single T2 lesion on baseline scan had highest sensitivity (89%) but poor specificity (36%).3) The combination of T2 lesions on baseline scan and new T2 lesions on follow-up scan yielded positive predictive value of 55%, sensitivity of 83%, and specificity of 76%. 4) The combination of enhancing lesions on T1 images of both examinations had the highest positive predictive value (70%) and specificity (94%), but had a very low sensitivity (39%).

This sutility McDothe ideseriallPoserQUALPatienregardYesFollow 

CHAMPS StudyGroup, 2002 

Prospective cohort studyDuration of follow up: 18mo Location: 50 sites in the US and Canada 

Total no. at start:190 Dropouts: NRCompleted: NR Age (mean ± SD):33 ± 7 

Patients were enrolled in an RCT comparing interferon beta-1a (30 μg weekly by IM injection; n = 193) vs. placebo (n = 190); all were 

First occurrence of an isolated, well-defined neurological event consistent with demyelination and involving the optic nerve (unilateral optic neuritis; n = 97), spinal cord (incomplete transverse myelitis; n = 42), or brain stem or cerebellum (n = 51); ≥ 2 clinically silent T2-hyperintense brain MRI lesions (≥ 3 mm in size, at least one 

Baseline MRI performed ≥ 4 days after patient completed initial IV corticosteroid therapy(commenced within 14 days of symptom onset and lasted 3 days), but while patient still receiving oral prednisone (lasted 15 days after IV therapy stopped);median time from onset of symptoms = 18 days, range = 8-39 days MRI – performed ≥ 4 days after initial corticosteroid therapy

1) Overall, 27% of patients (51/190) developed clinically definite MS by 18 mo.2) The best predictive model for clinicallydefinite MS by 18 mo consisted only of whether patients had ≥ 2 enhancing 

lesions. None of the other MRI characteristics at their optimized cutpoints improved the model fit. 3) A higher percentage of those patients meeting the Barkhof criteria (≥ 9 T2

lesions) developed clinically definite MS (31%) by 18 mo than did patients who did not meet the criteria (16%) (RR = 1.94, 95% CI = 1.02 to 3.72). 4) The highest risk of clinically definite 

This sMRI ddefinitcriteriainformadditiocriteriaQUALPatienregardYesFollow not cle
29 

Evidence Table 1a. Diagnostic reliability of McDonald criteria (continued) Study Study Design Patients Clinical

Presentation

Additional DataUsed for Diagnosis

Results Com

treated with a course of corticosteroidsbefore the start ofthe trial. Onlyplacebo patients are considered in this publication.

characteristic of MS [periventricular orovoid]); onset of symptoms 14 days or less before start of IV corticosteroid and 27 days or less before randomization (see under “Patients”); age 18-50 

(see above) and at 6, 12, and 18 months for those patients not meeting the primary study endpoint of clinically definite MS due to recurrence 

MS was seen among those with ≥ 2 

enhancing lesions, with 52% of these patients reaching clinically definite MS by18 mo compared with 24% of those with < 2 enhancing lesions (RR = 2.16, 95% CI = 1.35 to 3.46). 

Comi, Filippi, Barkhof, et al., 2001 

Prospective cohort studyDuration of follow up: 2 yr Location: 57 sites in 14 European countries 

Total no. at start:309 Dropouts: 31 Completed: 278Age: Mean, 28.5Patients were enrolled in an RCT comparing interferon β-1a (22 μg weekly by SCinjection; n = 154) vs. placebo (n = 155); patients were offered open-label interferon after conversion to clinically definite MS

Clinical syndromeindicating unifocal or multifocal involvement of the CNS; first neurological episode suggesting MS in the previous 3 mo; 1 or more abnormalities on neurological exam; positive brain MRI (presence of ≥ 4 white-matter lesions on T2-weighted scans or presence of ≥ 3 white-matter lesions if at least one of these was intratentorial or contrast enhancing); age 18-40 

Baseline MRI performed as part of pre-studyscreening, within 3 mo of first neurological episode suggesting MS 1) MRI – performed as part of the initial baseline evaluation and again at 12 and 24 mo 2) CSF – performed onlyin those patients with initial manifestations suggestive of spinal cord lesion 

1) 34% of patients treated with interferon β-1a (52/154) and 45% of patients treated with placebo (69/154) converted toclinically definite MS during the 2-yr study.2) The only baseline clinical and MRI variables that were significantly predictive of outcome were multifocal onset (odds ratio 1.99 [95% CI, 1.14 to 3.46]; p = 0.015) and T2 lesion number > 8 (3.64 [1.30 to 10.2]; p = 0.014). 

This wtrial in syndrosmall predicthe diaused pcontaiperforstudy questibackgutility QUALPatienregardYesFollow 
30 

Evidence Table 1a. Diagnostic reliability of McDonald criteria (continued) Study Study Design Patients Clinical

Presentation

Additional DataUsed for Diagnosis

Results Com

Dalton, Brex, Jenkins, et al., 2002 

Prospective cohort studyDuration of follow up: Median, 12 mo (range, 11-16mo) Location: London, UK 

Total no. at start:55 Dropouts: 0 Completed: 55 Age: Mean, 29.6;range, 21-41 

Clinically isolated syndrome suggestiveof MS, defined as a single event of acute onset in the CNSsuggestive of demyelination. Instudy population, 38 had unilateral optic neuritis, 11 brain stem syndrome, 5 spinal cordsyndrome, and 1 a hemianopia due to an MRI lesion in the optic tract. Exclusion criteria: History of neurological symptoms suggestive of demyelination; age < 17 or > 50 

Baseline MRIs conducted within 3 mo of onset of symptoms MRI – performed at baseline, 3 mo later, and approximately 1 yr after presentation 

14/55 patients (25%) developed clinicallydefinite MS and 4 (7%) probable MS according to Poser criteria during the 1-yr follow up. 27 of 55 patients met McDonald criteria for MS at 1 yr. 

This srelativMcDoprimademonMcDoMRI dchangQUALPatienregardYesFollow 

Dalton, Brex, Miszkiel, et al., 2002 

Prospective cohort studyDuration of follow up: 3 mo to 3 yr (follow up ongoing – see under “Patients,” at right) Location: London, UK 

Total no. at start:119 Follow up ongoingat time of publication: 95 patients studied at 3 mo, 79 at 1 yr, and 50 at 3 yr Dropouts: 1 (died of asthmatic attack) Completed: Followup ongoing; see above Age: Median at onset, 31; range,16-50 

Clinically isolated syndrome, defined as an acute isolated event affecting one region of the CNS and presumed to be demyelinating, with no previous history of possible demyelinating events. In study population, 87 had acute unilateral optic neuritis, 2 bilateral consecutive optic neuritis, 19 brain stem syndrome, 10 spinal cordsyndrome, and 1demyelinating optic 

Baseline MRIs conducted within 3 mo of onset of symptoms MRI of the brain was performed at baseline, 3 mo, 1 yr, and 3 yr. MRI of the spinal cord was performed at baseline, 1 yr, and 3 yr. 

1) Clinically definite MS was present in 7% of patients (7/95) at 3 mo, 20% (16/79) at 1 yr, and 38% (19/50) at 3 yrfollow up. 2) Performance of the McDonald criteria at 3-mo evaluation for predicting the development of clinically definite MS at 1 yr:  Sensitivity = 73%  Specificity = 87%  PPV = 58%  NPV = 93%  Accuracy = 84% 3) Performance of the McDonald criteria at 1-yr evaluation for predicting the development of clinically definite MS at 3 yr:  Sensitivity = 94% 

This sperforcompais a prwhich complstudy increacriteriaQUALPatienregardYesFollow this refewer 1-yr e
31 

Evidence Table 1a. Diagnostic reliability of McDonald criteria (continued) Study Study Design Patients Clinical

Presentation

Additional DataUsed for Diagnosis

Results Com

tract lesion. Maximal symptoms and signs evident within 14days of symptomonset. Alternative diagnoses excluded. Age 16-50. 

 Specificity = 83%  PPV = 77%  NPV = 96%  Accuracy = 87% 

Filippi, Horsfield, Morrissey,et al., 1994 

Prospective cohort studyDuration of follow up: Mean ± SD, 63 ± 11 

mo; range, 43-84 mo Location: London, UK 

Total no. at start:129 Dropouts: 40 of original cohort not included in this 5-yrfollow up Completed: 89 reexamined and rescanned at 5-yr follow up; 84 hadcomplete data available (initial MRI unavailable at followup for 5)Age at baseline presentation: Mean, 31; range,13-50 

Clinically isolated syndrome of the optic nerves (n = 40),brainstem (n = 16), or spinal cord (n = 28) suggestive of MS; syndrome fullydeveloped within 14 days of symptomonset; age 10-50 at presentation; appropriate studies (including initial MRI)ruled out alternative diagnoses 

Baseline MRIs were conducted within 60 daysof onset of symptoms in 69/84 patients (82%), later in remaining 15 patients 1) MRI – repeat MRI scans were performed after a mean of 63 mo. Quantitative semiautomated computer assessment of T2 lesion load was performed in a manner shown to have an intraraterreproducibility of 6%. 2) Clinical examination – patients were reexamined after a mean of 63 mo with assessment of EDSS. MS was diagnosed solelyon clinical grounds using Poser criteria. 

1) During 5-yr follow up, 34 patients (40%) developed clinically definite MS: 18 of 40 (45%) with initial optic neuritis, 10 of 28 (36%) with initial spinal cord syndrome, and 6 of 16 (38%) with initial brainstem syndrome. 4 patients (5%) developed clinically probable MS – 2 with initial optic neuritis and one each with spinal cord or brainstem syndrome. 2) 52 patients with abnormal MRI at presentation with median total brain lesion volume 0.83 cm3 (range, 0.09-52.41), with 

median infratentorial lesion volume of 0 cm3 (range, 0-1.82) 

3) Patients developing MS had significantly higher total and infratentorial lesion loads at presentation than those who did not: median total lesion volumes were 1.15 cm3 (range, 0-52.41) versus 0 

cm3 (range, 0-25.6), p < 0.0001; the 

median infratentorial lesion volumes were 0 cm3 (range, 0-1.82) versus 0 cm3

(range, 0-0.59), p < 0.0001. 4) Lesion load of 1.23 cm3 at 

presentation afforded the highest probability of separating patients developing MS from those who did not. Patients then divided into three groups: Group A - patients with total lesion volume ≥ 1.23 cm3, Group B - patients 

with abnormal MRI but total lesion volume < 1.23 cm3, and Group C - patients with 

normal MRI at baseline. Results: 

The Mthose not prsuppodiagnowith thMcDoAdditiopopulaMiller, O’Rio1998, QUALPatienregardYesFollow 
32 

Evidence Table 1a. Diagnostic reliability of McDonald criteria (continued) Study Study Design Patients Clinical

Presentation

Additional DataUsed for Diagnosis

Results Com

Group A - 19 of 21 (90%) patients developed MS (18 clinically definite, 1 clinically probable) Group B - 17 of 31 (55%) developed MS (15 definite and 2 probable)Group C – 2 of 32 (6%) developed MS (1 definite and 2 probable) 5) 18 of 20 (90%) patients with infratentorial lesions developed MS (all clinically definite), whereas 44 of 64(69%) without such lesions did not. 6) A significant correlation was found between total and infratentorial lesion load on the initial MRI (Spearman rank correlation coefficient = 0.649; p < 0.0001). 

Ghezzi, Martinelli, Torri, et al., 1999 

Prospective cohort studyDuration of follow up: Mean ± SD, 6.3 ± 2.2 

yr; median, 5 yr Location: Gallarate, Italy

Total no. at start:112 Dropouts: 10 lost to follow up Completed: 102Age: Mean ± SD, 29.2 ± 9.0 

Acute isolated optic neuritis 

Baseline paraclinical tests performed within 6 mo of onset of optic neuritis; mean interval, 45 ± 24 days 

1) MRI – performed at baseline only – details not delineated 2) CSF IgG Index was the parameter utilized; definition of abnormal not stated 3) VEP – Multiple Evoked Potential studies were performed at baseline. No details regarding technique werepresented. 

36% of patients (37/102) developed clinically definite MS in 2.3 ± 1.6 yr of 

follow up after initial attack of opticneuritis. Number of patients developing MS in relation to the results of paraclinical tests performed at baseline:  MS+ MS- P-value1) MRI: 0.0001 Negative 37 34 Positive 0 31 2) CSF: 0.19 Negative 22 29 Positive 12 31 3) VEP: 0.95 Negative 10 16 Positive 26 48 4) BAEP, median nerve SEP, and upper limb MEP: 0.7 Negative 2 7 

This sparacpatiensyndrodevelopreseninformparacevaluathe pathe saMcDoQUALPatienregardYesFollow 
33 

Evidence Table 1a. Diagnostic reliability of McDonald criteria (continued) Study Study Design Patients Clinical

Presentation

Additional DataUsed for Diagnosis

Results Com

Positive 17 31 5) BAEP, median and tibial nerve SEP: 0.02 Negative 9 5 Positive 6 21 

Morrissey,Miller, Kendall, et al., 1993 

Prospective cohort studyDuration of follow up: Mean, 63.6 mo; range, 43-84 moLocation: London, UK 

Total no. at start:132 Dropouts: 43 of original cohort not included in 5-yrfollow up Completed: 89 reexamined and rescanned at 5-yr follow up Age at baseline presentation: Mean, 31.3; range, 13-50 

Clinically isolated syndrome of the optic nerves (n = 44),brainstem (n = 17), or spinal cord (n = 28) suggestive of MS; syndrome acute or subacute in onset; age 10-50 at presentation; appropriate studies (including initial MRI)ruled out alternative diagnoses 

Baseline MRIs were conducted within 60 daysof onset of symptoms in 74/89 patients (83%), later in remaining 15 patients 1) MRI – performed at baseline and a mean of 1.3 yr later and again at 5.3 yr – all scans were unenhanced 2) CSF – not performed in patients with clinicallyisolated optic neuritis, but was performed inpatients with isolated spinal cord or brainstem syndromes 

After 5 yr, progression to clinically definite MS occurred in 41 of 57 (72%) of patients who had had abnormal initial scans, but in only 2 of 36 (6%) patients whose initial scan was normal (P < 0.0001). 

This sinformthe diaMRI in McDonot anAdditiopopulaHorsfiand Oal., 19QUALPatienregardYesFollow 

Optic Neuritis StudyGroup, 1997 

Prospective cohort studyDuration of follow up: 5 yr Location: 15 sites in the US 

Total no. at start:388 Dropouts: 47 Completed: 341 followed up for 5 yr Age (mean ± SD):32 ± 7 

Patients were participants in an RCT comparing IVmethylprednisolone 

Acute unilateral optic neuritis with visual symptoms of 8 days or less; no previous history of optic neuritis or ophthalmoscopic signs of optic atrophyin the affected eye; no evidence of a systemic disease other than MS that might be associated with the optic neuritis; no previous treatment 

Baseline MRIs performed“on study entry” (within 8 days of onset of acute symptoms)MRI – brain MRI was performed at baseline according to standardized protocols 

1) 27% of patients (106/388) developed clinically definite MS with 5 yr, and an additional 9% (35 patients) developed probable MS. 2) The presence of MRI abnormalities at the time of optic neuritis was the single most important predictor of the development of clinically definite MS by 5 yr. The probability of clinically definite MS was 16% in the 202 patients with no MRI abnormalities, 37% in the 60 patients with 1-2 MRI abnormalities, and 51% in the 89 patients with ≥ 3 MRI abnormalities. 

This sinformthe diaMRI dthe catherefdirect McDoQUALPatienregardYesFollow 
34 

Evidence Table 1a. Diagnostic reliability of McDonald criteria (continued) Study Study Design Patients Clinical

Presentation

Additional DataUsed for Diagnosis

Results Com

vs. oral prednisone 

vs. oral placebo 

with corticosteroids for MS or for opticneuritis in the opposite eye; age 18-46 yr Patients with a diagnosis of clinicallydefinite or probable MS were excluded 

O’Riordan,Thompson, Kingsley, et al., 1998 

Prospective cohort studyDuration of follow up: Mean, 9.7 yr Location: London, UK 

Total no. at start:129 Dropouts: 48 of original cohort not included in this 10-yr follow up Completed: 81 reexamined and rescanned at 10-yrfollow up Age at baseline presentation: Mean, 32.3; range, 17-49 

Clinically isolated syndrome (defined as an acute or subacute episode suggestive of demyelination affecting the optic nerves [n = 42], brainstem [n = 16], or spinal cord [n = 23]); age 10-50 at presentation; appropriate studies (including initial MRI)ruled out alternative diagnoses 

Not clear when baseline MRIs conducted 1) MRI – baseline and follow-up scans up to the 5-yr scans were performed on a 0.5 T scanner using SE2000/60 sequences. 10-yr scans wereperformed on a 1.5 T scanner and usedconventional dual spin echo technique. All scans were evaluated only for the presence of hyperintense lesions. Scans were considered abnormal only if one or more asymptomatic lesions characteristic for demyelination were present. The number of lesions compatible with demyelination was recorded. All scans were read with the baseline and 5-yr scans side-byside for comparison. 2) Diagnosis of MS was made solely on the basis of Poser criteria after 10 yr of follow up 

1) Patients with a normal baseline MRI (n = 27): Only 3 patients (11%) progressed to clinically definite MS, all of whom had benign disease. 2 additional patients (7%) had clinically probable MS. Of these 5 patients, 4 had 10-yr follow-up MRIs and all had developed new lesions. 22 patients of these original 27 (81%) were still classified as having clinicallyisolated syndromes. 2) Patients with abnormal MRI atbaseline (n = 54): After 10 yr, only 7 patients (13%) still had a diagnosis of clinically isolated syndrome, 2 patients (4%) had clinically probable MS, and 45 patients (83%) had progressed toclinically definite MS. Of those withclinically definite MS, 21 patients (39%) had benign disease, 11 patients (20%) relapsing/remitting disease with an EDSS of > 3, and 13 patients (24%) developed secondary progressive MS. For those with an abnormal baseline MRI, the presence of infratentorial lesions did not confer any greater risk for the subsequent development of clinicallydefinite MS. 

The Mthose not prsuppodiagnowith thMcDoAdditiopopulaHorsfiMorrisaboveQUALPatienregardYesFollow 10-yr 

cohort 
35 

Evidence Table 1a. Diagnostic reliability of McDonald criteria (continued) Study Study Design Patients Clinical

Presentation

Additional DataUsed for Diagnosis

Results Com

SastreGarriga, Tintoré, Rovira, etal., 2003 

Prospective cohort studyDuration of follow up: Mean, 37 mo Location: Barcelona, Spain 

Total no. at start:59 Dropouts: 8 (excluded because follow-up shorter than 12 mo) Completed: 51 Age: Mean at assessment, 29; range, 14-49 

Episode of clinical brainstem dysfunction suggestive of inflammatorydemyelination; clinical assessment within 3 mo of onset of symptoms; age < 50; other possible diagnoses excluded 

Mean time between onset of symptoms and initial MRI 29 days1) MRI – 1.0 or 1.5 T scanners including transverse proton densityand T2-weightedconventional spin echo or fast spin echo, and T1-weighted spin echo. T1 images wererepeated after administration of gadolinium. Sagittal T2 or transverse T2 FLAIR were also performed on most patients. A blinded neuroradiologist recorded the number and sites of abnormalities. The MRI diagnostic criteria of Paty, Fazekas, and Barkhof were then studied. 2) CSF – presence of oligoclonal bands were assessed, but not used in the diagnosis of MS 3) VEP – values of VEP and SEP results were assessed but not used in the diagnosis of MS 

1) Paty MRI criteria:  Sensitivity = 89% 

Specificity = 52%

 PPV = 50% 

NPV = 89% 

Accuracy = 65%

2) Fazekas MRI criteria:  Sensitivity = 89% 

Specificity = 48% 

PPV = 48% NPV = 89% 

 Accuracy = 63% 3) Barkhof MRI criteria:  Sensitivity = 78% 

Specificity = 61%PPV = 52% 

 NPV = 83% 

Accuracy = 67% 

4) CSF – presence of oligoclonal bands:  Sensitivity = 100% Specificity = 42%  PPV = 44%  NPV = 100%  Accuracy = 63% 5) Evoked potential studies – no statistically significant differences for baseline VEP or SSEP parameters were found between patients who did and those who did not convert to MS 

Clinicabased symptrequirneurois mormost cPoser evaluaparam

develowere ntheir cQUALPatienregard– symrequirabnorFollow 
36 

Evidence Table 1a. Diagnostic reliability of McDonald criteria (continued) Study Study Design Patients Clinical

Presentation

Additional DataUsed for Diagnosis

Results Com

Tintoré, Rovira, Río, et al., 2003 

Cohort study; data collected prospectively, McDonald criteria applied retrospectivelyDuration of follow up: Mean, 39 ± 17.2 mo; range, 12-77 mo; all patients were followed up for at least 1 yr(inclusion criterion), 122 for at least 2 yr, and 86 for at least 3 yrLocation: Barcelona, Spain 

Total no. at start:139 Dropouts: 17 by 2 yr; 53 by 3 yr Completed: 139 were followed up for at least 1 yr(inclusion criterion), 122 for at least 2 yr, and 86 for at least 3 yr Age: Mean, 30; range, 13-49 

Clinically isolated syndrome suggestiveof CNS demyelination involving the optic nerve (41.5%), brainstem (24.5%), spinal cord (28%), or combinations of the above (6%), and not attributable to other diseases; age < 50 yrAnalysis included only patients withclinical and MRI examinations within 3 mo of onset of symptoms and clinical follow up of at least 12 mo 

Baseline MRIs completed within 3 mo of onset of symptoms 1) MRI – standard MRI techniques used after the first demyelinating event and 12 mo later 2) CSF – the presence of oligoclonal bands was assessed after the first demyelinating event 

1) At 1 yr, 15 patients (11%) had a second clinical attack and therefore fulfilled the requirement for dissemination in time and space necessary for clinicallydefinite MS according to the Poser criteria. Of these 15 patients, 10 also fulfilled the radiologic conditions ofdissemination in time and space. 2) Fifty-one patients (37%) fulfilled MRI requirements for dissemination in time and space and therefore were considered to have MS according to the McDonald criteria. Ten of these 51 patients (20%) had a second clinical event during the first year of follow up. In total, 56 of 139 patients (40%) fulfilled the McDonald criteria for MS either by MRI or clinically. 3) The McDonald criteria showed a sensitivity of 74%, specificity of 85%, PPV of 80%, NPV of 80%, and accuracy of 80% in predicting conversion to clinicallydefinite MS: 

 Clinically definite MS 

 at 3 yr 

+ -

McDonald + 28 7 criteria at 1 yr - 10 41 4) In the first year the Poser criteria allowed the diagnosis of clinically definite MS in 11% compared with 37% with the McDonald criteria. 

This aevaluaQUALPatienregard

YesFollow 
Evidence Table 1b. Inter-rater reliability of diagnosis with McDonald and Poser criteria 

Study Study Design Patients & 

Physicians 

Patients’ Clinical Presentation

Diagnostic Criteriaand Data Available

Results Com

Ford, Johnson, and Rigby,1996 

Cross-sectional diagnostic test study(retrospective) Single-center Setting: Generalneurology outpatient clinic Location: Leeds,UK 

Patients: N = 85 Age: Mean, 46; range, 23-74 Physicians: N = 2 (both neurologists) 

Patients had been diagnosed according to Posercriteria as having clinically definite MS, laboratorysupported definite MS, clinicallyprobable MS, laboratorysupported probable MS, or suspected MS, or as “unable to classify”; all wereoutpatients at studyclinic

1) Diagnostic criteria used: Poser 2) Data available for diagnosis: Diagnoses made entirely on basis of data contained in case records of patients; precise data contained in these unclear 

Overall, there was substantial agreement between the two observers in classifying multiple sclerosis according to the Posercriteria (κ = 0.65, 95% CI = 0.52 to 0.78). There was poor agreement in thehistorical data used to classify the cases (κ = 0.30, 95% CI = 0.03 to 0.57).

This scase revaluapatienvariatiThe aanalysextent This scriteria The aof obslack ocontaiQUALEvaluaanotheDid stspectrcases

Zipoli,Portaccio, Siracusa, etal., 2003 

Cross-sectional diagnostic test studySingle-center Setting: Universitydepartment of neurology Location: Florence, Italy

Patients: N = 44 Age (mean ± SD):31 ± 7.5 

Physicians: N = 4 neurologists 

All cases consecutivelyadmitted for diagnostic assessment at study site between Sep 2001 and June 2002 and prospectivelyfollowed up for ≥ 6 

mo; data collected via chart reviewPatients’ (preexisting) diagnoses as follows: 41 MS (15 relapsing-remitting, 

1) Diagnostic criteria used: Poser McDonald 2) Data available for diagnosis: Family and patient clinicalhistoryComplete neurological exam Lab tests (blood counts, etc.) Occurrence of new orworsening symptoms Brain MRI Spinal cord MRI (when appropriate) CSF examinationEvoked potentials 

Poser criteria: Diagnosis of MS: κ = 0.57 Dissemination in time: κ = 0.69 Dissemination is space: κ = 0.46 Diagnosis of clinically definite MS:κ = 0.39 Diagnosis of clinically probable MS: κ = 0.37 McDonald criteria: Diagnosis of MS (all categories): κ = 0.52 Diagnosis of MS: κ = 0.52 Diagnosis of possible MS: κ = 0.49 Diagnosed not MS: κ = 0.64 

This sinter-rMcDodata dThe p

criteria agreespeciflesion that thevaluaprevioradioginterptime wpatiensymptneurointerp

37 
Evidence Table 1b. Inter-rater reliability of diagnosis with McDonald and Poser criteria (continued) 

Study Study Design Patients & 

Physicians 

Patients’ Clinical Presentation

Diagnostic Criteriaand Data Available

Results Com

2 secondaryprogressive, 5 primary progressive, 19 presenting withfirst clinical attack) 1 cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy1 migraine with aura1 Leber’s hereditaryoptic neuropathy

“Other examinations performed for thedifferential diagnosis” 

McDo

providlesion QUALEvaluaanotheDid stspectrcases

38 
Evidence Table 2. Predictors of ph

y

sical and mental impairments at 12 months 

39 

Stu

d

y

S

electe

d

Inclusion/ Exclusion Criteria

Stu

d

y Design Patients Possible 

Predictors Considered

R

esults C

o

m

Chapman,Sylantiev,Nisipeanu, et al., 1999 

Inclusion: Clinicallydefinite MS; relapsing-remittingcourse Exclusion: None 

Prospective, population-based, cohort studyDuration of follo

w

up: Follo

w up 

conducted every3 mo for a periodof 2 yr

Total no. at start: 47 APO

E ε4: 

N = 9 heterozygous for APO

E ε4 allele 

N = 1 homozygous for APO

E ε4 allele 

N = 37 

without allele 

Completed: N = 8 APO

E ε4 

N = 33 Non-APOE ε4

Dropouts: N = 2 APO

E ε4 

N = 4 Non-AP

O

E ε4 

Age (mean): APO

E ε4: 34.0 ± 1.4 

Non-AP

O

E ε4: 36.0 

± 2.3 years Baseline measures of physical and mental functioning: APO

E ε4: 

EDSS Mean: 3.10 ±0.45 EDSS Range: 1.5-6.0 Exacerbation rate, per year: 1.05 ± 0.05Non-AP

O

E ε4: 

EDSS Mean: 2.62 ±0.25 EDSS Range: 0-6.0 Exacerbation rate, per year: 1.12 ± 0.06

Presence of APO

E

ε4 allele 

1) Significant interaction of genotype 

with 

change in disability over 2-yr time period (P = 0.02): APO

E ε4: Mean EDSS deteriorated to 4.00 

± 0.63 Non-AP

O

E ε4: Mean EDSS stable at 2.74 ±

0.31 2) No significant difference (P > 0.35) for the three possible predictors: a. Duration of illness at entry:APO

E ε4: 48 ± 12 mo

Non-AP

O

E ε4: 57 ± 10 mo 

b. Exacerbation rate over previous 2 yr: APO

E ε4: 1.05 ± 0.05 per yr 

Non-AP

O

E ε4: 1.12 ± 0.06 per yr

c. EDSS score: APO

E ε4: 3.10 ± 0.45 

Non-AP

O

E ε4: 2.62 ± 0.25 

3) Exacerbation characteristics: Mean EDSS before peak: APO

E ε4: 3.67 ± 1.30 

Non-AP

O

E ε4: 2.00 ± 0.54 

Mean EDSS at peak: APO

E ε4: 4.67 ± 1.30 

Non-AP

O

E ε4: 3.37 ± 0.44 

Mean EDSS at resolution of exacerbation: APO

E ε4: 4.50 ± 1.26 

Non-AP

O

E ε4: 2.04 ± 0.52 

Borderline significant interaction (P = 0.049, 1-tailed) between groups for E

D

S

S scores at 

peak and at resolution, indicating impaired recovery in APOE ε4 carriers

For alwas canalysof obsfor

war

Q

UAL

Study No SampcommdiseasSampearly pdiseasFollow Outcoscale?OutcoUncleIf subgidentifa) 

was 

prognb) 

was 

NA 
40 

Evidence Table 2. Predictors of physical and mental impairments at 12 months (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Possible 

Predictors Considered

Results Com

Cottrell, Kremenchutzky,Rice, et al., 1999a and Cottrell, Kremenchutzky,Rice, et al., 1999b 

Inclusion: Primaryprogressive MS Exclusion: None specified 

Prospective, population-based, cohort studyDuration of followup: Original cohort followed up for mean of 23yr; follow-up timefor 2nd cohort NR

Total no. at start:Original cohort, 216; 2nd cohort, 165 

Dropouts: NRCompleted: NR Age: Mean age at onset, 38.5 in original cohort, 38.9 in 2nd

cohort Baseline measures of physical and mental functioning: Mean DSS score at presentation (4) reported for 2nd

cohort only

DSS at time 0 – evaluated in relation to 3 different groups of patients: a) Original cohort; b) Simulated group of patients at DSS 3, 4, or 5 who had progressed one level in the last yrand had reachedDSS 3 by 5 yr; c) Simulated group of patients at DSS 4, 5, or 6 who had progressed one level in the last yearand had reachedDSS 4 by 10 yrPrognostic factors considered: a) Sex b) Age of onset c) System involved 

at onset 

d) Number of 

systems 

e) Rate of early

disability

Probability of progression to next DSS level within 1 year (original cohort, n = 216): DSS 

Level Probability Median N entering

1 0.87 0.6 yr 190 2 0.26 1.9 yr 182 3 0.31 1.8 yr 179 4 0.40 1.3 yr 171 5 0.33 1.6 yr 163 6 0.04 4.0 yr 174 7 0.10 3.9 yr 131 8 0.02 11.5 yr 125 9 0.08 7.2 yr 48 Multiple regression (accelerated failure time)analysis of prognostic factors for DSS 8:  Regression Effect 

Factor Coefficient SE P-value Tested

Sex 0.037 0.078 0.63 M vs. F Age at onset -0.001 0.004 0.15 Linear Years toDSS 3 0.067 0.011 0.0001 Linear No. of systems -0.457 0.19 0.01 3 vs. 1 No. of systems -0.09 0.08 0.27 2 vs. 1 Origin of case -0.08 0.1 0.41 Middlesex 

 vs. Non- Middlesex

QUALStudy YesSampcommdiseasSampearly pdiseasFollow Outcoscale?OutcoUncleIf subgidentifa) was prognb) was No 
41 

Evidence Table 2. Predictors of ph

y

sical and mental impairments at 12 months (contin

ued) 

Stu

d

y

S

electe

d

Inclusion/ Exclusion Criteria

Stu

d

y Design Patients Possible 

Predictors Considered

R

esults C

o

m

Fuhr, BorggrefeChappuis, Schindler, et al., 2001 

Inclusion: Clinicallydefinite MS; relapsing-remitting or secondaryprogressive course; EDSS score ≥ 2 and ≤ 6.5; MRI during last 12 mo consistent with MS diagnosis; MRI during 2 

wk before 

entry sho

wing at least 

one gadoliniumenhancing lesion Exclusion: Chronic steroid or immunosuppressive drug treatment during past 6 mo; acute steroid treatment for a relapse during past 4 wk

Prospective caseseries Duration of follo

w

up: 2 yr 

Total no. at start: 30 25 relapsing-remitting5 secondaryprogressive Completed: 30 Dropouts: 0 Age: Median 37.5 (range, 26-50) Sex:Male: 6 (20

%) 

Female: 24 (80

%) 

Baseline measures of physical and mental functioning: Median EDSS at entry: 4.65 (range, 2-6.5) Mean disease duration at entry: 9.2 years (range, 1.5-22 years) 

Combined motor evoked potentials (MEPs) and visual evoked potentials (VEPs), sum of Ztransformed latencies at baseline

∆ EDSS 0 to 24 mo 

> 0 ≤ 0 

> 0 9 3

Sum of Ztransformed 

latencies ≤

0 8 7

Sensitivity = 9/17 (53%) Specificity = 7/10 (70%) PPV = 9/11 (82

%) 

NPV = 7/15 (47

%) 

Prevalence = 12/27 (44

%) 

Median EDSS at entry: 4.65 (range, 2-6.5)Median EDSS at end of study: 5.1 (range,2-9) 

Table predicby absfor sum 

Q

UAL

Study No SampcommdiseasSampearly pdiseasFollow Outcoscale?OutcoNo If subgidentifa) 

was 

prognb) 

was 

NA 

Goodkin, Hertsgaard, and Rudick, 1989 

Inclusion: Definite or probable MS Exclusion: None specified 

Prospective, clinic-based, cohort studyDuration of follo

w

up: 1-5 yr (mean2.6 yr) 

Total no. at start:425 336 definite MS 89 probable MS Completed: 254 definite MS Dropouts: 82 definite MS 89 probable MS Age: No mean reported 

Disease type (determined frompatient historyand neurological records)Disease types: S = stable RRS = relapsing remitting stable RRP = relapsing remitting progressive CP = chronic 

Change in EDSS score at 2 yr (mean ± SD) 

(P = 0.1296): S = 0.108 ± 1.275 RRS = 0.098 ± 1.693 RRP = 0.717 ± 2.340 CP = 0.689 ± 1.301 No significant difference 

was found among 

the various disease types for changes in EDSS over the 2-yr time period No significant difference in exacerbation rates by disease type 

Q

UAL

Study No SampcommdiseasSampearly pdiseasFollow Outcoscale?OutcoUncle
42 

Evidence Table 2. Predictors of physical and mental impairments at 12 months (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Possible 

Predictors Considered

Results Com

Baseline measures of physical and mental functioning: EDSS at entry (mean ± SD) (P < 0.0001): S = 4.054 ± 6.025 RRS = 2.646 ± 3.878 RRP = 3.760 ± 2.770 CP = 5.844 ± 3.163 Disease type at entry(N): S = 80 RRS = 155 RRP = 48 CP = 142 

progressive If subg

identifa) was prognb) was NA 

Koziol, Wagner, Sobel, et al., 2001 

Inclusion: MS; relapsing-remittingdisease course Exclusion: Not evaluable at 12 mo 

Prospective, population-based, RCT Duration of followup: Examinationsperformed every month for 12 mo

Total no. at start: 50 N = 24 placebo N = 26 Cladribine Completed: 50 Dropouts: 0 Age (mean): Placebo: 40.1 yr(range 31-52) Cladribine: 44.0 yr (range 31-52) Baseline measures of physical and mental functioning: EDSS: Placebo: Mean = 3.8 Range = 2.5-6.5Cladribine: Mean = 3.9 Range = 2-6.5 

1) Presence of enhancing lesions on MRI 2) Occurrence ofnew enhancing lesions on MRI 3) Occurrence ofnew hypointenselesions (“black holes”) on MRI 

1) Enhancing lesions in 3 consecutive monthly MRI images immediately preceding exacerbation: PPV = 0.21 (0.121-0.306) NPV = 0.89 (0.859-0.923) Sensitivity = 0.36 (0.220-0.508) Specificity = 0.85 (0.778-0.903) Prevalence = 0.69 2) New enhancing lesions in 3 consecutive monthly MRI images immediately preceding exacerbation: PPV = 0.23 (0.124-0.357) NPV = 0.89 (0.857-0.920) Sensitivity = 0.31 (0.180-0.459) Specificity = 0.89 (0.841-0.929) Prevalence = 0.64 3) New black holes in 3 consecutive monthly MRI images immediately preceding exacerbation: PPV = 0.20 (0.041-0.426) NPV = 0.89 (0.855-0.916) Sensitivity = 0.19 (0.085-0.321) Specificity = 0.94 (0.911-0.959) 

Prevausing PrevaQUALStudy YesSampcommdiseasSampearly pdiseasFollow Outcoscale?OutcoUncleIf subgidentifa) was prognb) was NA 
43 

Evidence Table 2. Predictors of physical and mental impairments at 12 months (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Possible 

Predictors Considered

Results Com

SNRS: Placebo: Mean = 75.8 Range = 54-98 Cladribine: Mean = 76.1 Range = 41-93 

Prevalence = 0.42 4) Conclusion – presence of possible predictors 1, 2 and/or 3 (MRI imagingderived markers) are not useful in predicting exacerbations within 6 mo, but absence of predictors is associated with fewer relapses 

Nortvedt, Riise, Myhr, et al., 2000 

Inclusion: Clinical or laboratory-supported definite relapsingremitting MS; EDSS ≤ 5.5; ≥ 2 relapses 

during 2 yr preceding enrollment; stable disease at inclusion Exclusion: Age < 18 or > 50; pregnant or lactating women;

interferon treatment; immunosuppressive treatment during the previous year; steroid treatment during the month before inclusion; chronic progressive course; liver or renal disease; other serious concomitant disease

Prospective, not population-based, based on subjects in a double-blind RCTDuration of followup: 12 mo 

Total no. at start: 97 Completed: 91 Dropouts: 6 lost to follow-up before 12 mo Age: Mean: 34 Range: 21-48 Baseline measures of physical and mental functioning:  Mean EDSS: 2.9 (range 0-5.5)Mean disease duration: 6.9 years Baseline QOL ratings (n): Poor = 5 Fair = 33 Good = 43 Very good = 9 Excellent = 1 

Quality of life as reported by SF-36 Health Survey

Mean change in EDSS over 12 mo: Increase of 0.19 (range: -1 to 2.5)Baseline EDSS score was not correlated to change in EDSS score (P = 0.65) 

Increased EDSS

Initial QOL over 12 mo

Poor/Fair 16/38 (42%) Good/Very Good/ 12/53 (23%) Excellent Relative risk = 1.9 (CI, 1.0 to 3.5)The risk of experiencing a worsening EDSS score was 1.9 (95% CI, 1.0 to 3.5) for those who evaluated their health as poor or fair compared to good, very good, or excellent. No other measure in the SF-36 was predictive of EDSS worsening, after adjusting for multiple comparisons. 

QUALStudy No SampcommdiseasSampearly pdiseasFollow Outcoscale?OutcoNo If subgidentifa) was prognb) was NA 
44 

Evidence Table 2. Predictors of physical and mental impairments at 12 months (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Possible 

Predictors Considered

Results Com

Rovaris, Comi, Ladkani, et al., 2003 

Inclusion: Age 18-50; clinically definite MS for at least 1 yr; relapsing-remittingdisease course; EDSS 0.0-5.0; ≥ 1 documented relapse in preceding 2 yr; ≥ 1 contrast-enhancing lesion on screening brain MRI images; clinically relapse-free and without steroid treatment in the 30 days before study Exclusion: None specified 

Cohort derived from subjects in a RCT Duration of followup: 9 mo 

Total no. at start: 239 (119 received 20 mg glatiramer acetate [GA]; 120 received placebo) Placebo group: Completed: 113 Dropouts: 7 Age: 34.0 ± 7.5years GA group: Completed: 112 Dropouts: 7 Age: 34.1 ± 7.4years Baseline measures of physical and mental functioning: Disease duration(mean ± SD): Placebo: 7.9 ± 5.5 yr

GA: 8.3 ± 5.5 yr

Prior 2-yr relapse rate (mean ± SD): Placebo: 2.5 ± 1.4

GA: 2.8 ± 1.8 

EDSS score (mean ±SD): Placebo: 2.4 ± 1.2

GA: 2.3 ± 1.1 

No. of enhancing lesions (mean ± SD): Placebo: 4.4 ± 7.1

GA: 4.2 ± 4.8 

Overall burden (volume) of T2-hyperintense at baseline (T2BLV) or T1-hypointense (T1BLV) lesions 

Spearman rank correlation coefficients between measure and EDSS Score (p value): All Patients (n = 239) 

Measure Baseline Change

T2BLV 0.28 (< 0.001) 0.16 (0.02) T1BLV 0.19 (0.003) 0.18 (0.006) Multivariate regression reported to show that number of relapses during the study period was correlated with the number of relapses in the 2 yr before randomization (p = 0.005); when number of contrast-enhancing lesions at baseline was added, it was significant (p < 0.001). 

DetailincludQUALStudy No SampcommdiseasSampearly pdiseasFollow Outcoscale?OutcoUncleIf subgidentifa) was prognb) was No 
45 

Evidence Table 2. Predictors of physical and mental impairments at 12 months (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Possible 

Predictors Considered

Results Com

Runmarker, Andersson,Odén, et al., 1994 

Inclusion: Definite or probable MS; relapsing-remittingcourse; acute onset Exclusion: Progressive course from onset; lack of sufficient patient data 

Prospective, population-based, cohort studyDuration of followup: 25 yr 

Total no. at start:308 255 with definite or probable disease200 with sufficient data for analysis and non-progressive disease at onset Completed: 200Dropouts (from original cohort): 4 lost to follow up63 died before end of 25-yr follow up Age (at onset):< 19: 25 20-29: 71 30-39: 65 40-49: 32 ≥ 50: 7 Baseline measures of physical and mental functioning: NR 

1) Age at onset (Age) 2) Sex (1 = female) 3) Degree of remission after relapse (Remis, 1 = incomplete)4) Mono- or polyregional symptoms (Region, 1 = polyregional)5) Type of affected nerve fibers (1 = afferent with origin inside CNS, 2 = efferent or mixed)(Type 1 or Type 2) 6) Number of affected neurological systems (# Sys)7) Time since onset (Time since onset) 

(Probability of event = EXP(Σ coeff x value) Model 1 – analysis from onset, start of progressive disease as endpoint (n = 200): 

Factor Coeff SE Risk Ratio

Constant -4.550 0.5446 Age 0.04748 0.01611 1.049 Sex 0.8388 0.6150 2.314 Remis 0.2659 0.2028 1.305 Type 1 0.1639 0.3886 1.178 Type 2 0.4954 0.2822 1.641 Region 0.07666 0.3971 1.080 (Age) x -0.04222 0.01895 0.959 (Sex) (Remis) x 1.046 0.5329 2.846 (Region) Model 2 – analysis from onset, DSS 6 as endpoint: 

Factor Coeff SE Risk Ratio

Constant -4.917 0.4323 Age 0.02498 0.009119 1.025 Type 1 0.6290 0.4145 1.876 Type 2 0.7872 0.3327 2.197 Region 0.7978 0.2639 2.221 Model 3 – analysis from end of 5th calendar 

year, start of progressive disease as endpoint (n = 151): 

Factor Coeff SE Risk Ratio

Constant -2.921 0.4767 Sex -0.07462 0.2891 0.928 # Sys -0.8975 0.4228 0.408 Remis 0.6295 0.4108 1.877 Type 1 0.3800 0.5765 1.462 Type 2 -0.08682 0.4639 0.917 (# Sys) x 0.3330 0.1284 1.395 (Remis) (# Sys) x 0.8177 0.4592 2.265 (Type 1) (# Sys) x 0.8991 0.4277 2.457 

QUALStudy YesSampcommdiseasSampearly pdiseasFollow Outcoscale?OutcoUncleIf subgidentifa) was prognb) was Yes
46 

Evidence Table 2. Predictors of physical and mental impairments at 12 months (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Possible 

Predictors Considered

Results Com

(Type 2) (Sex) x -0.9739 0.4610 0.378 (Remis) Model 4 – analysis from end of 5th calendar 

year after onset, DSS 6 as endpoint: 

Factor Coeff SE Risk Ratio

Constant -4.258 0.4007 # Sys -0.05465 0.09212 0.947 Remis -0.3798 0.3717 0.684 Type 1 1.004 0.4760 2.729 Type 2 0.6038 0.3927 1.829 Region 0.7181 0.4292 2.051 (# Sys) x 0.4114 0.1324 1.509 (Remis) Model 5 – model for the relationship between age at onset, current age, and the risk of start of progressive course: 

Factor Coeff SE Risk RatioConstant -7.572 1.211 Time since 0.3569 0.08758 1.429 onset Age at 0.1631 0.05984 1.177 onset (Time since -0.007357 0.002389 0.993 onset)2(Age at -0.001447 0.0007719 0.999 onset)2Remis 0.3588 0.1774 1.432 (Time since -0.006126 0.001816 0.994 onset) x (Age at onset) 

Stevenson, Leary,Losseff, etal., 1998 

Inclusion: Patients recruited from previous cohort –patients had clinicallydefinite MS; control subjects – healthy (non-MS) 

Prospective, not population-based, case series Duration of followup: 1 yr 

Total no. at start: 41 (28 patients, 13 controls) Patient disease types: 12 primary progressive (PPMS); 

Baseline crosssectional area of spinal cord

Change in cord size, patients vs. controls: Mean change in cord area, mm2 (%):

Controls: -0.77 (-0.92) Patients: -2.26 (-3.71) p = 0.05 (% change, p = 0.03) Patient subgroups: Number of patients with definite change in 

QUALStudy No SampcommdiseasSampearly p
47 

Evidence Table 2. Predictors of physical and mental impairments at 12 months (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Possible 

Predictors Considered

Results Com

Exclusion: None 

specified 

6 secondaryprogressive (SPMS); 6 relapsing-remitting (RRMS); 4 benign (BMS) Completed: 41 Dropouts: 0 Age: Control: 46.3 (range 30-59); Patients: 45.1 (range 27-65) Baseline measures of physical and mental functioning:  Mean disease duration in years (range): PPMS: 10.9 (4-22) SPMS: 19.3 (17-24) RRMS: 5.6 (2-9)BMS: 17.3 (13-22) Median EDSS (range): PPMS: 5.75 (3.0-8.5)SPMS: 7.25 (6.0-8.0)RRMS: 3.25 (1.5-6.5) BMS: 2.25 (2.0-3.0) Mean cord size (mm2): 

PPMS: 71.98 SPMS: 57.03 RRMS: 83.97 BMS: 71.35 Control: 80.95

EDSS: PPMS: 2/12 SPMS: 2/6 RRMS: 1/6 BMS: 3/4 Mean change in cord area, mm2 (%):

PPMS: -3.52 (-5.2), p ≤ 0.001 

SPMS: -0.26 (-0.7), p = NS RRMS: -2.98 (-3.8), p ≤ 0.001 BMS: -0.41 (-0.8), p = NS Compared with 20 patients without definite increase in EDSS over 12 months, the 8 patients with definite increase in EDSS had similar cord area at baseline (p = 0.69) and similar change in cord area during the year(p = 0.51). 

diseasFollow Outcoscale?OutcoUncleIf subgidentifa) was prognb) was No 
48 

Evidence Table 2. Predictors of ph

y

sical and mental impairments at 12 months (contin

ued) 

Stu

d

y

S

electe

d

Inclusion/ Exclusion Criteria

Stu

d

y Design Patients Possible 

Predictors Considered

R

esults C

o

m

Trotter, Clifford, McInnis, et al., 1989 

Inclusion: DefiniteMS (chronic progressive or stable); age 20-50Exclusion: Chronic progressive MS with an increase over the prior year of > 8points on MRD or > 3 points on EDSS 

Prospective, not population-based, case series Duration of follo

w

up: 18 mo 

Total no. at start: 42 30 chronic progressive MS (CPMS; 15 untreated [placebo] patients); 10 stable MS patients; 12 normal control subjects Completed: 37 Dropouts: 5 fromCPMS placebo groupAge, mean ± SD (range): Total CPMS patients: 41.3 ± 8.9 (22-57); 

Untreated CPMSpatients (subset):40.4 ± 10.2 (22-57); 

Stable MS patients: 36.2 ± 13.1 (26-60); 

Normal controls: 36.2 ± 10.4 (26-58) Baseline measures of physical and mental functioning: EDSS: Untreated CPMS (n = 9): 5.7 ± 1.2 (3.0-7.0);Stable MS (n = 10): 5.9 ± 0.9 (3.5-6.5) 

1) Concanavalin A suppressor assay 2) Mitogen stimulation 3) Phenotyping of peripheral blood mononuclear cells 4) Interleukin-2 levels 

IL-2 baseline vs. 

∆ EDSS over 18 months 

R = 0.66 P = 0.01 Illustrative 2 x 2 table (derived fro

m Figure 5; 

retrospectively selected cutpoint of 40 U/mL)

∆ EDSS over 18mo 

≥ 1 < 1 

IL-2 > 40 4 0 (U/mL) ≤ 40 2 6

Sensitivity = 67% Specificity = 100%PPV = 100% NPV = 75% Prevalence 50%No other measures correlated 

with

prognosis 

Multippriori cprovidnormaprogrepatienreportQ

UAL

Study No SampcommdiseasSampearly pdiseasFollow Outcoscale?OutcoUncleIf subgidentifa) 

was 

prognb) 

was 

NA 
49 

Evidence Table 2. Predictors of physical and mental impairments at 12 months (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Possible 

Predictors Considered

Results Com

Villar, Masjuan,GonzálezPorqué, et al., 2002 

Inclusion: MS diagnosis, Exclusion: 

Prospective caseseries Duration of followup (months): Overall: Mean: 21.6 ±

2.28 Range: 6-36 Group 1 (intrathecal IgM synthesis [ITMS]) (mean): 18.00 ± 2.83 

Group 2 (noITMS) (mean): 24.67 ± 3.29 

(between-group difference NS) Lumbar punctureto determine presence/ absence of ITMSperformed within 6 mo of clinical onset (mean 1.14± 0.33 mo)

Total no. at start: 22 21 relapsing-remitting 1 primary progressive Group 1: 10 Group 2: 12 Completed: 22 Dropouts: 0 Age: Group 1: 27.91 ±2.86 Group 2: 29.00 ±2.91 EDSS: Group 1: 1.05 ± 0.27

Group 2: 1.17 ± 0.24

Mo. since onset: Group 1: 1.53 ± 0.65 

Group 2: 0.83 ± 0.25 

Albumin index: Group 1: 5.42 ± 0.81

Group 2: 4.40 ± 0.49

IgG quotient: Group 1: 4.23 ± 0.63

Group 2: 4.32 ± 0.64

IgM index: Group 1: 0.248 ±0.059 Group 2: 0.063 ±0.016 P = 0.003 Cells: Group 1: 6.00 ± 3.48

Group 2: 8.75 ± 3.24

Presence of ITMS Mean EDSS score at end of follow-up 

period: Group 1: 1.70 ± 0.23 

Group 2: 0.79 ± 0.22 

P = 0.02 Probability of progression of at least 1 unit in the EDSS after at least 1 yr of evolution (n = 18; those who made it to at least 1 yr offollow-up):Group 1: 50% Group 2: No increase in EDSS shown P = 0.01 Mean number of relapses during year 1: Group 1: 1.86 ± 0.46 

Group 2: 0.2 ± 0.13 P = 0.0068 Probability of remaining without interferon-β

treatment: Group 1: 0% after 20 months Group 2: 45.7% at end of study P = 0.0001 

QUALStudy 

Yes/NSampcommdiseasSampearly pdiseasFollow Outcoscale?OutcoYesIf subgidentifa) was prognb) was NA 
Evidence Table 3a. Disease-modifying therapies and long-term improvement

50 

Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Achiron,Gabbay, Gilad, et al., 1998 

Inclusion: Clinicallydefinite relapsing remitting MS of > 1 yrduration; averageyearly exacerbation rate 0.5-3 in 2 yr preceding study;EDSS score 0-6.0; age 18-60 Exclusion: Secondaryprogression disease course; serum immunoglobulin deficiency; long-term steroid or cytotoxic treatment 12 mo prior to study; major psychiatric disorder; major cognitive impairment 

RCT (parallelgroup, doubleblind, singlecenter) Duration of study treatment/followup: 2 yr Provider specialty:Neurologists Location: Tel Hashomer, Israel 

No. of patients randomized: 40Dropouts: 2 Completed: 38 Age (mean ± SE): IV IgG: 35.4 ± 2.1 

Placebo: 33.8 ±

2.4 Baseline EDSS (mean ± SE):IV IgG: 2.90 ±

0.43 Placebo: 2.82 ±

0.37 Baseline relapse rate (mean ± SE per yr in 2 yr preceding study):IV IgG: 1.85 ±

0.26 Placebo: 1.55 ±

0.17 

1) IV immunoglobulin (IV IgG); loading dose of 0.4g/kg/body weight per day for 5 consecutive days,followed by booster doses of 0.4 g/kg/bodyweight once dailyevery 2 mo for 2 yr (n = 20) 2) Placebo (n = 20) 

1) Physical functioning: Definition of “improvement”: 1.0-point change in EDSS compared with baseline Proportion of patients with “improvement”: In the IV IgG group 23.5% of patients improved vs. 10.8% in the placebo group Other (non-improvement) outcomes: No significant change in mean EDSS in treatment arm 2) Relapse frequency:Definition of “relapse”: The rapid appearance, reappearance, or worsening of one or more neurological abnormalities, persisting at least 48 hr, after a relativelystable or improving neurological state of at 

least 30 days. A relapse was confirmed only when the patient’s symptoms were accompanied by objective changes on neurological examination by a blinded neurologist. Definition of “improvement”: Not specified on a per patient basis Proportion of patients with “improvement”: Not specified Other (non-improvement) outcomes: a) Yearly exacerbation rates  IV IgG Placebo P-valueBaseline 1.85 1.55 0.34 Year 1 0.75 1.8 0.0002 Year 2 0.42 1.42 0.0009 2-yr total 0.59 1.61 0.0006 

This apropoimprovIV IgG definitpoint ino datmay hpoint. QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of No 
51 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

b) Exacerbation-free patients:  IV IgG Placebo P-valueYear 1 8 1 0.001 Year 2 12 3 0.001 Total study 6 0 0.001 c) Median time to first exacerbation (days):  IV IgG Placebo P-value 233 82 0.003 

Bastianello, Pozzilli, D’Andrea, et al., 1994 

Inclusion: Definitediagnosis of MS; relapsing-remittingdisease course (≥ 2 relapses in 24 mo prior to study entry);disease duration 1-10 yr; EDSS 2.0-5.0;age 18-45; selected to undergo serial MRI scans (subgroup of total studypopulation) Exclusion: HIVpositive; previouscardiovasculardisease; left ventricular ejection fraction < 50% byechocardiography; renal, liver, and/orrespiratory dysfunction; diabetes; malignancy;psychiatric illness; pregnancy or nocontraception; use of immunosuppressant drugs or steroids in previous 3 mo 

RCT (parallelgroup, doubleblind, multicenter)Duration of study treatment/followup: 1 yr (preliminaryresults from planned 2-yr trial)Provider specialty:Neurologists Location: 7 sites in Italy

No. of patients randomized: 25 (subgroup of total study population selected to undergo serial MRI scans) Dropouts: 0 Completed: 25 Age (mean ± SD):MTX: 29.9 ± 5.2 Placebo: 28.5 ±

6.5 Baseline EDSS (mean ± SD): MTX: 3.7 ± 0.7 Placebo: 3.5 ± 1.0

Baseline relapse rate (mean inprevious 2 yr ±SD): MTX: 2.8 ± 1.2 Placebo: 3.3 ± 1.2

1) Mitoxantrone (MTX) 8 mg/m2 by 30-

min IV infusion everymonth for 1 yr (n = 13)2) Placebo (n = 12) 

1) Physical functioning: Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: No statistical difference was observed in mean EDSS change at 1 yr (p = 0.18) 2) Relapse frequency:Definition of “relapse”: The appearance of new symptom or worsening of an old one, attributable to MS and lasting at least 24 hours in the absence of fever Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes:  MTX Placebo P value MER 0.54 1.67 0.014 PWE 5(38%) 10(83%) 0.02 MER = Mean exacerbation rate PWE = Number (%) of patients with exacerbations 

This trdemonin redbut doinformimprovbaseliQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
52 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Bornstein, Miller, Slagle, et al., 1987 

Inclusion: DefiniteMS; relapsingremitting form of MS; ≥ 2 well-demarcated and well-documented relapses in previous 2 yr; EDSS ≤ 6; emotionally stable; age 20-35 Exclusion: None specified 

RCT (parallelgroup, doubleblind, singlecenter, matchedpairs design) Duration of study treatment/followup: 2 yr Provider specialty:Neurologists Location: 1 site in Bronx, NY

No. of patients randomized: 50Dropouts: 7 dropped out before 2 yr, but 5 of these were included in analysis Completed: 43 completed trial; 48 included in analysis Age (mean): Cop 1: 30.0 Placebo: 31.0 Baseline EDSS (mean): Cop 1: 2.9 Placebo: 3.2 Baseline relapse rate (mean over 2 yr):Cop 1: 3.8 Placebo: 3.9 

1) Glatiramer acetate = Copolymer 1 (Cop 1) by SC injection, 20 mg self-injected daily for 2 yr (n = 25) 2) Placebo (n = 25) 

1) Physical functioning: Definition of “improvement”: Reduction in EDSS by 1, 2, or 3 points over 2 yr Proportion of patients with “improvement”:  Placebo Cop 1 1.0 point 8.7% 20.0% 2.0 points 0 12.0% 3.0 points 4.4% 02) Relapse frequency:Definition of “relapse”: The rapid onset of new symptoms or a worsening of preexisting symptoms that persisted for 48 hours or more, when accompanied by observed objective changes on the neurological examination involving an increase of a atl east one grade in the score for one of the eight functional groups or the Kurtzke Scale Definition of “improvement”: Decrease in 2-yr relapse rate in comparison with individual baseline relapse rate Proportion of patients with “improvement”: Placebo – 12 of 23 patients experienced a decrease in relapse rate over the 2yr period Cop 1 – 24 of 25 patients experienced a decrease in relapse rate over the 2-yr treatment periodOther (non-improvement) outcomes: Exacerbation-free patients: Placebo – 26% Cop 1 – 56% P = 0.036 

This eCopolrelapsbenefrelaps

statusthe nuimprovsignifiblindincorrecplacebQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
53 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Bornstein, Miller, Slagle, et al., 1991 

Inclusion: Definitediagnosis of MS byPoser criteria; evidence of a chronic-progressive course for ≥ 18 mo; ≤ 2 exacerbations in previous 24 mo; EDSS score 2.0-6.5; emotionally stable and able to participate in clinical trial; age 20-60 During a 6- to 15-mo pre-trial observation period, patients required to demonstrate progression in one of following ways:worsening of 2 grades in a functional system; worsening of 1 grade in 2 unrelated functional systems; worsening of 2 units on the Ambulation Index; or worsening of 1 grade on the EDSS. Must not have progressed beyond 6.5 on EDSS or have had > 1 exacerbation during pre-trial observation period. Exclusion: None specified 

RCT (parallelgroup, doubleblind, two-center)Duration of study treatment/followup: 2 yr or until confirmed progression (whichever first) Provider specialty:Neurologists Location: Bronx,NY; and Houston,TX 

No. of patients randomized: 106 Dropouts: 20 Completed: 86 Age (mean): Cop 1: 41.6 Placebo: 42.3 Baseline EDSS: Mean: Cop 1: 5.7 Placebo: 5.5 

 Cop 1 Plac

< 5: 22% 27%5-5.5: 8% 15% 6-6.5: 71% 58%Baseline relapse rate: NR 

1) Copolymer 1(Cop 1) by SCinjection; 15 mg selfinjected twice per dayfor 2 yr (n = 51) 2) Placebo (n = 55) 

1) Physical functioning: Definition of “improvement”: Not defined Proportion of patients with “improvement”: Cop 1: 19.6% improved 37.3% remained stable  41.1% worsenedPlacebo: 14.5% improved 34.6% remained stable  50.9% worsenedOther (non-improvement) outcomes: The primary endpoint, confirmed progression of 1.0 or 1.5 units (depending on baseline disability) on the Kurtzke Disability Status Scale, was not statistically different in the two groups 2) Relapse frequency:Definition of “relapse”: Not definedDefinition of “improvement”: Not assessed Proportion of patients with “improvement”: Not delineated 

This sinformpatienQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
54 

Evidence Table 3a. Disease modifying therapies and long-term impro

vement (continued) 

Stu

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Study Design Patients Interv

entions Outcomes/Results Com

British and Dutch MultipleSclerosis Azathioprine Trial Group, 1988 

Inclusion: Clinicallydefinite MS (≥ 2 

episodes and 2 clinical lesions or 2 episodes and 1 subclinical lesion[revealed by VEP or CT]); or laboratory confirmed MS (≥ 2 

anatomicallyseparate episodes, 1 clinical lesion, and oligoclonal bands or increased IgG in the CSF); or currently progressive MS (2separate lesions [of which 1 might besubclinical], oligoclonal bands, or increased IgG in the CSF, and progression for at least 6 mo); patients 

with

relapsing-remittingdisease had to have been in a remittent phase for ≥ 1 mo and have had ≥ 1 relapses in the previous year; EDSS ≤ 6 (ambulant); age 15-50; not on other immunomodulatorydrugs or hyperbaric oxygen treatmentExclusion: Concomitant systemic disease; mental deficit that precluded understanding and 

RCT (parallelgroup, doubleblind, multicenter)Duration of study treatment/follo

w

up: 3 yr Provider specialty:Neurologists Location: 20 sites in the UK and The Netherlands 

No. of patients randomized: 354 (199 [56

%] 

clinically definite, 37 [10%] laboratory confirmed; 51 [14%] progressive from onset; 67 [19%] progressive after remission) Lost to follow up(cumulative totals): 20 at 1 yr, 24 at 2 yr, 22 at 3 yr, 153 at 4 yrDiscontinued treatment (cumulative totals): 48 at 1 yr, 64 at 2 yr, 75 at 3 yr Completed: 279 completed treatment, 332 followed up through 3 yr Age (mean ± SD):Azathioprine: 39 ±

8.6 Placebo: 38 ± 8.3 Baseline EDSS (mean ± SD): Azathioprine: 3.69 ± 1.50 Placebo: 3.66 ±

1.62 Baseline relapse 

1) Azathioprine PO 2.5 mg/kg (to thenearest 25 mg) daily(n = 174) 2) Placebo (n = 180) 

1) Physical functioning: Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: The only statistically significant result 

was a 

reduction in the deterioration of the Ambulation Index in the azathioprine group compared 

with the placebo group after 3 yr 

The trmargindelinewith reQ

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55 

Evidence Table 3a. Disease modifying therapies and long-term impro

vement (continued) 

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Study Design Patients Interv

entions Outcomes/Results Com

cooperation rate (months since 

last relapse): 

 Az Plac 

1-6: 43

% 45% 

7-12: 20

% 18% 

> 12: 37% 37% 

Canadian CooperativeMultipleSclerosis StudyGroup, 1991 

Inclusion: Clinicallydefinite or laboratorysupported definite MS in a progressive phase (deterioration of at least 1 point on EDSS over preceding 12 mo); EDSS 4.0-6.5; age ≥ 15 Exclusion: Previous treatment with cyclophosphamide, cyclosporin, antilymphocyte globulin, or interferon; treatment with azathioprine or plasma exchange in preceding yr or corticosteroids inpreceding mo; illnesses that might be adversely affected by study treatments; substantial cognitive impairment; un

willingness to use 

contraception during trial and for 2 yr after; weekly venous access difficult 

RCT (parallelgroup, not double-blinded, multicenter)Duration of study treatment/follo

w

up: Duration of treatment variable (see at right, under “Interventions”); patients followedup for at least 12mo; mean follo

w

up, 30.4 mo Provider specialty:Neurologists Location: 9 sites in Canada 

No. of patients randomized: 168 (81 relapsingprogressive, 86 chronicprogressive, 1 unkown) Dropouts: 2 (died)Completed: 166Age (mean at disease onset ±

SD): Cyclophosphamide IV: 31.9 ± 10.3 

Plasma exchange: 29.9 ± 7.9 

Placebo: 32.1 ±

9.7 Baseline EDSS (mean ± SD): Cyclophosphamide IV: 5.79 ± 0.61 

Plasma exchange: 5.66 ± 0.72 

Placebo: 5.79 ±

0.64 Baseline relapse rate: NR 

1) Cyclophosphamide IV + prednisone PO (n = 55). 

Cyclophosphamide 1g given 

intravenously on alternate days until WBC count fell below

4.5 x 109

/L or until total 

dose of 9 g reached. Prednisone 40 mggiven orally for 10days, then reduced by10 mg on alternate days and discontinued on day 16. 2) Plasma exchange + cyclophosphamide PO + prednisone PO (n = 57). Plasmaexchange of one plasma volume (40 mL/kg) done weeklyfor 20 wk with either intermittent (5 sites) or continuous (4 sites) flow-type centrifuges. Replacement = 5

%

serum albumin. Oral cyclophosphamide 1.5-2.0 mg/kg given daily for 22 

wk; dose 

adjusted to achieve target WBC of 4.0-5.0 x 109

/L. Oral 

prednisone 20 mggiven every other day

1) Physical functioning: Definition of “improvement”: 1.0-point improvement on EDSS sustained for 6 mo Proportion of patients with “improvement”: No statistically significant difference among the treatment arms Number of patients improved: 

 Cycl PEX Placebo 

1 yr 3 (6%) 4 (8%) 1 (2%)2 yr 2 (6%) 1 (3%) 0 3 yr 2 (4%) 1 (2%) 1 (2%)Other (non-improvement) outcomes: No statistically significant difference between treatment arms in any outcome measure 

This saddreimprovresults benefQ

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56 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

and tapered over 22 wk.3) Placebo (placebo oral cyclophosphamide and prednisone for 22 wk + shamplasma exchange for 20 wk) (n = 56) 

Cohen, Cutter, Fischer, et al., 2002 

Inclusion: Clinicallydefinite secondary progressive MS, with or without recent relapses; disease progression overprevious 1 yr; cranial MRI demonstrating lesions consistentwith MS; EDSS 3.5-6.5; age 18-60 Exclusion: Primaryprogressive disease course; inability to complete MS Functional Composite at baseline; prior treatment with interferon-β

RCT (parallelgroup, doubleblind, multicenter)Duration of study treatment/followup: 2 yr Provider specialty:Neurologists Location: 42 sites in US, Europe, andCanada 

No. of patients randomized: 436 Dropouts: 115; ofthese, 63 had complete 2-yr follow up Completed: 321 completed treatment; 384 followed up for 2 yrAge (mean ± SD):IFNβ-1a: 47.2 ±

8.2 Placebo: 47.9 ±

7.7 Baseline EDSS (mean ± SD): IFNβ-1a: 5.2 ± 1.1

Placebo: 5.2 ± 1.1

Baseline relapse rate (mean ± SD,prior 3 yr):IFNβ-1a: 1.5 ± 2.1

Placebo: 1.3 ± 2.1

1) Interferon β-1a

(IFNβ-1a) 60 μg 

weekly by IM injection for 2 yr (n = 217); half dose (30 μg) given for first four doses to

minimize adverse events 2) Placebo for 2 yr (n = 219) 

1) Physical functioning: Definition of “improvement”: Not defined for individual patients Proportion of patients with “improvement”: Improvement based on EDSS – baseline to 24 months Placebo – 7.3% IFNβ-1a – 7.5% 

No statistically significant difference Other (non-improvement) outcomes: 24-month MSFC data-median:  Placebo IFNβ-1a P value 

MSFC -0.161 -0.362 0.033 9HPT -0.290 -0.202 0.024 Timed 25-ft walk – no statistical difference PASAT – no statistical difference 2) Relapse frequency:Definition of “relapse”: New or recurrent neurological symptoms, not associated with fever or infection, lasting at least 48 hours and accompanied by objective change on the examining neurologist’s examination at an unscheduled visit corresponding to the reported symptoms Definition of “improvement”: Not delineated on individual patients Proportion of patients with “improvement”: 

This s

1a in sassesMSQLeffects the firsscale treatmprimaupper focuseand ppatienQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
57 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Not delineated Other (non-improvement) outcomes: Annual relapse rate: Placebo – 0.30 IFNβ-1a – 0.20 

P = 0.008 Relapse-free patients – intention to treat: Placebo – 63% IFNβ-1a – 74% 

P=0.023 3) Quality of life: The MS Quality of Life Inventory (MSQLI) was administered to English-speaking subjects at baseline, 12 months, and 24 months Definition of “improvement”: Not defined Proportion of patients with “improvement”: NR Other (non-improvement) outcomes: Significant benefit favoring IFNβ-1a treatment was observed on 8 of 11subscales of the MSQLI, with a favorable trend on the remaining three scales. The IFNβ-1a group improved from baseline to 

month 24 on 10 of 11 subscales (all except Bladder Control Scale). In contrast, the placebo group worsened from baseline to month 24 on 10 of 11 subscales, the Modified Fatigue Impact Scale being the only subscale showing improvement. Data not shown (reference made to 

www.neurology.org web site). 
58 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Currier, Haerer, and Meydrech,1993 

Inclusion: DefiniteMS; a worsening in function or an exacerbation in the previous yr; understanding and willingness to cooperate Exclusion: History orevidence of renal or hepatic disease; gross obesity;diabetes 

RCT (parallelgroup, doubleblind, singlecenter) Duration of study treatment/followup: Initially 1 yr; changed during trial to 18 mo Provider specialty:Neurologist Location: Jackson, MS 

No. of patients randomized: 45 (20 “exacerbating remitting” and 24“chronic” MS [latter includes 18 “exacerbating progressive,” 3 “chronic progressive,” and 3 “spinal patients”]) Dropouts: 9 Completed: 36 Age (median, reported only byMS type): Exacerbating remitting: 39.5 Chronic: 46.8 Baseline EDSS: NR Baseline relapse rate (total number of exacerbations in 12 mo precedingtrial; reported only for patients with “exacerbating remitting” MS): Methotrexate: 9 in 9 patients Placebo: 12 in 11 patients 

1) Methotrexate PO; 2.5 mg every 12 hr for 3 consecutive doses once per wk (7.5 mg/ wk) for 18 mo (n = 22) 2) Placebo (n = 22) 

1) Physical functioning: Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: 2) Relapse frequency:Definition of “relapse”: 1.0-point EDSS worsening (unsustained) Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: No statistically significant difference in treatment groups except for a difference in the mean number of exacerbations p = 0.05 – data presented in graphical form only

This sindivid

therapQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
59 

Evidence Table 3a. Disease modifying therapies and long-term impro

vement (continued) 

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Study Design Patients Interv

entions Outcomes/Results Com

De Castro, Cartoni, Millefiorini, et al., 1995 

Inclusion: Definitediagnosis of MS according to Posercriteria; relapsingremitting disease course; ≥ 2 relapses 

in 24 mo prior to study entry; disease duration 1-10 yr; EDSS 2.0-5.0; age 18-45 Exclusion: HIVpositive; heart, renal, lung, or liver disease; psychiatric disease; pregnancy or lactation; known allergy to corticosteroids; other neurological disease; use of corticosteroids during previous 3 mo; use of levamisol,isoprinosin, or plasmapheresis during previous 3 mo; treatment with interferon; immunosuppressive therapy during previous 12 mo 

RCT (parallelgroup, doubleblind, singlecenter) Duration of study treatment/follo

w

up: 1 yr Provider specialty: NR (presumably neurologists and cardiologists)Location: 1 site in Italy

No. of patients randomized: 20Dropouts: N

R

(implied 0) Completed: NR(implied 20) Age (mean ± SD):MTX: 31 ± 5 Placebo: 30 ± 4 Baseline EDSS (mean ± SD): MTX: 3.77 ± 0.72Placebo: 3.33 ±

0.75 Baseline relapse rate (mean inprevious 2 yr ±SD): MTX: 2.82 ± 0.98Placebo: 3.00 ±

1.94 

1) Mitoxantrone (MTX) 8 mg/m2 by 30-

min IV infusion everymonth for 1 yr (n = 13)2) Placebo (n = 12) 

1) Physical functioning: Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: No statistically significant difference between treatment arms 

with respect to changes in 

EDSS 2) Relapse frequency:Definition of “relapse”: Not definedDefinition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Difference in relapse rate favored treatment with mitoxantrone p = 0.005 

This ssignifirate in includimprovQ

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Evidence Table 3a. Disease modifying therapies and long-term impro

vement (continued) 

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Study Design Patients Interv

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EuropeanStudyGroup onInterferon beta-1b inSecondaryProgressiveMS, 1998 

Inclusion: Clinicallyor laboratory supported definite diagnosis of secondaryprogressive MS; EDSS 3.0-6.5; ≥ 2 relapses or ≥ 1.0-point increase in EDSS in previous 2 yr; age 18-55Exclusion: None specified 

RCT (parallelgroup, doubleblind, multicenter)Mean duration oftreatment/follo

w

up: Treatment scheduled to last 36 mo, 

with 3-mo

follow up; article reports results of prospectivelyplanned interim analysis of all patients in studyfor ≥ 2 yr; mean 

follow up time 901 days for IFNβ-1b and 892

days for placeboProvider specialty: NR (presumably neurologists) Location: 32 sites in Europe 

No. of patients randomized: 718 Lost to follow up:57Withdre

w from 

treatment, but had complete follow up: 130 Completed treatment and follow up: 531 Age (mean ± SD):IFNβ-1b: 41.1 ±

7.2 Placebo: 40.9 ±

7.2 Baseline EDSS (mean ± SD): IFNβ-1b: 5.1 ± 1.1

Placebo: 5.2 ± 1.1

Baseline relapse rate (

% of patients 

without relapse in 2 yr preceding 

study): IFNβ-1b: 31.9%

Placebo: 28.2%

1) Interferon β-1b

(IFNβ-1b) by SC 

injection; initial dose 0.5 mL (4 MIU) everyother day, increased after 2 

wk to 1.0 mL (8 

MIU) every other dayfor up to 3 yr (n = 360)2) Placebo (n = 358) 

1) Physical functioning: Primary endpoint was time to confirmed progression in disability defined as a 1.0-point increase on EDSS sustained for at least 3 months, or a 0.5-point increase if the baseline EDSS was 6.0 or 6.5 Results: Significant difference in time to confirmed progression of disability in favor of IFNβ1-b (p = 0.0008) 

On average IF

Nβ1-b delayed confirmed 

progression by 9-12 months in this patient population Confirmed EDSS progression: Placebo: 46.7%IFNβ1-b: 38.9%

p = 0.0048 2) Relapse frequency:Definition of “relapse”: Not definedDefinition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: a) Mean annual relapse rate:  Placebo IFN β-1b p Overall 0.64 0.44 0.0002 Year 1 0.82 0.57 0.0095 Year 2 0.47 0.35 0.0201 Year 3 0.35 0.24 0.1624 b) Proportion of patients with moderate to severe relapse: Placebo: n = 190 (53.1

%) 

IFNβ1-b: n = 157 (43.6

%) 

p = 0.008 

This aIFNβ-

rate orelapsregardpatienstatusSee aPozzilQ

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Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Fazekas, Deisenhammer, StrasserFuchs, et al., 1997a and Fazekas, Deisenhammer, StrasserFuchs, et al., 1997b and StrasserFuchs, Fazekas, Deisenhammer, et al., 2000 

Inclusion: Clinicallydefinite diagnosis of relapsing-remittingMS; EDSS score 1.0-6.0; ≥ 2 clearly

identified and documented relapses during previous 2 yr; age 15-64; first manifestation of MS at age 10-59 Exclusion: Immunosuppressive or immunomodulatorytherapy in previous 3 mo; corticosteroids in previous 2 wk; primary or secondaryprogressive MS; benign course of disease as indicated by a deteriorationrate (EDSS scoredivided by duration of disease in years) < 0.25 

RCT (parallelgroup, doubleblind, multicenter)Duration of study treatment/followup: 2 yr Provider specialty:Neurologists Location: 13 sites in Austria 

No. of patients randomized: 150 Lost to follow up:2 (before start of treatment) Stopped treatment: 28 Completed treatment: 120 Age (mean [95%CI]): IV IgG: 36.7 (34.3-39.1) Placebo: 37.3 (35.0-39.6) Baseline EDSS (mean [95% CI]):IV IgG: 3.3 (3.0-3.6) Placebo: 3.3 (2.9-3.7) Baseline relapse rate (mean per yr[95% CI]): IV IgG: 1.3 (1.1-1.5) Placebo: 1.4 (1.2-1.6) 

1) IV immunoglobulin (IV IgG); 0.15-0.20 g/kg body weight once per month for 2 yr (n = 75) 2) Placebo (n = 73) 

1) Physical functioning: Definition of “improvement”: 1.0-point decrease in EDSS by the end of the studyProportion of patients with “improvement”: IV IgG – 31% of patients improved Placebo – 14% of patients improved Other (non-improvement) outcomes: Between-group differences in the absolute change on the EDSS score and in the proportion of patients stable or worsened 2) Relapse frequency:Definition of “relapse”: The appearance or reappearance of one or more neurological abnormalities that persisted for at least 24 hours and had been preceded by a stable or improving neurological state of at least 30 days. A relapse was confirmed only if the patient’s symptoms were accompanied byobjective changes of at least one grade in 

the scored for one of the eight functional groups on the EDSS. Definition of “improvement”: Not delineated Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes:  IV IgG Placebo P Relapse-free 53% 36% 0.03  Patients Mean Annual Relapse Rate 

Year 1 0.49 1.30 0.011 Year 2 0.42 0.83 0.006 

3) Quality of life: Incapacity Status Scale and the Environmental Status Scale 

These treatmregardMoreoincreademonover thQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
62 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Definition of “improvement”: Not defined prospectivelyProportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: The mean change of rating scores of 15 of 16 items was more favorable following IV IgG treatment. The total mean change of ratings over all ISS items was significantly in favor of IV IgG-treated patients (P = 0.01) Similarly, IV IgG-treated patients noted improvement in 4 of 7items of the ESS compared to no item rated as improved byplacebo patients. 

Ghezzi, Di Falco, Locatelli, et al., 1989 

Inclusion: DefiniteMS Exclusion: Disease duration < 1 yr; EDSS > 7; concomitant diseases contraindicating immunosuppression 

RCT (parallelgroup, openlabel, singlecenter) Duration of study treatment/followup: 18 mo Provider specialty: NR (presumably neurologists) Location: 1 site in Gallarate, Italy

No. of patients randomized: 185 (74 relapsing, 111 relapsingprogressive) Dropouts: 50 Completed: 135Age (mean at onset [with range], completers only):Relapsing (R)-azathioprine: 26 (15-42) R-control: 26 (18-42) Relapsingprogressive (RP)-azathioprine: 29 (12-44) RP-placebo: 31 (16-47) Baseline EDSS (mean [with range], 

1) Azathioprine PO 2.5 mg/kg per day for 18 mo (n = 69) 2) No azathioprine (n = 66) 

1) Physical functioning: Definition of “improvement”: Not defined Proportion of patients with “improvement”: Relapsing patients who improved:Azathioprine – 5 of 32 Controls – 0 of 22P > 0.10 Relapsing-progressive patients: Azathioprine – 2 of 37 Controls – 3 of 44p > 0.10 Other (non-improvement) outcomes: No statistical difference between the treatment arms with respect to EDSS 2) Relapse frequency:Definition of “relapse”: Not definedDefinition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated 

This uMS didiffereData aindividQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
63 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

completers only):R-azathioprine: 2.1 (1-5) R-control: 2.2 (1-5) RP-azathioprine:3.8 1-6.5)RP-placebo: 3.7(1-7) Baseline relapse rate (mean [with range], completers only, time frame not specified): mean at onset [with range], completers only):R-azathioprine: 1.2 (0.2-4) R-control: 1.1 (0.2-3) RP-azathioprine:0.6 (0.1-3.3) RP-placebo: 0.4(0.1-2.5) 

Other (non-improvement) outcomes: No statistically significant difference in treatment arms 

Goodkin, Bailly,Teetzen, et al., 1991 

Inclusion: Clinicallydefinite or laboratorysupported definite MS; seen at study clinic from 1983 to1989; relapsingremitting disease course (≥ 2 exacerbations in previous 18 mo); no exacerbation in previous 1 mo; EDSS 2.0-6.5; AI 1.0-6.0; age 18-65 Exclusion: Chronic 

RCT (parallelgroup, doubleblind [patients and examining physician, not treating physician], singlecenter) Duration of study treatment/followup: 2 yr Provider specialty:Neurologists 

No. of patients randomized: 59 randomized, 54 began treatmentNo. followed for 2 yr: 52 No. treated per protocol for 2 yr: 43 Age (mean ± SD atonset; n = 54 starting treatment): Azathioprine: 29.4 

1) Azathioprine PO; initial dose 50 mg 3 times per day,adjusted to target dose of 3 mg/kg, with increases made in increments of 25 mg per day no more than once per month; WBC maintained at 3500-4000/μL (n = 29)2) Placebo (n = 25) 

1) Physical functioning: Definitions of “improvement”: Score reflects combined results of change lasting more than 2 mo in any of following: ≥ 1.0-point on EDSS for patients with baseline EDSS ≤ 5.0, or

≥ 0.5-point on EDSS for patients with baseline EDSS ≥ 5.5, or

≥ 1.0 point on AI, or

≥ 20% deterioration from baseline in 9HPT or BBT Proportion of patients with “improvement”: Placebo = 20% Azathioprine = 22.2% 

This sbenefexacedata rwho imEDSS The pwas, hamong QUALDescrMethodescriConceDescrPatien
64 

Evidence Table 3a. Disease modifying therapies and long-term impro

vement (continued) 

Stu

d

y

S

electe

d

Inclusion/ Exclusion Criteria

Study Design Patients Interv

entions Outcomes/Results Com

progressive disease (worsening in functional status measurements over 6 mo 

without 

exacerbation); use of corticosteroids inprevious 1 mo; use of immunosuppressant medication in previous 1 yr; pregnant; un

willing to 

practice birth control; systemic illness of medical condition that precluded safe administration of study drugs 

Location: 1 site in Fargo, N

D

± 8.5 Placebo: 30.0 ±

6.8 Baseline EDSS (mean ± SD; n = 54 starting treatment): Azathioprine: 3.18 ± 1.19 Placebo: 3.72 ±

1.60 Baseline relapse rate (mean ± SD in previous 18 mo; no = 54 starting treatment): Azathioprine: 2.34 ± 0.55 Placebo: 2.32 ±

0.63 

Other (non-improvement) outcomes: Difference in mean change in EDSS 2) Relapse frequency:Definition of “relapse”: Objective worsening in the EDSS of ≥ 0.5 points, Ambulation Index (AI) of ≥ 1.0 points, or ≥ 20% deterioration from baseline performance on the nine-hole peg test (9HPT) or box-andblock test (BBT) in patients who were stable or improving 

within the last month 

Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Mean on-trial exacerbation rates for each group:  AZA Placebo P Year 1 0.74 1.17 0.16 Year 2 0.30 0.79 0.05 Total 2 year 1.04 1.88 0.08 

InvestOutcoNo. of Yes

Goodkin, Rudick, VanderBrug Medendorp,et al., 1995 

Inclusion: Clinicallydefinite chronic progressive MS; progressive neurological impairment during period of ≥ 6 mo prior to start of study; no exacerbation for previous 8 mo; ≤ 1 exacerbation in previous 2 yr; disease duration > 1 yr; EDSS 3.0-6.5; AI 2.0-6.0; no corticosteroids during previous 1 mo or

RCT (parallelgroup, doubleblind, singlecenter) Duration of study treatment/follo

w

up: 2 yr Provider specialty:Neurologists Location: 1 site in Cleveland, OH

No. of patients randomized: 60 (18 primaryprogressive, 42 secondaryprogressive) Dropouts: 9 Completed: 51 Age (mean ± SD):METH: 43 ± 9.3

Placebo: 46 ± 8.8 Baseline EDSS (mean): 

1) Methotrexate (METH), one 7.5-mg oral tablet per week for 2 yr (n = 31) 2) Placebo (n = 29) 

1) Physical functioning: Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: The primary outcome measure was time to treatment failure on a composite measure of physical functioning that utilized EDSS, Ambulation Index, Box and Block Test and 9-Hole Peg Test for 2 mo or more.Treatment failure was pre-defined on the basis of specific levels of deterioration on any of these scales. There was a significant relationship bet

ween 

This sdose oin patiand focompofunctioobservfunctioindividprovidthe prQ

UAL

DescrMethodescriConce
65 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

immunosuppressant medication for previous 1 yr; no prior lymphoid irradiation; willing to use contraception; age 21-60 Exclusion: Pregnancy; systemic illness or medical condition that precluded safe administration of study drugs; clinicallyevident cognitiveimpairment 

METH: 5.5 Placebo: 5.3 Baseline relapse rate: NR 

sustained progression and treatment group favoring the METH treatment: METH = 51.6%, Placebo = 82.8% (p = 0.011). This treatment effect was strongest for the 9HPT and was seen to a lesser extent (p = NS) for the BBT and EDSS. 

DescrPatienInvestOutcoNo. of Yes

Hartung, Gonsette, König, et al., 2002 

Inclusion: Worsening relapsing-remittingMS (stepwise progression of disability between relapses) or secondaryprogressive MS; EDSS 3.0-6.0; worsening of ≥ 1 point on EDSS in previous 18 mo; no relapse in previous 8 wk; no treatment with glucocorticosteroids in previous 8 wk; no previous treatment with mitoxantrone, interferons, glatiramer acetate, cytotoxic drugs, ortotal-body lymphoid irradiation; left ventricular ejection fraction > 50%; WBC, 

RCT (parallelgroup, doubleblind [patients and assessors, not treating physicians], multicenter)Duration of study treatment/followup: Treatment lasted 2 yr; patients followedfor total of 3 yr Provider specialty:Neurologists Location: 17 sites in Belgium, Germany,Hungary, andPoland 

No. of patients randomized: 194 randomized; 188included in baseline measures (94 worsening relapsing-remitting, 94 secondary progressive) Dropouts: 56 Completed: 138 assessed at 3 yrAge (mean ± SD):MTX 12 mg: 39.94 ± 6.85 MTX 5 mg: 39.92± 8.06 Placebo: 40.02 ±7.88 Baseline EDSS (mean ± SD): 

1) Mitoxantrone (MTX) 12 mg/m2 by

slow IV infusion every3 months for 2 yr; dose could be reduced in response to adverse events, infection, or low WBC or platelet count (n = 63) 2) Mitoxantrone (MTX) 5 mg/m2 by

slow IV infusion every3 months for 2 yr; dose could be reduced in response to adverse events (n = 66) 3) Placebo (n = 65) 

1) Physical functioning: EDSS, Ambulation Index, and standard neurological status scores were established at each scheduled and unscheduled visit Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Mean and median EDSS change, Ambulation Index change, SNS change 2) Relapse frequency:Definition of “relapse”: Severe relapse defined as the occurrence of new symptoms lasting for longer than 48 hours with a change in functional system score of more than 2 points, or a deterioration of at least 1 point in at least one of the four following systems: pyramidal, brainstem, cerebellar, or visual Definition of “improvement”: Not defined 

This smitoxa

monthrelapsprogrestatisttreatmoutcomanalyschangtotal nfirst trestanda5-mg/

convinprovidindividQUALDescrMethodescriConceDescrPatienInvest
66 

Evidence Table 3a. Disease modifying therapies and long-term impro

vement (continued) 

Stu

d

y

S

electe

d

Inclusion/ Exclusion Criteria

Study Design Patients Interv

entions Outcomes/Results Com

neutrophil, and platelet counts in normal ranges; age 18-55 Exclusion: None specified 

MTX 12 mg: 4.45± 1.05 MTX 5 mg: 4.64 ±1.01 Placebo: 4.69 ±

0.97 Baseline relapse rate (mean ± SD in previous 1 yr): MTX 12 mg: 1.27± 1.12 MTX 5 mg: 1.42 ±1.26 Placebo: 1.31 ±

1.14 

Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Number of treated relapses per patient (median, with range): Placebo: 1 (0-5)MTX 12 mg: 0 (0-2) p = 0.0002 

OutcoNo. of Yes

Hauser, Da

wson, 

Lehrich, et al., 1983 

Inclusion: Clinicallydefinite MS; severe progressive disease, with worsening inprevious 9 mo (defined as a decrease of ≥ 1 

points on functional status or disabilityscales, eithercontinuous decline or continuous decline with superimposed exacerbations); nocorticosteroid therapyin previous month; no immunosuppressive therapy in previous yrExclusion: Medical illnesses incompatible with safe administration of study medications 

RCT (parallelgroup, not double-blinded, two-center) Duration of study treatment/follo

w

up: Treatment duration variable (see at right, under “Interventions”; patients followedfor total of 1 yr Provider specialty: NR (presumably neurologists) Location: 2 sites in Boston, MA 

No. of patients randomized: 58Dropouts: 0 Completed: 58 Age (mean ± SE): ACTH: 35.2 ± 1.5 

CYCL

O + AC

T

H: 

32.9 ± 1.8 

PEX + CYCL

O +

ACTH: 36.3 ± 1.7 

Baseline EDSS (mean ± SE):ACTH: 5.6 ± 0.2CYCL

O + AC

T

H: 

5.8 ± 0.2 

PEX + CYCL

O +

ACTH: 5.6 ± 0.2Baseline relapse rate: NR 

1) Adrenocorticotropic hormone (ACTH) (n = 20). Initially given intravenously dailyover 8-hr period, 

with 

doses as follows: 25 units on days 1-3, 20 units on days 4-6, 15 units on days 7-9, 10 units on days 10-12, and 5 units on days13-15. IM injections then given on days 16-18 (40 units each) and days 19-21 (20 units each), after which treatment discontinued. 2) High-dose cyclophosphamide (CYCL

O) + AC

T

H (n = 

20). CYCLO administered intravenouslydaily for 10-14 days at dosage of 400-500 mg 

1) Physical functioning: Definition of “improvement”: Decrease of one or more points on either the A

mbulation 

Index or the Disability-Status Scale, as compared 

with the score at the time of entry

Proportion of patients with “improvement”: ACTH alone – 5%ACTH + C

Y

CLO – 40% 

ACTH, PEX and oral C

YCLO – 20% 

Other (non-improvement) outcomes: Physician’s clinical assessment of stabilized neurological status 2) Relapse frequency:Definition of “relapse”: Not definedDefinition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated 

This sintens(partichigh-dsignifithe poseverespecifpropoclinicaAmbutherapThe ais not recomregimeshould treatmselectunremhave nregimebased studiethat th
67 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

per day in 4 divided doses (total dose 80-100 mg/kg body weight). Discontinued when WBC count fell to approximately4000/mm3. Large 

volumes of fluids administered orallyand by IV to prevent bladder toxicity. ACTH given as above, beginning on same day as CYCLO. 3) Plasma exchange (PEX) + low-dose CYCLO + ACTH (n = 18). PEX performed by means of continuous-glowexchange; approximately 1-1.5 plasma volumes removed perexchange and replaced with 5%serum albumin. 4-5 exchanges given over a 2-wk period. CYCLO given at lowdose (2 mg/kg/day) for 8 wk (dose decreased if WBC count fell below 4000/mm3). 

ACTH as above. All 3 treatments started together. 

signifiQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
68 

Evidence Table 3a. Disease modifying therapies and long-term impro

vement (continued) 

Stu

d

y

S

electe

d

Inclusion/ Exclusion Criteria

Study Design Patients Interv

entions Outcomes/Results Com

IFNB MultipleSclerosis StudyGroup, 1993 and IFNB StudyGroup and the Universityof British Columbia MS/MRI AnalysisGroup, 1995 and IFNB StudyGroup and the Universityof British Columbia MS/MRI AnalysisGroup, 1996 and Pliskin, Hamer, Goldstein, et al., 1996 

Inclusion: Clinicallydefinite or laboratorysupported definite MS for > 1 yr; E

DSS 

≤ 5.5; ≥ 2 acute 

exacerbations in previous 2 yr; clinically stable for at least 30 days before entry; no ACT

H or 

prednisone during 30 days prior to entry; age 18-50 Exclusion: Prior treatment with azathioprine or cyclophosphamide 

RCT (parallelgroup, doubleblind, multicenter)Duration of study treatment/follo

w

up: Original study period 2 yr;later extended; median time on study was 48.0 mo for the IFNβ1b 8 MIU group, 45.0 mo for the IFNβ-1b 1.6 MIU

group, and 46.0 mo for the placebo group Provider specialty:Neurologists Location: 4 sites in Canada and 7 in US 

No. of patients randomized: 372 Dropouts: Sixtyfive patients discontinued treatment during the first 2 yr (23 placebo, 18 in the 1.6 MIU, and 24 in the 8 MIU groups) 154 (over entire study period)Completed: 307 through 2 yr; 218through end of studyAge (mean ± SE): IFNβ-1b 8 MIU: 

35.2 ± 0.6 

IFNβ-1b 1.6 MIU:

35.3 ± 0.7 

Placebo: 36.0 ±

0.6 Baseline EDSS (mean ± SE):IFNβ-1b 8 MIU: 

3.0 ± 0.1 

IFNβ-1b 1.6 MIU:

2.9 ± 0.1 

Placebo: 2.8 ± 0.1

Baseline relapse rate (mean in past 2 yr ± SE): IFNβ-1b 8 MIU: 

3.4 ± 0.2 

IFNβ-1b 1.6 MIU:

3.3 ± 0.1 

1) Recombinant interferon β-1b (IFNβ1b), 8 MIU selfadministered by SC injection every other day for duration of study (n = 124) 2) Recombinant IFNβ1b, 1.6 MIU selfadministered by SC injection every other day for duration of study (n = 125) 3) Placebo (n = 123) 

1) Physical functioning: A secondary endpoint, progression in disability, was defined as a persistent increase of one or more EDSS points confirmed on t

wo consecutive evaluations 

separated by at least 3 months Results: Median time to progression (yr)  Placebo – 4.18 1.6 MIU – 3.49 8 MIU – 4.79Time to progression (placebo vs. 8 MIU)  P = 0.096 2) Relapse frequency:Definition of “relapse”: Appearance of a ne

w

sy

mptom or worsening of an old symptom, 

attributable to M

S; accompanied by an 

appropriate ne

w neurological abnormality;

lasting at least 24 hours in the absence of fever; and preceded by stability orimprovement for at least 30 daysAnnual relapse rate: Year 1 Placebo – 1.44 

1.6 MIU – 1.22

8 MIU – 0.96 

Placebo vs. 8 MIU: p < 0.001 

Year 2 Placebo – 1.18 

1.6 MIU – 1.04

8 MIU – 0.85 

Placebo vs. 8 MIU: p ≤ 0.03 

Year 3 Placebo – 0.92 

1.6 MIU – 0.80

8 MIU – 0.66 

Placebo vs. 8 MIU: p = 0.084 

Year 4 Placebo – 0.88 

1.6 MIU – 0.68

8 MIU – 0.67 

Placebo vs. 8 MIU: p = 0.166 

Year 5 Placebo – 0.81 

1.6 MIU – 0.66

These of IFNexacediseasdemonof any 

Q

UAL

DescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
69 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Placebo: 3.6 ± 0.1 8 MIU – 0.57 

Placebo vs. 8 MIU: p = 0.393 

3) Cognitive functioning: Immediate and delayed recall memory and visual reproduction subtests of the Wechsler Memory Scale, forms 1 and 2, attention/mental speed (Trailmaking Test part B; Stroop Color-Word Test), dominant and nondominant morot function (Purdue Pegboard), and Beck Depression Inventory were administered to patients in all groups during the course of the study. No baseline measurements were made. Results: A significant main effect for time (F = 15.75 [2, 27], p < 0.001) and an interaction effect between treatment condition and time of testing (F = 4.15 [2, 27], p < 0.03) were found for WMS VRDelayed Recall. Follow-up pairwise comparisons indicated an improvement in delayed visual reproduction between the second and fourth years of treatment in the high-dose group (WMS VR-Delayed Recall; p < 0.003). The placebo and low-dose groups did not change significantly. No other neuropsychological parameters demonstrated a significant difference between the groups during the study.

Jacobs, Cookfair, Rudick, et al., 1996 and Rudick, Goodkin, Jacobs, et al., 1997 and 

Inclusion: DefiniteMS for ≥ 1 yr; EDSS 

1.0-3.5; relapsing disease course, with ≥ 2 documented exacerbations in previous 3 yr and no exacerbations for at least past 2 mo; age 18-55 Exclusion: Prior 

RCT (parallelgroup, doubleblind, multicenter)Duration of study treatment/followup: Variable (enrollment date varied, but endof-study date same for all patients) 

No. of patients randomized: 301 Dropouts: Not completely clear; 23 earlywithdrawals,variable treatment durations Completed: 287 followed up through 1 yr; 172

1) Interferon β-1a

(IFNβ-1a) 6 million 

units by IM injection weekly for up to 3 yr (n = 158) 2) Placebo for up to 3 yr (n = 143) 

1) Physical functioning: Definition of “improvement”: ≥ 0.5- or 1.0-point improvement on EDSS Proportion of patients with “improvement”:  Placebo IFNβ-1a Improved Unsustained 

≥ 1.0 10 (11.5%) 16 (19.3%) 

 0.5 10 (11.5%) 13 (15.7%) Improved 

The stdemonwith reas merelapsvariouparamIFNβ-

of the treatmdata oSome the nu
70 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Fischer, Priore, Jacobs, et al., 2000 and Jacobs, Rudick, and Simon, 2000 and Rudick, Fisher, Lee, et al., 2000 

immunosuppressant or interferon therapy;adrenocorticotropic hormone orcorticosteroidtreatment in previous 2 mo; pregnancy or nursing; unwilling to practice contraception; chronic progressive MS; any disease other than MS compromising organ function 

Provider specialty:Neurologists Location: 4 sites in US 

through 2 yr; 31 through 3 yr Age (mean ± SE): IFNβ-1a: 36.7 ±

0.57 Placebo: 36.9 ±

0.64 Baseline EDSS (mean ± SE):IFNβ-1a: 2.4 ±

0.06 Placebo: 2.3 ±

0.07 Baseline relapse rate (mean ± SE,time frame not specified): IFNβ-1a: 1.2 ±

0.05 Placebo: 1.2 ±

0.05 

Sustained ≥ 1.0 5 (8.9%) 10 (18.2%)  0.5 9 (16.1%) 14 (25.5%) Other (non-improvement) outcomes: Time to sustained progression of disability,the primary outcome measure, was significantly greater in IFNβ-1a-treated 

patients than in placebo-treated patients (p = 0.02) 2) Relapse frequency:Definition of “relapse”: Appearance of newneurological symptoms or worsening of preexisting neurological symptoms lasting at least 48 hours in a patient who had been neurologically stable or improving for the previous 30 days accompanied by objective change on neurological examination 

(worsening of 0.5 point on the EDSS or a worsening by ≥ 1.0 point on the pyramidal, 

cerebellar, brainstem, or visual functional system scores)Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Annual relapse rates:  Placebo IFNβ-1a P value 

All patients 0.82 0.67 0.04 104 week patient subset 0.90 0.61 0.002 3) Cognitive functioning: The Comprehensive NP Battery is a broadspectrum battery comprising measures from the core battery recommended by the National MS Society Cognitive Function Study Group as well as additional measures covering cognitive domains of theoretical 

EDSS QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
71 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

interest Definition of “improvement”: Not defined for individual patients Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Relapsing MS patients treated with IFNβ-1a 

for 2 yr performed significantly better than placebo patients on a composite of information processing and learning/recent memory measures (set A from the Comprehensive NP Battery). A similar trend was observed on a composite measure of visuospatial abilities and executive functions (set B) but not on the set C composite (verbal abilities and attention span).

Johnson, Brooks, Cohen, et al., 1995 and Weinstein, Schwid, Schiffer, et al., 1999 and Liu, Blumhardt, and the Copolymer 1 Multiple Sclerosis StudyGroup, 2000 and 

Inclusion: Clinicallydefinite or laboratorysupported MS; relapsing-remittingcourse; ambulatory,with EDSS 0-5.0; ≥ 2 

clearly documented relapses in 2 yr prior to entry; onset of first relapse ≥ 1 yr before 

randomization; neurological stabilityand freedom fromcorticosteroid therapyfor ≥ 30 days prior to 

entry; age 18-45Exclusion: Previous Copolymer 1 therapy;previous immunosuppressive therapywith cyctotoxic chemotherapy or

RCT (parallelgroup, doubleblind, multicenter)Duration of study treatment/followup: 2 yr Provider specialty:Neurologists Location: 11 sites in the US 

No. of patients randomized: 251 Dropouts: 36 Completed: 215Age (mean ± SD):Cop 1: 34.6 ± 6.0 Placebo: 34.3 ±

6.5 Baseline EDSS (mean ± SD): Cop 1: 2.8 ± 1.2Placebo: 2.4 ± 1.3

Baseline relapse rate (mean ± SD for prior 2 yr): Cop 1: 2.9 ± 1.3Placebo: 2.9 ± 1.1

1) Glatiramer acetate = Copolymer 1 (Cop 1) by SC injection; 20 mg self-injected daily for 2 yr (n = 125) 2) Placebo (n = 126) 

1) Physical functioning: Definition of “improvement”: ≥ 1.0-point 

EDSS reduction Proportion of patients with “improvement”: Original 2-yr trial: Cop 1 – 24.8% Placebo – 15.2%Extension study:Cop 1 – 27.2% Placebo – 12.0%Other (non-improvement) outcomes: Mean change in EDSS, Ambulation Index, proportion of progression-free patients, area under curve analyses of EDSS progression 2) Relapse frequency:Definition of “relapse”: Appearance or reappearance of one or more neurological 

This sCopolrelapspatienon EDQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
72 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Johnson, Brooks, Cohen, et al., 1998 

lymphoid irradiation; need for aspirin or chronic NSAIDs during trial; [othergeneric exclusions] 

abnormalities persisting for at least 48 hours 

and immediately preceded by a relativelystable or improving neurological state of at least 30 days. A relapse was confirmed onlywhen a patient’s symptoms wereaccompanied by objective changes on the neurological examination consistent with an increase of at least a half a step on the EDSS, two points on one of the seven functional systems, or one point on two or more of the functional systems. Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Relapse rate:  Cop 1 Placebo P-value Relapse rate 24 months 1.19 1.68 0.007 Annual relapse rate 0.59 0.84 Relapse free 33.6% 27.0% 0.098 Extension Relapse rate 1.34 1.98 0.002 Extension Annual relapse rate 0.58 0.81 3) Cognitive functioning: Brief Repeatable Battery of Neuropsychological Tests – consisting of 5 tests including measures of sustained attention and concentration (Paced Auditory Serial Addition Test and Symbol Digit Modalities Test), verbal learning and delayed recall (Buschke Selective Reminder Test), visuospatial learning and delayed recall (10/36 Spatial Recall Test), and semantic retrieval (Word 
73 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

List Generation Test) Definition of “improvement”: Not defined Proportion of patients with “improvement”: Mean neuropsychologic test scores were improved at 12 and 24 months compared with baseline for placebo and glatiramer groups. No differences were detected between the treatment groups for any of the neuropsychologic test results. Other (non-improvement) outcomes: 

Kappos, Polman, Pozzilli, et al., 2001 and Freeman, Thompson, Fitzpatrick, et al., 2001 

Inclusion: Clinicallyor laboratory supported definite diagnosis of secondaryprogressive MS; EDSS 3.0-6.5; ≥ 2 relapses or ≥ 1.0-point increase in EDSS in previous 2 yr; age 18-55Exclusion: None specified 

RCT (parallelgroup, doubleblind, multicenter)Mean duration oftreatment/followup: Treatment lasted up to 36 mo; article reports results at study termination;mean follow-up time 1068 ± 176 days for IFNβ-1b

and 1054 ± 199 days for placeboProvider specialty: NR (presumably neurologists) Location: 32 sites in Europe 

No. of patients randomized: 718 Lost to follow up:88Withdrew from treatment: 132 Completed treatment and follow up: 498 Age (mean ± SD):IFNβ-1b: 41.1 ±

7.2 Placebo: 40.9 ±

7.2 Baseline EDSS (mean ± SD): IFNβ-1b: 5.1 ± 1.1

Placebo: 5.2 ± 1.1

Baseline relapse rate (% of patients without relapse in 2 yr preceding study): 

1) Interferon β-1b

(IFNβ-1b) by SC 

injection; initial dose 0.5 mL (4 MIU) everyother day, increased after 2 wk to 1.0 mL (8 MIU) every other dayfor up to 3 yr (n = 360)2) Placebo (n = 358) 

1) Physical functioning: Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Time to confirmed progression in EDSS favored IFNβ-1b, p = 0.007 Percent of patients progression-free Placebo – 46.1%IFNβ-1b – 54.7%

P = 0.031 2) Relapse frequency:Definition of “relapse”: Previously defined Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not assessed Other (non-improvement) outcomes: Percent of patients relapse-free: Placebo – 36.3%IFNβ-1b – 42.5%

P = 0.083 

These analysfrom tconduGroup ProgreSignifrelapsparamstudy improvrates.QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
74 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

IFNβ-1b: 31.9%

Placebo: 28.2%

Percent of patients relapse-free or decrease in relapse rate: Placebo – 45.0%IFNβ-1b – 53.1%

P = 0.031 3) Quality of life: The SIP is a generic self-report questionnaire of health-related quality of life, which examines the individual’s perception of the impact of the disease process on behavior in everyday life. The total score ranges from 0 (best) to 100 (worst). The GEMS scale was developed specificallyfor this study and provides a global evaluation of the neurologist’s perception of change in terms of disease status and disability. The scale provides 7 points ranging from “very much better” to “verymuch worse.” No published information is available determining its measurement properties. Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: The difference in total SIP score for the twogroups shows a non-statistically significant trend in favor of IFNβ-1b. 

The SIP physical dimension score demonstrates a statistically significant benefit in favor of IFNβ-1b therapy at 6 and 

12 months. A significant treatment effect of IFNβ-1b was 

demonstrated in the psychosocial dimension scores at 18 months but not at the end of the study.
75 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Khatri, McQuillen, Harrington,et al., 1985 

Inclusion: Clinicallydefinite MS; chronic progressive disease course (continuous worsening on serial neurological exams during previous 12mo); patient insured, and insurance company would payfor plasma exchange Exclusion: None specified 

RCT (parallelgroup, doubleblind, singlecenter) Duration of study treatment/followup: 18 mo Provider specialty:Neurologists Location: 1 site in Milwaukee, WI

No. of patients randomized: 59Dropouts: 4 Completed: 55 Age (mean, completers): Genuine: 37.8 Sham: 42.2 Baseline EDSS (mean, completers): Genuine: 6.6 Sham: 6.3 Baseline relapse rate: NR 

1) Plasma exchange (n = 30); during each exchange, plasmavolume equivalent to 5% of patient’s bodyweight exchanged for 5% albumin solution and normal saline in equal ratios; exchanges performed once per week for 20 wk2) Sham plasmaexchange (patient’s plasma returned after it had been separated) (n = 29); exchanges performed once per week for 20 wkPatients in both groups also received: a) Oral cyclophosphamide (1.5 mg/kg per day, rounded tonearest 50 mg); b) prednisone (1 mg/kg every other day,gradually decreasing doses after 15th wk);

and c) pooled human immune serum globulin (40 ml in 4 divided IM injections over 2 days after each exchange) 

1) Physical functioning: Two scoring scales were used in measuring clinical change, the Kurtzke DSS and the Canter Scale, which measures changes in activities of daily living Definition of “improvement”: ≥ 1-point improvement on DSS Proportion of patients with “improvement”: At 5 mo, 14 plasmapheresis patients improved and 8 sham pheresis patients improved with details as follows: 5-mo evaluation: PP Sham 3 or more 5 0 points 2 points 5 4 1 point 4 4 11-mo evaluation: PP Sham 3 or more 3 0 points 2 points 4 1 1 point 4 4 Other (non-improvement) outcomes: Not delineated 2) Relapse frequency:Definition of “relapse”: Not definedDefinition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Not delineated 3) Cognitive functioning: Standard 

This sthe treThe replasmmeasuObserimprovalthouQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
76 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

neurological examination Definition of “improvement”: Not defined Proportion of patients with “improvement”: 4 patients with cognitive deficits improved in these functions at the 15th PP treatment, but 

this did not occur in similar patients in the sham group 

Leary,Miller, Stevenson, et al., 2003 

Inclusion: Primaryprogressive MS (progressive historywithout relapse orremission, ≥ 2 typical lesions on MRI brain or spinal cod, and oligoclonal bands in the CSF not present in parallel serum orabnormal visual evoked potentials); disease duration ≥ 2 

yr; EDSS 2.0-7.0;age 18-60 Exclusion: Interferon, immunosuppressant, or chronic steroidtherapy in previous 3 mo; pregnancy orlactation; seizure in previous 3 mo; history of severe depression 

RCT (parallelgroup, doubleblind, singlecenter) No. of patients randomized: 50 Dropouts: 7 

withdrew fromtreatment; all but 1 of these followedup for 2 yr Completed: 43 completed treatment; 49followed up for 2 yrAge (mean [with range]):

Duration of study treatment/followup: 2 yr Provider specialty: NR (presumably neurologists) Location: 1 site in London, UK 

IFNβ-1a 60: 47 

(25-59) IFNβ-1a 30: 46.5 

(29-58) Placebo: 43 (30-59) Baseline EDSS (median [with range]):IFNβ-1a 60: 5.5 

(2.0-6.5) IFNβ-1a 30: 5.5 

(3.5-7.0) Placebo: 4.5 (2.0-7.0) Baseline relapse 

1) Interferon β-1a

(IFNβ-1a) 60 μg 

weekly by IM injection for 2 yr (n = 15) 2) IFNβ-1a 30 μg

weekly by IM injection for 2 yr (n = 15) 3) Placebo for 2 yr (n = 20) 

1) Physical functioning: Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Primary endpoint was time to sustained progression in disability, and there was no statistically significant difference among the treatment arms 

This sIFNβ-

progreof time found treatmregardimprovQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
77 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

rate: NA 

Milanese, La Mantia, Salmaggi, et al., 1988 

Inclusion: Clinicallydefinite MS bySchumacher’s criteria; relapsingremitting (with ≥ 2 

relapses in previous 3 yr) or progressive (with continuous worsening of neurological status over previous 1 yr) disease course Exclusion: Conditions which did not permit regular examination or which hampered patient’s reliability (e.g., DSS > 7 or psychic disturbances); contraindications to immunosuppressive treatment; previous use of immunosuppressive therapy;pregnancy 

RCT (parallelgroup, doubleblind, singlecenter) Duration of study treatment/followup: 1 yr (see “Comments”) Provider specialty:Neurologists Location: 1 site in Milan, Italy

No. of patients randomized: 23 included in 1-yranalysis reportedhere (13 relapsingremitting, 10 progressive) Dropouts: 0 (though 2 droppedout after 1 yr; see “Comments”) Completed: 23 Age (mean): AZA-relapsing: 33.1 Placebo-relapsing: 34.1 AZA-progressive: 38.1 Placeboprogressive: 42.4 Baseline EDSS (mean): AZA-relapsing: 2.17 Placebo-relapsing: 2.43 AZA-progressive: 5.00 Placeboprogressive: 3.86Baseline relapse rate (mean per yr): AZA-relapsing: 1.144 Placebo-relapsing: 0.890 

1) Azathioprine (AZA) PO 2-2.5 mg/kg per day for 1 yr (n = 9) 2) Placebo for 1 yr (n = 14) 

1) Physical functioning: Definition of “improvement”: Not delineated Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: No statistically significant difference at 1 yr2) Relapse frequency:Definition of “relapse”: Schumacher criteria Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Relapse rate – Progressive MS: 

Pre- Final

AZA 0.5 0.42 Placebo 0.32 0.42 Relapse rate – Relapsing-remitting MS: 

Pre- Final

AZA 1.14 0.98 Placebo 0.89 0.92 No statistically significant differences in relapse rates 

This sazathiremittstatistdetecttrial. ApatienresultiregardinformindividQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
78 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

AZA-progressive: 0.500 Placeboprogressive: 0.318

Millefiorini, Gasperini, Pozzilli, et al., 1997 

Inclusion: Clinicallydefinite or laboratorysupported relapsingremitting MS; disease duration 1-10 yr; EDSS 2-5; at least 2 exacerbations in previous 2 yr; age 18-45 Exclusion: HIVpositive; previouscardiovasculardisease; left ventricular ejection fraction < 50%; renal, liver, and/or respiratory dysfunction; diabetes; malignancy;psychiatric illness; pregnancy; women not using contraception; use of steroids in previous 3 mo; previous immunosuppressant therapy 

RCT (parallelgroup, doubleblind [patients and assessors, not treating physicians], multicenter)Duration of study treatment/followup: Treatment lasted 1 yr; patients followedfor total of 2 yr Provider specialty:Neurologists Location: 8 sites in Italy

No. of patients randomized: 51 (all relapsingremitting) Dropouts: 9 Completed: 42 completed all assessments (including MRIs) Age (mean ± SD):MTX: 30.9 ± 6.0 Placebo: 28.7 ±

6.5 Baseline EDSS (mean ± SD): MTX: 3.6 ± 0.9 Placebo: 3.5 ± 1.2

Baseline relapse rate (mean ± SD in previous 2 yr): MTX: 2.8 ± 1.2 Placebo: 2.8 ± 1.1

1) Mitoxantrone (MTX), 30-min IVinfusion (8 mg/m2) 

ever month for 1 yr (n = 27) 2) Placebo (n = 24) 

1) Physical functioning: Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: % of patients who progressed by 1.0 point on EDSS – found statistically significant benefit of mitoxantrone at 2 yr 2) Relapse frequency:Definition of “relapse”: Appearance of a newsymptom or worsening of an old symptom, attributable to MS, accompanied by a documented new neurological abnormality,lasting more than 48 hours and preceded bystability or improvement for at least 30 daysDefinition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Number of exacerbation (mean ± SD): MTX: 0.89 ± 2.1 Placebo: 2.62 ± 1.9 

p = 0.0002 Exacerbation-free patients: MTX: 17 (63%) Placebo: 5 (21%) p = 0.006 

This smitoxaremittisignifiregard rate rewith reimprovQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of No – a
79 

Evidence Table 3a. Disease modifying therapies and long-term impro

vement (continued) 

Stu

d

y

S

electe

d

Inclusion/ Exclusion Criteria

Study Design Patients Interv

entions Outcomes/Results Com

MultipleSclerosis StudyGroup, 1990 

Inclusion: Clinicallydefinite MS for ≥ 1 yr; EDSS 3.0-7.0; age 18-55; chronic and progressive clinical deterioration of ≥ 1 grade, but not > 3 grades, on EDS

S in 

previous 12 mo, 

with 

some decline in last 6 mo; no acute relapse in previous 3 mo; no immunosuppressive drugs in previous 3 mo; no unproventherapies for MS (e.g., hyperbaric oxygen, gangliosides, snake venom [!]) in previous 1 mo; noprior treatment with cyclophosphamide or radiation; no uncontrolled hypertension (SBP > 170 mmHg or DBP > 110 mmHg),malignancy, recent myocardial infarction, chronic pulmonary disease, active infection, hepatic or renal dysfunction, or other neurological disorders; not using medications kno

wn to 

interfere with studydrugs Exclusion: Known sensitivity or adverse reactions to immunosuppressive 

RCT (parallelgroup, doubleblind, multicenter)Duration of study treatment/follo

w

up: 2 yr Provider specialty:Neurologists Location: 12 sites in US 

No. of patients randomized: 547 Dropouts: 120 (cyclosporine) + 87 (placebo) = 207 Completed: 340 Age (mean ± SD):Cyclosporine: 40.5 ± 7.7 Placebo: 40.6 ±

8.2 Baseline EDSS (mean ± SD): Cyclosporine: 5.4 ± 1.2 Placebo: 5.4 ± 1.2

Baseline relapse rate: NR 

1) Cyclosporine PO (liquid suspension); initial dose of 6 mg/kg diluted in milk ororange juice and taken each morning 

with

breakfast; dose adjusted to achieve whole-blood cyclosporine trough level of 400-600 ng/mL, later reduced to 300-500 ng/mL; maximum dose permitted was 10mg/kg/day (n = 273) 2) Placebo (n = 274) 

1) Physical functioning: Extensive evaluations performed including EDSS, incapacity status scales, functional system scores of the Multiple Sclerosis Minimal Record of Disability, standardized neurological exa

mination, quantitative 

examination of neurological functional, Ambulation Index, physical exa

mination, and 

clinical evaluation Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Mean change in EDSS – found benefit of cyclosporine therapy with p = 0.006 in patients completing study, and p = 0.002 in all patients. 2) Relapse frequency:Definition of “relapse”: Not definedDefinition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: 

This stherappatienhigh ddemonbenefprogrenot primprovQ

UAL

DescrMethodescriConceDescrPatienInvestOutcoNo. of Yes – withdrnecesprimamodifianalys56% ocycloscontinthose succe(p=0.0
80 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

drug; severe dementia; paraplegia or gait ataxia sufficient to prevent walking; severeupper extremityataxia preventing independent feeding or dressing 

Noseworthy,O’Brien, Petterson, et al., 2001 

Inclusion: One ormore episodes ofdemyelinating optic neuritis occurring in the setting of clinically definite orlaboratory-supported definite MS or in the presence of cranial MRI changes consistent with MS; first episode of optic neuritis between ages of 18 and 45; age < 50 at enrollment; fixed,apparentlyirreversible loss of visual acuity in at least one eye thatmet following criteria: a) visual acuity worse than 20/40 for a period of at least 6 mo and unchanged on at least 2 exams separated by at least 1 mo; b) optic disc pallor as detected bystudy neuroophthalmologist; c) abnormal visual field measured on Humphrey Field 

RCT (parallelgroup, doubleblind, singlecenter) Duration of study treatment/followup: Treatment lasted 12 wk + 5 days; patients followed for total of 12 mo Provider specialty:Ophthalmologists and neurologists Location: 1 site in Rochester, MN

No. of patients randomized: 55 (42 relapsingremitting, 13 secondaryprogressive) Dropouts: 2 (both between 6 and 12mo) Completed: 53 Age (mean ± SD):IV IgG: 38.0 ± 7.2 

Placebo: 39.2 ±

6.7 Baseline EDSS (mean ± SD, excluding visual functional status scores): IV IgG: 3.6 ± 2.5

Placebo: 3.0 ± 2.5

Baseline relapse rate: NR 

1) IV immunoglobulin (IV IgG) 0.4 g/kg dailyfor 5 days, then once per month for 3 months (total of 8 infusions) (n = 27) 2) Placebo (n = 28) 

1) Physical functioning: Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Several measures of visual function were assessed, as well as EDSS. No measures demonstrated statistically significant benefit from therapy.2) Relapse frequency:Definition of “relapse”: Not defined

Definition of “improvement”: Not assessed Proportion of patients with “improvement”: Not assessed Other (non-improvement) outcomes: 

This sIgG in patienterminNo daindividQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
81 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Analyzer with a mean deviation ≤ -4.00 and a pattern of defect consistent with optic neuritis; no adrenocorticotropic hormone orcorticosteroids inprevious 2 mo Exclusion: Primaryprogressive MS; nondemyelinating cause for visual loss; preexisting ocular abnormalities; serious intercurrent medical illness; concomitant use of experimental drug for MS or other disease; serum creatinine > 1.5 times normal;pregnancy or unwillingness to use contraception; known antibody deficiencysyndrome; need for IV IgG administration 

Patti, L’Episcopo, Cataldi, et al., 1999 

Inclusion: DefiniteMS; disease course relapsing-remitting(with ≥ 2 documented 

relapses in previous 2 yr and EDSS ≤ 3.5) 

or secondary progressive (withdeterioration of ≥ 1.0 point on the EDSSover previous 2 yr and EDSS ≤ 7.0); emotionally stable; 

RCT (parallelgroup, doubleblind, singlecenter) Duration of study treatment/followup: 2 yr Provider specialty:Neurologists 

No. of patients randomized: 98 (58 relapsingremitting, 40 secondaryprogressive) Dropouts: 0 Completed: 98 Age (mean): Relapsing1) Natural interferon-β (nIFNβ) 6 MIU by IM injection three times per wk for 2 yr (n = 49) 2) Placebo for 2 yr (n = 49) 1) Physical functioning: Definition of “improvement”: Decrease of 0.5 or 1.0 in EDSS Proportion of patients with “improvement”: Relapsing-remitting patients: Placebo – 1 of 29 patients (3.4%) improved nIFNβ – 15 of 29 patients (52%) improved P = 0.002 Secondary progressive patients: Placebo – 1 of 20 patients (5%) improved nIFNβ – 8 of 20 patients (40%) improved This s

nIFNβ 

seconsignifitreatmpropoor 1.0 propoQUALDescrMethodescri
82 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

negative for HIV,HbsAg, and Borreliosis; free of other immune orneurological diseases; clinicallystable for ≥ 30 days; no ACTH orcorticosteroids inprevious 30 days; age 18-45 Exclusion: Pregnancy; prior treatment with azathioprine or cyclophosphamide (in previous 1 yr) 

Location: 1 site in Catania, Italy

remitting (RR)patients: 36.6 Secondaryprogressive (SP)patients: 36.9 Baseline EDSS (mean): RR-nIFNβ: 3.06RR-placebo: 3.1SP-nIFNβ: 5.8 SP-placebo: 6.0Baseline relapse rate (mean over previous 2 yr): RR-nIFNβ: 1.8 RR-placebo: 1.9SP-nIFNβ: 0.4 SP-placebo: 0.6

P = 0.006 2) Relapse frequency:Definition of “relapse”: Rapid onset of newsymptoms or a worsening of preexisting symptoms persisting for 48 hours or more and were accompanied by objective changes on the neurologic examination – an increase of at least one grade in the score for at least one of the functional groups of EDSS Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: The probability of remaining exacerbationfree was significantly higher in the nIFNβtreated group (presented in graphical form; 

p < 0.001) 

ConceDescrPatienInvestOutcoNo. of Yes

Patzold, Hecker, and Pocklington, 1982 

Inclusion: Confirmed MS; resident in district of study site Exclusion: None specified 

RCT (parallelgroup, openlabel, singlecenter) Duration of study treatment/followup: 2 yr Provider specialty:Neurologists Location: 1 site in Hanover, Germany

No. of patients randomized: 142 Dropouts: 27 before completing1 yr; 17 more before completing2 yrCompleted: 115 completed 1 yr (53 intermittent, 52 intermittentprogressive, 10 progressive); 98 completed 2 yr (47 intermittent, 43 intermittentprogressive, 8 progressive) 

1) Azathioprine PO, daily dose of 2 mg/kg for 2 yr (n = 74) 2) No azathioprine (n = 68) 

1) Physical functioning (EDSS notassessed): Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not assessed Other (non-improvement) outcomes: Patients were evaluated clinically and the severity of disease was calculated by means of an objective weighting scale corresponding to the data recorded by the examiner. In the untreated group on average MS deteriorated three times as rapidly as in the treated group. 2) Relapse frequency:

This sazathiThis trissues validaThe suncleadata rimprovQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of 
83 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Age: NR Baseline EDSS: NR Baseline relapse rate: NR 

Definition of “relapse”: Definite worsening of condition lasting for 24 hr or more, or the occurrence or recurrence of symptoms and signs after a period of 4 wk in which these had either disappeared or improvedDefinition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: No. of relapses: Azathioprine: 2.4 ± 2.0 Control: 1.9 ± 1.3 

Yes

PRISMS StudyGroup and the Universityof British Columbia MS/MRI AnalysisGroup, 1998 and Liu and Blumhardt, 1999 and Liu and Blumhardt, 2002 and Patten and Metz, 2001 

Inclusion: Clinicallydefinite or laboratorysupported definite MS of at least 1 yr duration; relapsingremitting MS with ≥ 2 relapses in preceding 2 yr and EDSS score 0-5.0; adult Exclusion: Any previous systemictreatment with interferons, lymphoid irradiation, or cyclophosphamide; other immunomodulatory or immunosuppressive treatment in previous 12 mo 

RCT (parallelgroup, doubleblind, multicenter)Duration of study treatment/followup: 2 yr Provider specialty:Neurologists Location: 22 sites in Canada, Australia, and 7 European countries 

No. of patients randomized: 560 Lost to follow up:27 Withdrew from treatment: 31Followed up to 2 yr: 533 Completed treatment to 2 yr:502 Age (median withIQR):IFNβ-1a 44 μg: 

35.6 (28.4-41.0)IFNβ-1a 22 μg: 

34.8 (29.3-39.8)Placebo: 34.6 (28.8-40.4) Baseline EDSS (mean ± SD): 

1) Interferon β-1a

(IFNβ-1a) by SC 

injection, 44 μg (12 MIU), 3 times weekly(n = 184) 2) IFNβ-1a by SC

injection, 22 μg (6 MIU), 3 times weekly(n = 189) 3) Placebo (n = 187) 

1) Physical functioning: Definition of “improvement”: In the categorical disability trend analysissustained improvement was defined as a decrease of at least 1.0 EDSS point confirmed at 3 months and sustained until the end of the study

Proportion of patients with “improvement”: Not stated – in the categorical disabilitytrend analysis data were not reported on the number of patients with sustained improvement. 31% of treated patients and 20% of placebo patients attained stable course. Other (non-improvement) outcomes: 22-mcg dose and 44-mcg dose patients both had mean reduction in EDSS compared with placebo of 0.25 2-yr change in EDSS: 

Mean AUC 

Placebo +0.48 +0.48 22-mcg dose +0.23 +0.05 44-mcg dose +0.24 +0.06 

This sregardplacebEDSS are reno datpatienstatusQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
84 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

IFNβ-1a 44 μg: 

2.5 ± 1.3 

IFNβ-1a 22 μg: 

2.5 ± 1.2 

Placebo: 2.4 ± 1.2

Baseline relapse rate (mean relapses in previous 2 yr [±SD]: IFNβ-1a 44 μg: 

3.0 ± 1.1 

IFNβ-1a 22 μg: 

3.0 ± 1.1 

Placebo: 3.0 ± 1.3

2) Relapse frequency (primary outcome measure): Definition of “relapse”: As defined bySchumacher criteria, required theappearance of a new symptom or worsening of an old symptom over at least 24 hr that could be attributed to MS activity and was preceded by stability or improvement for at least 30 daysDefinition of “improvement”: Proportion of patients with “improvement”: - Not stated Other (non-improvement) outcomes: Relapses per patient:  Placebo – 2.56 22 mcg dose – 1.82  44 mcg dose – 1.73 % reduction in relapses vs. placebo:  22 mcg dose – 29  44 mcg dose – 32 % relapse free over 1 year:  Placebo – 22 22 mcg dose – 37  44 mcg dose – 45 % relapse free over 2 years:  Placebo – 16 22 mcg dose – 27  44 mcg dose – 32 Moderate or severe relapses - % with no relapses:  Placebo – 42 22 mcg dose – 61  44 mcg dose – 62 % with no admissions for MS: 
85 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

 Placebo – 75 22 mcg dose – 77  44 mcg dose - 82 3) Cognitive functioning [describe scale/ instrument used]:Definition of “improvement”: Not assessed Proportion of patients with “improvement”: Not assessed 5) Quality of life: Center for Epidemiological Studies Depression Rating Scale was used to assess whether treatment with IFNβ-1a was associated with depression Other (non-improvement) outcomes: Proportion of patients exceeding cut-point did not vary significantly across treatment groups 

Rice, Filippi, and Comi, 2000 

Inclusion: Clinicallydefinite or laboratorysupported MS according to Schumacher or Poser criteria; chronic progressive disease course (slowprogression of signs and symptoms over preceding 12 mo); EDSS 3.0-6.5; serum creatinine < 1.5 mg/dL and creatinine clearance ≥ 80% of 

age-adjusted normal; aspartate and alanine transaminase and alkaline phosphatase levels < twice the normal upper limit; 

RCT (parallelgroup, doubleblind, multicenter)Duration of study treatment/followup: 12 mo Provider specialty: NR (presumably neurologists) Location: 6 sites in Canada and the US 

No. of patients randomized: 159 (111 secondary progressive, 48 primaryprogressive) Dropouts: 4 Completed: 155Age (mean): High-dose: 43.8Low-dose: 44.6 Placebo: 44.2 Baseline EDSS (mean): High-dose: 5.6 Low-dose: 5.6 Placebo: 5.6 

1) Cladribine by SC injection, 6 monthlycourses of 0.07 mg/kg/day for 5 consecutive days (total dose 2.1 mg/kg),followed by 2 monthlycourses of placebo (n = 52) 2) Cladribine by SC injection, 2 monthlycourses of 0.07 mg/kg/day for 5 consecutive days (total dose 0.7 mg/kg),followed by 6 monthlycourses of placebo (n = 53) 3) Placebo, 8 monthlycourses (n = 54)

1) Physical functioning: Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Primary outcome measure was mean change in EDSS – no statistical difference in treatment groups observed 2) Relapse frequency:Definition of “relapse”: Not assessed Definition of “improvement”: Not delineated Proportion of patients with “improvement”: Not assessed 

This sof cladsignifioutcomregardimprovQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of No – 9study
86 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

neutrophil count > 1600/μL; plateletcount > 130,000/μL; clinically normal ECGand chest X-ray; age 21-60 Exclusion: Significant history of medical disease in previous 2 yr; use of corticosteroids or other immunosuppressants in previous 3 mo; total lymphoid irradiation; persistent leukopenia or thrombocytopenia after treatment with immunosuppressive agents; alcohol or drug abuse orattempted suicide in previous 1 yr; malignancy in previous 5 yr; pregnancy or nursing; HIV+; use of experimental drug or device in last 60 days; previous participation in cladribine trial 

Baseline relapse rate: NR 

Romine, Sipe, Koziol, et al., 1999 

Inclusion: Clinicallydefinite relapsingremitting MS for at least 1 yr; ≥ 2 relapses in previous 2 yr; EDSS ≤ 6.5Exclusion: Treatment with immunosupRCT (parallel- group, double- blind, single- center) Duration of study treatment/follow up: Treatment lasted 8 mo; 

patients followed

No. of patients randomized: 52Dropouts: 2 before 12 mo, plus 6 more before 18 moCompleted: 50 to12 mo, 44 to 18mo 

1) Cladribine by SC injection; 5 consecutive daily injections of 0.07 mg/kg/day given monthly for 6 mo for total cumulative dose of 2.1 mg/kg; during remaining 2 mo of 8-mo treatment period, placebo given unless 

1) Physical functioning: Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not assessed Other (non-improvement) outcomes: No significant differences between the two groups with regard to EDSS or SNRS scores over the 18-mo period 

This scladribpatienstatistregard benefwith reThe dto clinpatien
87 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

pressive drugs in previous 3 mo; serum creatinine > 1.5 mg/dL; serum glutamic-oxaloacetic transaminase/serum glutamic-pyruvic transaminase or alkaline phosphatase elevated to twice the upper limit of normal; neutrophil counts of < 1600/μL or platelet counts < 130,000/μL; previous total lymphoid irradiation or extensive myelosuppressive chemotherapy 

for total of 18 moProvider specialty:Neurologists Location: 1 site in La Jolla, CA 

Age (mean, with range): Cladribine: 43.4 (30-52) Placebo: 39.8 (31-52) Baseline EDSS (mean, with range): Cladribine: 3.9 (2.0-6.5) Placebo: 3.8 (2.0-6.5) Baseline relapse rate (number inprevious 1 yr): Cladribine: 1: 5 (19%) 2: 16 (59%) 3-4: 6 (22%) Placebo: 1: 13 (52%) 2: 5 (20%) 3-4: 7 (28%) 

investigators had had to substitute placebo for a monthly dose earlier due to blood count inadequacy, in which case active drug could be given during mo 7 or 8 (n = 27) 2) Placebo (n = 25) 

2) Relapse frequency:Definition of “relapse”: Appearance of newsymptoms or worsening of an existing symptom, attributable to MS and accompanied by objective worsening of neurological findings and must have been preceded by disease stability or improvement lasting for at least 30 days, and the worsening must have lasted at least 24 hours and occur in the absence of fever Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Relapse rate: Cladribine – 0.77 (95% CI, 0.37 to 1.41) Placebo – 1.67 (95% CI, 1.02 to 2.57) 

QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes

Schwartz, CoulthardMorris, Cole, et al., 1997 

Inclusion: Relapsingremitting MS Exclusion: None specified 

RCT (see under“Comments”) Duration of study treatment/followup: 1 yr Provider specialty: NR Location: NR; patients had applied to lotteryto gain access to experimental drug 

No. of patients randomized: NRDropouts: NRCompleted: 79 Age (mean): IFNβ-1b: 43.9 

Control: 43.3 Baseline EDSS: NR Baseline relapse rate: NR 

1) Recombinant interferon β-1b (IFNβ1b); dose, route of administration, and treatment regimen not described (n = 34) 2) Usual care (n = 45)

1) Physical functioning: Not assessed 2) Relapse frequency: Not assessed 3) Cognitive functioning: Multiple scales used as belowDefinition of “improvement”: Improvement was defined as population mean change Proportion of patients with “improvement”: Not assessed Other (non-improvement) outcomes: Wechsler Memory Scale delayed visual recall demonstrated improvement in the 

As recsamplfinding of the functioStudy advan

1b in a controand fosurvey responQUALDescr
88 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

high-dose group compared with placebo (p < 0.003). Other measures failed to reach statistical significance. Individual patient data and percentage of patients improving not reported. 

MethodescriConceDescrPatienInvestOutcoNo. of Yes

Sipe, Romine, Koziol, etal., 1994 

Inclusion: Clinicallydefinite or laboratorysupported definite chronic progressive MS for more than 2 yrExclusion: Serum creatinine ≥ 132 

μmol/L or creatinine clearance < 80% of age-adjusted normal; serum transaminases or hepatic alkaline phosphatase more than twice the upper limit of normal; neutrophil count < 1600 μL or platelet count < 130,000/μL; inadequate birth control; plans to father a child during study; treatment with corticosteroids or other immunosuppressive medications in previous 6 mo; decreased marrowreserve asmanifested byleukopenia or thrombocytopenia for > 6 wk after 

RCT (designed as 2-yr crossovertrial, but analyzedas parallel-grouptrial after 1 yr; double-blind [examining physicians and patients, not treating physicians], single-center, matched-pair design) Duration of study treatment/followup: 1 yr Provider specialty:Neurologists Location: 1 site in La Jolla, CA 

No. of patients randomized: 51 (49 initially entered + 2 replacements for dropouts) Dropouts: 3 cladribine patients (2 of whom werereplaced), 1 placebo patient (included in analyses) Completed: 47 (48 analyzed) Age (mean, with range): Cladribine: 43.0 (28-53) Placebo: 42.7 (21-54) Baseline EDSS (mean ± SE):Cladribine: 4.7 ±0.3 Placebo: 4.6 ± 0.3

Baseline relapse rate: NR 

Central venous access device surgicallyimplanted in all patients for study drug administration 1) Cladribine administered bycontinuous 7-day IV infusion at the rate of 0.1 mg/kg daily; total of 4 monthly courses given (n = 24) 2) Placebo infusion (n = 24) 

1) Physical functioning: Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Paired differences in the two groups were significant in favor of cladribine: 

EDSS SNRS

Cladribine 4.4 ± 2.0 74.8 ± 10.3 

Placebo 5.6 ± 1.5 62.6 ± 11.3 

P-value p < 0.01 p < 0.001 2) Relapse frequency:Definition of “relapse”: Not definedDefinition of “improvement”: Not defined Proportion of patients with “improvement”: Not assessed Other (non-improvement) outcomes: None 

This scladribprogresignifiwith reprogreSNRSregard patienQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
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Evidence Table 3a. Disease modifying therapies and long-term impro

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Study Design Patients Interv

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conclusion of immunosuppressive treatment 

SPECTRIMS StudyGroup, 2001 

Inclusion: Clinicallydefinite secondary progressive MS (defined as progressive deterioration of disability for ≥ 6 mo, 

with increase of ≥ 1 EDSS point over the last 2 yr [or 0.5 point bet

ween EDSS 6.0 

and 6.5], 

with or

without superimposed exacerbations, following an initial relapsing-remittingcourse); EDSS 3.0-6.5; pyramidal functional score ≥ 2; 

age 18-55 Exclusion: Immunosuppressive or immunomodulatorytreatments during previous 3-12 mo(depending on drug); corticosteroid use or disease exacerbation in previous 8 wk;severe concurrent illness; pregnancy or lactation; unwillingness to use contraception 

RCT (parallelgroup, doubleblind, multicenter)Duration of study treatment/follo

w

up: 3 yr Provider specialty:Neurologists Location: 22 sites in Europe, Canada, and Australia 

No. of patients randomized: 618 Dropouts: 112 withdrew fromtreatment; 65 of these were followed up for 3 yrCompleted: 506 completed treatment; 571 were follo

wed up

for 3 yr Age (mean ± SD):IFNβ-1a 44: 42.6 

± 7.3 IFNβ-1a 22: 43.1 

± 7.2 Placebo: 42.7 ±

6.8 Baseline EDSS (mean ± SD): IFNβ-1a 44: 5.3 ±

1.1 IFNβ-1a 22: 5.5 ±

1.1 Placebo: 5.4 ± 1.1

Baseline relapse rate (mean ± SD in 

previous 2 yr): IFNβ-1a 44: 0.9 ±

1.3 IFNβ-1a 22: 0.9 ±

1.4 Placebo: 0.9 ± 1.2

1) Interferon β-1a

(IFNβ-1a) 44 μg by SC 

injection three times weekly for 3 yr (n = 204) 2) IFNβ-1a 22 μg by

SC injection three times weekly for 3 yr(n = 209) 3) Placebo (n = 205) 

1) Physical functioning: Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: The primary outcome, time to sustained progression, revealed no statisticallysignificant difference among treatment arms.2) Relapse frequency:Definition of “relapse”: Appearance of a ne

w

sy

mptom or worsening of an old symptom 

attributable to M

S, accompanied by an 

appropriate ne

w neurologic abnormality or

focal neurologic dysfunction lasting at least 24 hours in the absence of fever and preceded by stability or improvement for at least 30 daysDefinition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Mean annual relapse rate: IFN 22 mcg Placebo IFN 44 mcg  0.50 0.71 0.50  p < 0.001 p < 0.001 

This s

1a in tprogresignifiprimaconfirmbenefito relaimprovpatienQ

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DescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
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Evidence Table 3a. Disease modifying therapies and long-term impro

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Study Design Patients Interv

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van deWyngaert,Beguin, D’Hooghe, et al., 2001 

Inclusion: Definiteclinical diagnosis of MS by Poser criteria; relapsing, secondaryprogressive disease course; at least partial recovery from last relapse at least 1 mo before study entry; E

DSS 3.0-6.0; 

worsening of EDSS by 1 point in previous 12 mo; effective birth control; normal isotopic cardiac ventriculography and routine blood analysis at entry; age 18-50 Exclusion: Remittent disease course, primary progressive disease, or secondaryprogressive disease without relapses; major illness otherthan MS or immunosuppressive drugs other than corticosteroids inprevious 3 yr

RCT (parallelgroup, doubleblind, singlecenter) Duration of study treatment/follo

w

up: Treatment lasted 32 mo; patients followedup for an additional 4 mo Provider specialty:Neurologists Location: 1 site in Belgium 

No. of patients randomized: 49Dropouts: 25 Completed: 24 Age (mean ± SD):MTX: 38.3 ± 6.9 MP: 39.2 ± 7.8 

Baseline EDSS (mean, with range): MTX: 5.1 (3.0-6.0)MP: 5.0 (3.0-6.0) Baseline relapse rate (mean inprevious 12 mo ±SD): MTX: 2.3 ± 1.0 MP: 2.2 ± 1.2 

1) Mitoxantrone (MTX) 12 mg/m2

initially given intravenously over one hour once per month for 3 mo; then given once every 3 mo, 10 times, until month 32; each treatment preceded by IV administration of 3 vials of alizapride (anti-emetic) (n = 28) 2) Methylprednisolone (MP) 1 g initially given intravenously over one hour between 8 and 10 a.m. once permonth for 3 mo; then given once every 3 mo, 10 times, until month 32 (n = 21) 

1) Physical functioning: Definition of “improvement”: Not defined Proportion of patients with “improvement”: 35% of patients receiving MTX improved clinically compared 

with 22% receiving 

placebo – difference not statisticallysignificant Other (non-improvement) outcomes: 2) Relapse frequency:Definition of “relapse”: Not definedDefinition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Mean number of relapses/patient/year was significantly lower in the MTX group after 2 and 3 years of treatment (p = 0.016 and 0.029, respectively) 

This scladribprogredemonfavor onumbeprecisnot givhave csignifiQ

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Evidence Table 3a. Disease-modifying therapies and long-term improvement

50 

Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Achiron,Gabbay, Gilad, et al., 1998 

Inclusion: Clinicallydefinite relapsing remitting MS of > 1 yrduration; averageyearly exacerbation rate 0.5-3 in 2 yr preceding study;EDSS score 0-6.0; age 18-60 Exclusion: Secondaryprogression disease course; serum immunoglobulin deficiency; long-term steroid or cytotoxic treatment 12 mo prior to study; major psychiatric disorder; major cognitive impairment 

RCT (parallelgroup, doubleblind, singlecenter) Duration of study treatment/followup: 2 yr Provider specialty:Neurologists Location: Tel Hashomer, Israel 

No. of patients randomized: 40Dropouts: 2 Completed: 38 Age (mean ± SE): IV IgG: 35.4 ± 2.1 

Placebo: 33.8 ±

2.4 Baseline EDSS (mean ± SE):IV IgG: 2.90 ±

0.43 Placebo: 2.82 ±

0.37 Baseline relapse rate (mean ± SE per yr in 2 yr preceding study):IV IgG: 1.85 ±

0.26 Placebo: 1.55 ±

0.17 

1) IV immunoglobulin (IV IgG); loading dose of 0.4g/kg/body weight per day for 5 consecutive days,followed by booster doses of 0.4 g/kg/bodyweight once dailyevery 2 mo for 2 yr (n = 20) 2) Placebo (n = 20) 

1) Physical functioning: Definition of “improvement”: 1.0-point change in EDSS compared with baseline Proportion of patients with “improvement”: In the IV IgG group 23.5% of patients improved vs. 10.8% in the placebo group Other (non-improvement) outcomes: No significant change in mean EDSS in treatment arm 2) Relapse frequency:Definition of “relapse”: The rapid appearance, reappearance, or worsening of one or more neurological abnormalities, persisting at least 48 hr, after a relativelystable or improving neurological state of at 

least 30 days. A relapse was confirmed only when the patient’s symptoms were accompanied by objective changes on neurological examination by a blinded neurologist. Definition of “improvement”: Not specified on a per patient basis Proportion of patients with “improvement”: Not specified Other (non-improvement) outcomes: a) Yearly exacerbation rates  IV IgG Placebo P-valueBaseline 1.85 1.55 0.34 Year 1 0.75 1.8 0.0002 Year 2 0.42 1.42 0.0009 2-yr total 0.59 1.61 0.0006 

This apropoimprovIV IgG definitpoint ino datmay hpoint. QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of No 
51 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

b) Exacerbation-free patients:  IV IgG Placebo P-valueYear 1 8 1 0.001 Year 2 12 3 0.001 Total study 6 0 0.001 c) Median time to first exacerbation (days):  IV IgG Placebo P-value 233 82 0.003 

Bastianello, Pozzilli, D’Andrea, et al., 1994 

Inclusion: Definitediagnosis of MS; relapsing-remittingdisease course (≥ 2 relapses in 24 mo prior to study entry);disease duration 1-10 yr; EDSS 2.0-5.0;age 18-45; selected to undergo serial MRI scans (subgroup of total studypopulation) Exclusion: HIVpositive; previouscardiovasculardisease; left ventricular ejection fraction < 50% byechocardiography; renal, liver, and/orrespiratory dysfunction; diabetes; malignancy;psychiatric illness; pregnancy or nocontraception; use of immunosuppressant drugs or steroids in previous 3 mo 

RCT (parallelgroup, doubleblind, multicenter)Duration of study treatment/followup: 1 yr (preliminaryresults from planned 2-yr trial)Provider specialty:Neurologists Location: 7 sites in Italy

No. of patients randomized: 25 (subgroup of total study population selected to undergo serial MRI scans) Dropouts: 0 Completed: 25 Age (mean ± SD):MTX: 29.9 ± 5.2 Placebo: 28.5 ±

6.5 Baseline EDSS (mean ± SD): MTX: 3.7 ± 0.7 Placebo: 3.5 ± 1.0

Baseline relapse rate (mean inprevious 2 yr ±SD): MTX: 2.8 ± 1.2 Placebo: 3.3 ± 1.2

1) Mitoxantrone (MTX) 8 mg/m2 by 30-

min IV infusion everymonth for 1 yr (n = 13)2) Placebo (n = 12) 

1) Physical functioning: Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: No statistical difference was observed in mean EDSS change at 1 yr (p = 0.18) 2) Relapse frequency:Definition of “relapse”: The appearance of new symptom or worsening of an old one, attributable to MS and lasting at least 24 hours in the absence of fever Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes:  MTX Placebo P value MER 0.54 1.67 0.014 PWE 5(38%) 10(83%) 0.02 MER = Mean exacerbation rate PWE = Number (%) of patients with exacerbations 

This trdemonin redbut doinformimprovbaseliQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
52 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Bornstein, Miller, Slagle, et al., 1987 

Inclusion: DefiniteMS; relapsingremitting form of MS; ≥ 2 well-demarcated and well-documented relapses in previous 2 yr; EDSS ≤ 6; emotionally stable; age 20-35 Exclusion: None specified 

RCT (parallelgroup, doubleblind, singlecenter, matchedpairs design) Duration of study treatment/followup: 2 yr Provider specialty:Neurologists Location: 1 site in Bronx, NY

No. of patients randomized: 50Dropouts: 7 dropped out before 2 yr, but 5 of these were included in analysis Completed: 43 completed trial; 48 included in analysis Age (mean): Cop 1: 30.0 Placebo: 31.0 Baseline EDSS (mean): Cop 1: 2.9 Placebo: 3.2 Baseline relapse rate (mean over 2 yr):Cop 1: 3.8 Placebo: 3.9 

1) Glatiramer acetate = Copolymer 1 (Cop 1) by SC injection, 20 mg self-injected daily for 2 yr (n = 25) 2) Placebo (n = 25) 

1) Physical functioning: Definition of “improvement”: Reduction in EDSS by 1, 2, or 3 points over 2 yr Proportion of patients with “improvement”:  Placebo Cop 1 1.0 point 8.7% 20.0% 2.0 points 0 12.0% 3.0 points 4.4% 02) Relapse frequency:Definition of “relapse”: The rapid onset of new symptoms or a worsening of preexisting symptoms that persisted for 48 hours or more, when accompanied by observed objective changes on the neurological examination involving an increase of a atl east one grade in the score for one of the eight functional groups or the Kurtzke Scale Definition of “improvement”: Decrease in 2-yr relapse rate in comparison with individual baseline relapse rate Proportion of patients with “improvement”: Placebo – 12 of 23 patients experienced a decrease in relapse rate over the 2yr period Cop 1 – 24 of 25 patients experienced a decrease in relapse rate over the 2-yr treatment periodOther (non-improvement) outcomes: Exacerbation-free patients: Placebo – 26% Cop 1 – 56% P = 0.036 

This eCopolrelapsbenefrelaps

statusthe nuimprovsignifiblindincorrecplacebQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
53 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Bornstein, Miller, Slagle, et al., 1991 

Inclusion: Definitediagnosis of MS byPoser criteria; evidence of a chronic-progressive course for ≥ 18 mo; ≤ 2 exacerbations in previous 24 mo; EDSS score 2.0-6.5; emotionally stable and able to participate in clinical trial; age 20-60 During a 6- to 15-mo pre-trial observation period, patients required to demonstrate progression in one of following ways:worsening of 2 grades in a functional system; worsening of 1 grade in 2 unrelated functional systems; worsening of 2 units on the Ambulation Index; or worsening of 1 grade on the EDSS. Must not have progressed beyond 6.5 on EDSS or have had > 1 exacerbation during pre-trial observation period. Exclusion: None specified 

RCT (parallelgroup, doubleblind, two-center)Duration of study treatment/followup: 2 yr or until confirmed progression (whichever first) Provider specialty:Neurologists Location: Bronx,NY; and Houston,TX 

No. of patients randomized: 106 Dropouts: 20 Completed: 86 Age (mean): Cop 1: 41.6 Placebo: 42.3 Baseline EDSS: Mean: Cop 1: 5.7 Placebo: 5.5 

 Cop 1 Plac

< 5: 22% 27%5-5.5: 8% 15% 6-6.5: 71% 58%Baseline relapse rate: NR 

1) Copolymer 1(Cop 1) by SCinjection; 15 mg selfinjected twice per dayfor 2 yr (n = 51) 2) Placebo (n = 55) 

1) Physical functioning: Definition of “improvement”: Not defined Proportion of patients with “improvement”: Cop 1: 19.6% improved 37.3% remained stable  41.1% worsenedPlacebo: 14.5% improved 34.6% remained stable  50.9% worsenedOther (non-improvement) outcomes: The primary endpoint, confirmed progression of 1.0 or 1.5 units (depending on baseline disability) on the Kurtzke Disability Status Scale, was not statistically different in the two groups 2) Relapse frequency:Definition of “relapse”: Not definedDefinition of “improvement”: Not assessed Proportion of patients with “improvement”: Not delineated 

This sinformpatienQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
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Evidence Table 3a. Disease modifying therapies and long-term impro

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British and Dutch MultipleSclerosis Azathioprine Trial Group, 1988 

Inclusion: Clinicallydefinite MS (≥ 2 

episodes and 2 clinical lesions or 2 episodes and 1 subclinical lesion[revealed by VEP or CT]); or laboratory confirmed MS (≥ 2 

anatomicallyseparate episodes, 1 clinical lesion, and oligoclonal bands or increased IgG in the CSF); or currently progressive MS (2separate lesions [of which 1 might besubclinical], oligoclonal bands, or increased IgG in the CSF, and progression for at least 6 mo); patients 

with

relapsing-remittingdisease had to have been in a remittent phase for ≥ 1 mo and have had ≥ 1 relapses in the previous year; EDSS ≤ 6 (ambulant); age 15-50; not on other immunomodulatorydrugs or hyperbaric oxygen treatmentExclusion: Concomitant systemic disease; mental deficit that precluded understanding and 

RCT (parallelgroup, doubleblind, multicenter)Duration of study treatment/follo

w

up: 3 yr Provider specialty:Neurologists Location: 20 sites in the UK and The Netherlands 

No. of patients randomized: 354 (199 [56

%] 

clinically definite, 37 [10%] laboratory confirmed; 51 [14%] progressive from onset; 67 [19%] progressive after remission) Lost to follow up(cumulative totals): 20 at 1 yr, 24 at 2 yr, 22 at 3 yr, 153 at 4 yrDiscontinued treatment (cumulative totals): 48 at 1 yr, 64 at 2 yr, 75 at 3 yr Completed: 279 completed treatment, 332 followed up through 3 yr Age (mean ± SD):Azathioprine: 39 ±

8.6 Placebo: 38 ± 8.3 Baseline EDSS (mean ± SD): Azathioprine: 3.69 ± 1.50 Placebo: 3.66 ±

1.62 Baseline relapse 

1) Azathioprine PO 2.5 mg/kg (to thenearest 25 mg) daily(n = 174) 2) Placebo (n = 180) 

1) Physical functioning: Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: The only statistically significant result 

was a 

reduction in the deterioration of the Ambulation Index in the azathioprine group compared 

with the placebo group after 3 yr 

The trmargindelinewith reQ

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Evidence Table 3a. Disease modifying therapies and long-term impro

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cooperation rate (months since 

last relapse): 

 Az Plac 

1-6: 43

% 45% 

7-12: 20

% 18% 

> 12: 37% 37% 

Canadian CooperativeMultipleSclerosis StudyGroup, 1991 

Inclusion: Clinicallydefinite or laboratorysupported definite MS in a progressive phase (deterioration of at least 1 point on EDSS over preceding 12 mo); EDSS 4.0-6.5; age ≥ 15 Exclusion: Previous treatment with cyclophosphamide, cyclosporin, antilymphocyte globulin, or interferon; treatment with azathioprine or plasma exchange in preceding yr or corticosteroids inpreceding mo; illnesses that might be adversely affected by study treatments; substantial cognitive impairment; un

willingness to use 

contraception during trial and for 2 yr after; weekly venous access difficult 

RCT (parallelgroup, not double-blinded, multicenter)Duration of study treatment/follo

w

up: Duration of treatment variable (see at right, under “Interventions”); patients followedup for at least 12mo; mean follo

w

up, 30.4 mo Provider specialty:Neurologists Location: 9 sites in Canada 

No. of patients randomized: 168 (81 relapsingprogressive, 86 chronicprogressive, 1 unkown) Dropouts: 2 (died)Completed: 166Age (mean at disease onset ±

SD): Cyclophosphamide IV: 31.9 ± 10.3 

Plasma exchange: 29.9 ± 7.9 

Placebo: 32.1 ±

9.7 Baseline EDSS (mean ± SD): Cyclophosphamide IV: 5.79 ± 0.61 

Plasma exchange: 5.66 ± 0.72 

Placebo: 5.79 ±

0.64 Baseline relapse rate: NR 

1) Cyclophosphamide IV + prednisone PO (n = 55). 

Cyclophosphamide 1g given 

intravenously on alternate days until WBC count fell below

4.5 x 109

/L or until total 

dose of 9 g reached. Prednisone 40 mggiven orally for 10days, then reduced by10 mg on alternate days and discontinued on day 16. 2) Plasma exchange + cyclophosphamide PO + prednisone PO (n = 57). Plasmaexchange of one plasma volume (40 mL/kg) done weeklyfor 20 wk with either intermittent (5 sites) or continuous (4 sites) flow-type centrifuges. Replacement = 5

%

serum albumin. Oral cyclophosphamide 1.5-2.0 mg/kg given daily for 22 

wk; dose 

adjusted to achieve target WBC of 4.0-5.0 x 109

/L. Oral 

prednisone 20 mggiven every other day

1) Physical functioning: Definition of “improvement”: 1.0-point improvement on EDSS sustained for 6 mo Proportion of patients with “improvement”: No statistically significant difference among the treatment arms Number of patients improved: 

 Cycl PEX Placebo 

1 yr 3 (6%) 4 (8%) 1 (2%)2 yr 2 (6%) 1 (3%) 0 3 yr 2 (4%) 1 (2%) 1 (2%)Other (non-improvement) outcomes: No statistically significant difference between treatment arms in any outcome measure 

This saddreimprovresults benefQ

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Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

and tapered over 22 wk.3) Placebo (placebo oral cyclophosphamide and prednisone for 22 wk + shamplasma exchange for 20 wk) (n = 56) 

Cohen, Cutter, Fischer, et al., 2002 

Inclusion: Clinicallydefinite secondary progressive MS, with or without recent relapses; disease progression overprevious 1 yr; cranial MRI demonstrating lesions consistentwith MS; EDSS 3.5-6.5; age 18-60 Exclusion: Primaryprogressive disease course; inability to complete MS Functional Composite at baseline; prior treatment with interferon-β

RCT (parallelgroup, doubleblind, multicenter)Duration of study treatment/followup: 2 yr Provider specialty:Neurologists Location: 42 sites in US, Europe, andCanada 

No. of patients randomized: 436 Dropouts: 115; ofthese, 63 had complete 2-yr follow up Completed: 321 completed treatment; 384 followed up for 2 yrAge (mean ± SD):IFNβ-1a: 47.2 ±

8.2 Placebo: 47.9 ±

7.7 Baseline EDSS (mean ± SD): IFNβ-1a: 5.2 ± 1.1

Placebo: 5.2 ± 1.1

Baseline relapse rate (mean ± SD,prior 3 yr):IFNβ-1a: 1.5 ± 2.1

Placebo: 1.3 ± 2.1

1) Interferon β-1a

(IFNβ-1a) 60 μg 

weekly by IM injection for 2 yr (n = 217); half dose (30 μg) given for first four doses to

minimize adverse events 2) Placebo for 2 yr (n = 219) 

1) Physical functioning: Definition of “improvement”: Not defined for individual patients Proportion of patients with “improvement”: Improvement based on EDSS – baseline to 24 months Placebo – 7.3% IFNβ-1a – 7.5% 

No statistically significant difference Other (non-improvement) outcomes: 24-month MSFC data-median:  Placebo IFNβ-1a P value 

MSFC -0.161 -0.362 0.033 9HPT -0.290 -0.202 0.024 Timed 25-ft walk – no statistical difference PASAT – no statistical difference 2) Relapse frequency:Definition of “relapse”: New or recurrent neurological symptoms, not associated with fever or infection, lasting at least 48 hours and accompanied by objective change on the examining neurologist’s examination at an unscheduled visit corresponding to the reported symptoms Definition of “improvement”: Not delineated on individual patients Proportion of patients with “improvement”: 

This s

1a in sassesMSQLeffects the firsscale treatmprimaupper focuseand ppatienQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
57 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Not delineated Other (non-improvement) outcomes: Annual relapse rate: Placebo – 0.30 IFNβ-1a – 0.20 

P = 0.008 Relapse-free patients – intention to treat: Placebo – 63% IFNβ-1a – 74% 

P=0.023 3) Quality of life: The MS Quality of Life Inventory (MSQLI) was administered to English-speaking subjects at baseline, 12 months, and 24 months Definition of “improvement”: Not defined Proportion of patients with “improvement”: NR Other (non-improvement) outcomes: Significant benefit favoring IFNβ-1a treatment was observed on 8 of 11subscales of the MSQLI, with a favorable trend on the remaining three scales. The IFNβ-1a group improved from baseline to 

month 24 on 10 of 11 subscales (all except Bladder Control Scale). In contrast, the placebo group worsened from baseline to month 24 on 10 of 11 subscales, the Modified Fatigue Impact Scale being the only subscale showing improvement. Data not shown (reference made to 

www.neurology.org web site). 
58 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Currier, Haerer, and Meydrech,1993 

Inclusion: DefiniteMS; a worsening in function or an exacerbation in the previous yr; understanding and willingness to cooperate Exclusion: History orevidence of renal or hepatic disease; gross obesity;diabetes 

RCT (parallelgroup, doubleblind, singlecenter) Duration of study treatment/followup: Initially 1 yr; changed during trial to 18 mo Provider specialty:Neurologist Location: Jackson, MS 

No. of patients randomized: 45 (20 “exacerbating remitting” and 24“chronic” MS [latter includes 18 “exacerbating progressive,” 3 “chronic progressive,” and 3 “spinal patients”]) Dropouts: 9 Completed: 36 Age (median, reported only byMS type): Exacerbating remitting: 39.5 Chronic: 46.8 Baseline EDSS: NR Baseline relapse rate (total number of exacerbations in 12 mo precedingtrial; reported only for patients with “exacerbating remitting” MS): Methotrexate: 9 in 9 patients Placebo: 12 in 11 patients 

1) Methotrexate PO; 2.5 mg every 12 hr for 3 consecutive doses once per wk (7.5 mg/ wk) for 18 mo (n = 22) 2) Placebo (n = 22) 

1) Physical functioning: Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: 2) Relapse frequency:Definition of “relapse”: 1.0-point EDSS worsening (unsustained) Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: No statistically significant difference in treatment groups except for a difference in the mean number of exacerbations p = 0.05 – data presented in graphical form only

This sindivid

therapQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
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Evidence Table 3a. Disease modifying therapies and long-term impro

vement (continued) 

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Study Design Patients Interv

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De Castro, Cartoni, Millefiorini, et al., 1995 

Inclusion: Definitediagnosis of MS according to Posercriteria; relapsingremitting disease course; ≥ 2 relapses 

in 24 mo prior to study entry; disease duration 1-10 yr; EDSS 2.0-5.0; age 18-45 Exclusion: HIVpositive; heart, renal, lung, or liver disease; psychiatric disease; pregnancy or lactation; known allergy to corticosteroids; other neurological disease; use of corticosteroids during previous 3 mo; use of levamisol,isoprinosin, or plasmapheresis during previous 3 mo; treatment with interferon; immunosuppressive therapy during previous 12 mo 

RCT (parallelgroup, doubleblind, singlecenter) Duration of study treatment/follo

w

up: 1 yr Provider specialty: NR (presumably neurologists and cardiologists)Location: 1 site in Italy

No. of patients randomized: 20Dropouts: N

R

(implied 0) Completed: NR(implied 20) Age (mean ± SD):MTX: 31 ± 5 Placebo: 30 ± 4 Baseline EDSS (mean ± SD): MTX: 3.77 ± 0.72Placebo: 3.33 ±

0.75 Baseline relapse rate (mean inprevious 2 yr ±SD): MTX: 2.82 ± 0.98Placebo: 3.00 ±

1.94 

1) Mitoxantrone (MTX) 8 mg/m2 by 30-

min IV infusion everymonth for 1 yr (n = 13)2) Placebo (n = 12) 

1) Physical functioning: Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: No statistically significant difference between treatment arms 

with respect to changes in 

EDSS 2) Relapse frequency:Definition of “relapse”: Not definedDefinition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Difference in relapse rate favored treatment with mitoxantrone p = 0.005 

This ssignifirate in includimprovQ

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DescrMethodescriConceDescrPatienInvestOutcoNo. of No 
60 

Evidence Table 3a. Disease modifying therapies and long-term impro

vement (continued) 

Stu

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Inclusion/ Exclusion Criteria

Study Design Patients Interv

entions Outcomes/Results Com

EuropeanStudyGroup onInterferon beta-1b inSecondaryProgressiveMS, 1998 

Inclusion: Clinicallyor laboratory supported definite diagnosis of secondaryprogressive MS; EDSS 3.0-6.5; ≥ 2 relapses or ≥ 1.0-point increase in EDSS in previous 2 yr; age 18-55Exclusion: None specified 

RCT (parallelgroup, doubleblind, multicenter)Mean duration oftreatment/follo

w

up: Treatment scheduled to last 36 mo, 

with 3-mo

follow up; article reports results of prospectivelyplanned interim analysis of all patients in studyfor ≥ 2 yr; mean 

follow up time 901 days for IFNβ-1b and 892

days for placeboProvider specialty: NR (presumably neurologists) Location: 32 sites in Europe 

No. of patients randomized: 718 Lost to follow up:57Withdre

w from 

treatment, but had complete follow up: 130 Completed treatment and follow up: 531 Age (mean ± SD):IFNβ-1b: 41.1 ±

7.2 Placebo: 40.9 ±

7.2 Baseline EDSS (mean ± SD): IFNβ-1b: 5.1 ± 1.1

Placebo: 5.2 ± 1.1

Baseline relapse rate (

% of patients 

without relapse in 2 yr preceding 

study): IFNβ-1b: 31.9%

Placebo: 28.2%

1) Interferon β-1b

(IFNβ-1b) by SC 

injection; initial dose 0.5 mL (4 MIU) everyother day, increased after 2 

wk to 1.0 mL (8 

MIU) every other dayfor up to 3 yr (n = 360)2) Placebo (n = 358) 

1) Physical functioning: Primary endpoint was time to confirmed progression in disability defined as a 1.0-point increase on EDSS sustained for at least 3 months, or a 0.5-point increase if the baseline EDSS was 6.0 or 6.5 Results: Significant difference in time to confirmed progression of disability in favor of IFNβ1-b (p = 0.0008) 

On average IF

Nβ1-b delayed confirmed 

progression by 9-12 months in this patient population Confirmed EDSS progression: Placebo: 46.7%IFNβ1-b: 38.9%

p = 0.0048 2) Relapse frequency:Definition of “relapse”: Not definedDefinition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: a) Mean annual relapse rate:  Placebo IFN β-1b p Overall 0.64 0.44 0.0002 Year 1 0.82 0.57 0.0095 Year 2 0.47 0.35 0.0201 Year 3 0.35 0.24 0.1624 b) Proportion of patients with moderate to severe relapse: Placebo: n = 190 (53.1

%) 

IFNβ1-b: n = 157 (43.6

%) 

p = 0.008 

This aIFNβ-

rate orelapsregardpatienstatusSee aPozzilQ

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Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Fazekas, Deisenhammer, StrasserFuchs, et al., 1997a and Fazekas, Deisenhammer, StrasserFuchs, et al., 1997b and StrasserFuchs, Fazekas, Deisenhammer, et al., 2000 

Inclusion: Clinicallydefinite diagnosis of relapsing-remittingMS; EDSS score 1.0-6.0; ≥ 2 clearly

identified and documented relapses during previous 2 yr; age 15-64; first manifestation of MS at age 10-59 Exclusion: Immunosuppressive or immunomodulatorytherapy in previous 3 mo; corticosteroids in previous 2 wk; primary or secondaryprogressive MS; benign course of disease as indicated by a deteriorationrate (EDSS scoredivided by duration of disease in years) < 0.25 

RCT (parallelgroup, doubleblind, multicenter)Duration of study treatment/followup: 2 yr Provider specialty:Neurologists Location: 13 sites in Austria 

No. of patients randomized: 150 Lost to follow up:2 (before start of treatment) Stopped treatment: 28 Completed treatment: 120 Age (mean [95%CI]): IV IgG: 36.7 (34.3-39.1) Placebo: 37.3 (35.0-39.6) Baseline EDSS (mean [95% CI]):IV IgG: 3.3 (3.0-3.6) Placebo: 3.3 (2.9-3.7) Baseline relapse rate (mean per yr[95% CI]): IV IgG: 1.3 (1.1-1.5) Placebo: 1.4 (1.2-1.6) 

1) IV immunoglobulin (IV IgG); 0.15-0.20 g/kg body weight once per month for 2 yr (n = 75) 2) Placebo (n = 73) 

1) Physical functioning: Definition of “improvement”: 1.0-point decrease in EDSS by the end of the studyProportion of patients with “improvement”: IV IgG – 31% of patients improved Placebo – 14% of patients improved Other (non-improvement) outcomes: Between-group differences in the absolute change on the EDSS score and in the proportion of patients stable or worsened 2) Relapse frequency:Definition of “relapse”: The appearance or reappearance of one or more neurological abnormalities that persisted for at least 24 hours and had been preceded by a stable or improving neurological state of at least 30 days. A relapse was confirmed only if the patient’s symptoms were accompanied byobjective changes of at least one grade in 

the scored for one of the eight functional groups on the EDSS. Definition of “improvement”: Not delineated Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes:  IV IgG Placebo P Relapse-free 53% 36% 0.03  Patients Mean Annual Relapse Rate 

Year 1 0.49 1.30 0.011 Year 2 0.42 0.83 0.006 

3) Quality of life: Incapacity Status Scale and the Environmental Status Scale 

These treatmregardMoreoincreademonover thQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
62 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Definition of “improvement”: Not defined prospectivelyProportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: The mean change of rating scores of 15 of 16 items was more favorable following IV IgG treatment. The total mean change of ratings over all ISS items was significantly in favor of IV IgG-treated patients (P = 0.01) Similarly, IV IgG-treated patients noted improvement in 4 of 7items of the ESS compared to no item rated as improved byplacebo patients. 

Ghezzi, Di Falco, Locatelli, et al., 1989 

Inclusion: DefiniteMS Exclusion: Disease duration < 1 yr; EDSS > 7; concomitant diseases contraindicating immunosuppression 

RCT (parallelgroup, openlabel, singlecenter) Duration of study treatment/followup: 18 mo Provider specialty: NR (presumably neurologists) Location: 1 site in Gallarate, Italy

No. of patients randomized: 185 (74 relapsing, 111 relapsingprogressive) Dropouts: 50 Completed: 135Age (mean at onset [with range], completers only):Relapsing (R)-azathioprine: 26 (15-42) R-control: 26 (18-42) Relapsingprogressive (RP)-azathioprine: 29 (12-44) RP-placebo: 31 (16-47) Baseline EDSS (mean [with range], 

1) Azathioprine PO 2.5 mg/kg per day for 18 mo (n = 69) 2) No azathioprine (n = 66) 

1) Physical functioning: Definition of “improvement”: Not defined Proportion of patients with “improvement”: Relapsing patients who improved:Azathioprine – 5 of 32 Controls – 0 of 22P > 0.10 Relapsing-progressive patients: Azathioprine – 2 of 37 Controls – 3 of 44p > 0.10 Other (non-improvement) outcomes: No statistical difference between the treatment arms with respect to EDSS 2) Relapse frequency:Definition of “relapse”: Not definedDefinition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated 

This uMS didiffereData aindividQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
63 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

completers only):R-azathioprine: 2.1 (1-5) R-control: 2.2 (1-5) RP-azathioprine:3.8 1-6.5)RP-placebo: 3.7(1-7) Baseline relapse rate (mean [with range], completers only, time frame not specified): mean at onset [with range], completers only):R-azathioprine: 1.2 (0.2-4) R-control: 1.1 (0.2-3) RP-azathioprine:0.6 (0.1-3.3) RP-placebo: 0.4(0.1-2.5) 

Other (non-improvement) outcomes: No statistically significant difference in treatment arms 

Goodkin, Bailly,Teetzen, et al., 1991 

Inclusion: Clinicallydefinite or laboratorysupported definite MS; seen at study clinic from 1983 to1989; relapsingremitting disease course (≥ 2 exacerbations in previous 18 mo); no exacerbation in previous 1 mo; EDSS 2.0-6.5; AI 1.0-6.0; age 18-65 Exclusion: Chronic 

RCT (parallelgroup, doubleblind [patients and examining physician, not treating physician], singlecenter) Duration of study treatment/followup: 2 yr Provider specialty:Neurologists 

No. of patients randomized: 59 randomized, 54 began treatmentNo. followed for 2 yr: 52 No. treated per protocol for 2 yr: 43 Age (mean ± SD atonset; n = 54 starting treatment): Azathioprine: 29.4 

1) Azathioprine PO; initial dose 50 mg 3 times per day,adjusted to target dose of 3 mg/kg, with increases made in increments of 25 mg per day no more than once per month; WBC maintained at 3500-4000/μL (n = 29)2) Placebo (n = 25) 

1) Physical functioning: Definitions of “improvement”: Score reflects combined results of change lasting more than 2 mo in any of following: ≥ 1.0-point on EDSS for patients with baseline EDSS ≤ 5.0, or

≥ 0.5-point on EDSS for patients with baseline EDSS ≥ 5.5, or

≥ 1.0 point on AI, or

≥ 20% deterioration from baseline in 9HPT or BBT Proportion of patients with “improvement”: Placebo = 20% Azathioprine = 22.2% 

This sbenefexacedata rwho imEDSS The pwas, hamong QUALDescrMethodescriConceDescrPatien
64 

Evidence Table 3a. Disease modifying therapies and long-term impro

vement (continued) 

Stu

d

y

S

electe

d

Inclusion/ Exclusion Criteria

Study Design Patients Interv

entions Outcomes/Results Com

progressive disease (worsening in functional status measurements over 6 mo 

without 

exacerbation); use of corticosteroids inprevious 1 mo; use of immunosuppressant medication in previous 1 yr; pregnant; un

willing to 

practice birth control; systemic illness of medical condition that precluded safe administration of study drugs 

Location: 1 site in Fargo, N

D

± 8.5 Placebo: 30.0 ±

6.8 Baseline EDSS (mean ± SD; n = 54 starting treatment): Azathioprine: 3.18 ± 1.19 Placebo: 3.72 ±

1.60 Baseline relapse rate (mean ± SD in previous 18 mo; no = 54 starting treatment): Azathioprine: 2.34 ± 0.55 Placebo: 2.32 ±

0.63 

Other (non-improvement) outcomes: Difference in mean change in EDSS 2) Relapse frequency:Definition of “relapse”: Objective worsening in the EDSS of ≥ 0.5 points, Ambulation Index (AI) of ≥ 1.0 points, or ≥ 20% deterioration from baseline performance on the nine-hole peg test (9HPT) or box-andblock test (BBT) in patients who were stable or improving 

within the last month 

Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Mean on-trial exacerbation rates for each group:  AZA Placebo P Year 1 0.74 1.17 0.16 Year 2 0.30 0.79 0.05 Total 2 year 1.04 1.88 0.08 

InvestOutcoNo. of Yes

Goodkin, Rudick, VanderBrug Medendorp,et al., 1995 

Inclusion: Clinicallydefinite chronic progressive MS; progressive neurological impairment during period of ≥ 6 mo prior to start of study; no exacerbation for previous 8 mo; ≤ 1 exacerbation in previous 2 yr; disease duration > 1 yr; EDSS 3.0-6.5; AI 2.0-6.0; no corticosteroids during previous 1 mo or

RCT (parallelgroup, doubleblind, singlecenter) Duration of study treatment/follo

w

up: 2 yr Provider specialty:Neurologists Location: 1 site in Cleveland, OH

No. of patients randomized: 60 (18 primaryprogressive, 42 secondaryprogressive) Dropouts: 9 Completed: 51 Age (mean ± SD):METH: 43 ± 9.3

Placebo: 46 ± 8.8 Baseline EDSS (mean): 

1) Methotrexate (METH), one 7.5-mg oral tablet per week for 2 yr (n = 31) 2) Placebo (n = 29) 

1) Physical functioning: Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: The primary outcome measure was time to treatment failure on a composite measure of physical functioning that utilized EDSS, Ambulation Index, Box and Block Test and 9-Hole Peg Test for 2 mo or more.Treatment failure was pre-defined on the basis of specific levels of deterioration on any of these scales. There was a significant relationship bet

ween 

This sdose oin patiand focompofunctioobservfunctioindividprovidthe prQ

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Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

immunosuppressant medication for previous 1 yr; no prior lymphoid irradiation; willing to use contraception; age 21-60 Exclusion: Pregnancy; systemic illness or medical condition that precluded safe administration of study drugs; clinicallyevident cognitiveimpairment 

METH: 5.5 Placebo: 5.3 Baseline relapse rate: NR 

sustained progression and treatment group favoring the METH treatment: METH = 51.6%, Placebo = 82.8% (p = 0.011). This treatment effect was strongest for the 9HPT and was seen to a lesser extent (p = NS) for the BBT and EDSS. 

DescrPatienInvestOutcoNo. of Yes

Hartung, Gonsette, König, et al., 2002 

Inclusion: Worsening relapsing-remittingMS (stepwise progression of disability between relapses) or secondaryprogressive MS; EDSS 3.0-6.0; worsening of ≥ 1 point on EDSS in previous 18 mo; no relapse in previous 8 wk; no treatment with glucocorticosteroids in previous 8 wk; no previous treatment with mitoxantrone, interferons, glatiramer acetate, cytotoxic drugs, ortotal-body lymphoid irradiation; left ventricular ejection fraction > 50%; WBC, 

RCT (parallelgroup, doubleblind [patients and assessors, not treating physicians], multicenter)Duration of study treatment/followup: Treatment lasted 2 yr; patients followedfor total of 3 yr Provider specialty:Neurologists Location: 17 sites in Belgium, Germany,Hungary, andPoland 

No. of patients randomized: 194 randomized; 188included in baseline measures (94 worsening relapsing-remitting, 94 secondary progressive) Dropouts: 56 Completed: 138 assessed at 3 yrAge (mean ± SD):MTX 12 mg: 39.94 ± 6.85 MTX 5 mg: 39.92± 8.06 Placebo: 40.02 ±7.88 Baseline EDSS (mean ± SD): 

1) Mitoxantrone (MTX) 12 mg/m2 by

slow IV infusion every3 months for 2 yr; dose could be reduced in response to adverse events, infection, or low WBC or platelet count (n = 63) 2) Mitoxantrone (MTX) 5 mg/m2 by

slow IV infusion every3 months for 2 yr; dose could be reduced in response to adverse events (n = 66) 3) Placebo (n = 65) 

1) Physical functioning: EDSS, Ambulation Index, and standard neurological status scores were established at each scheduled and unscheduled visit Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Mean and median EDSS change, Ambulation Index change, SNS change 2) Relapse frequency:Definition of “relapse”: Severe relapse defined as the occurrence of new symptoms lasting for longer than 48 hours with a change in functional system score of more than 2 points, or a deterioration of at least 1 point in at least one of the four following systems: pyramidal, brainstem, cerebellar, or visual Definition of “improvement”: Not defined 

This smitoxa

monthrelapsprogrestatisttreatmoutcomanalyschangtotal nfirst trestanda5-mg/

convinprovidindividQUALDescrMethodescriConceDescrPatienInvest
66 

Evidence Table 3a. Disease modifying therapies and long-term impro

vement (continued) 

Stu

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Inclusion/ Exclusion Criteria

Study Design Patients Interv

entions Outcomes/Results Com

neutrophil, and platelet counts in normal ranges; age 18-55 Exclusion: None specified 

MTX 12 mg: 4.45± 1.05 MTX 5 mg: 4.64 ±1.01 Placebo: 4.69 ±

0.97 Baseline relapse rate (mean ± SD in previous 1 yr): MTX 12 mg: 1.27± 1.12 MTX 5 mg: 1.42 ±1.26 Placebo: 1.31 ±

1.14 

Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Number of treated relapses per patient (median, with range): Placebo: 1 (0-5)MTX 12 mg: 0 (0-2) p = 0.0002 

OutcoNo. of Yes

Hauser, Da

wson, 

Lehrich, et al., 1983 

Inclusion: Clinicallydefinite MS; severe progressive disease, with worsening inprevious 9 mo (defined as a decrease of ≥ 1 

points on functional status or disabilityscales, eithercontinuous decline or continuous decline with superimposed exacerbations); nocorticosteroid therapyin previous month; no immunosuppressive therapy in previous yrExclusion: Medical illnesses incompatible with safe administration of study medications 

RCT (parallelgroup, not double-blinded, two-center) Duration of study treatment/follo

w

up: Treatment duration variable (see at right, under “Interventions”; patients followedfor total of 1 yr Provider specialty: NR (presumably neurologists) Location: 2 sites in Boston, MA 

No. of patients randomized: 58Dropouts: 0 Completed: 58 Age (mean ± SE): ACTH: 35.2 ± 1.5 

CYCL

O + AC

T

H: 

32.9 ± 1.8 

PEX + CYCL

O +

ACTH: 36.3 ± 1.7 

Baseline EDSS (mean ± SE):ACTH: 5.6 ± 0.2CYCL

O + AC

T

H: 

5.8 ± 0.2 

PEX + CYCL

O +

ACTH: 5.6 ± 0.2Baseline relapse rate: NR 

1) Adrenocorticotropic hormone (ACTH) (n = 20). Initially given intravenously dailyover 8-hr period, 

with 

doses as follows: 25 units on days 1-3, 20 units on days 4-6, 15 units on days 7-9, 10 units on days 10-12, and 5 units on days13-15. IM injections then given on days 16-18 (40 units each) and days 19-21 (20 units each), after which treatment discontinued. 2) High-dose cyclophosphamide (CYCL

O) + AC

T

H (n = 

20). CYCLO administered intravenouslydaily for 10-14 days at dosage of 400-500 mg 

1) Physical functioning: Definition of “improvement”: Decrease of one or more points on either the A

mbulation 

Index or the Disability-Status Scale, as compared 

with the score at the time of entry

Proportion of patients with “improvement”: ACTH alone – 5%ACTH + C

Y

CLO – 40% 

ACTH, PEX and oral C

YCLO – 20% 

Other (non-improvement) outcomes: Physician’s clinical assessment of stabilized neurological status 2) Relapse frequency:Definition of “relapse”: Not definedDefinition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated 

This sintens(partichigh-dsignifithe poseverespecifpropoclinicaAmbutherapThe ais not recomregimeshould treatmselectunremhave nregimebased studiethat th
67 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

per day in 4 divided doses (total dose 80-100 mg/kg body weight). Discontinued when WBC count fell to approximately4000/mm3. Large 

volumes of fluids administered orallyand by IV to prevent bladder toxicity. ACTH given as above, beginning on same day as CYCLO. 3) Plasma exchange (PEX) + low-dose CYCLO + ACTH (n = 18). PEX performed by means of continuous-glowexchange; approximately 1-1.5 plasma volumes removed perexchange and replaced with 5%serum albumin. 4-5 exchanges given over a 2-wk period. CYCLO given at lowdose (2 mg/kg/day) for 8 wk (dose decreased if WBC count fell below 4000/mm3). 

ACTH as above. All 3 treatments started together. 

signifiQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
68 

Evidence Table 3a. Disease modifying therapies and long-term impro

vement (continued) 

Stu

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d

Inclusion/ Exclusion Criteria

Study Design Patients Interv

entions Outcomes/Results Com

IFNB MultipleSclerosis StudyGroup, 1993 and IFNB StudyGroup and the Universityof British Columbia MS/MRI AnalysisGroup, 1995 and IFNB StudyGroup and the Universityof British Columbia MS/MRI AnalysisGroup, 1996 and Pliskin, Hamer, Goldstein, et al., 1996 

Inclusion: Clinicallydefinite or laboratorysupported definite MS for > 1 yr; E

DSS 

≤ 5.5; ≥ 2 acute 

exacerbations in previous 2 yr; clinically stable for at least 30 days before entry; no ACT

H or 

prednisone during 30 days prior to entry; age 18-50 Exclusion: Prior treatment with azathioprine or cyclophosphamide 

RCT (parallelgroup, doubleblind, multicenter)Duration of study treatment/follo

w

up: Original study period 2 yr;later extended; median time on study was 48.0 mo for the IFNβ1b 8 MIU group, 45.0 mo for the IFNβ-1b 1.6 MIU

group, and 46.0 mo for the placebo group Provider specialty:Neurologists Location: 4 sites in Canada and 7 in US 

No. of patients randomized: 372 Dropouts: Sixtyfive patients discontinued treatment during the first 2 yr (23 placebo, 18 in the 1.6 MIU, and 24 in the 8 MIU groups) 154 (over entire study period)Completed: 307 through 2 yr; 218through end of studyAge (mean ± SE): IFNβ-1b 8 MIU: 

35.2 ± 0.6 

IFNβ-1b 1.6 MIU:

35.3 ± 0.7 

Placebo: 36.0 ±

0.6 Baseline EDSS (mean ± SE):IFNβ-1b 8 MIU: 

3.0 ± 0.1 

IFNβ-1b 1.6 MIU:

2.9 ± 0.1 

Placebo: 2.8 ± 0.1

Baseline relapse rate (mean in past 2 yr ± SE): IFNβ-1b 8 MIU: 

3.4 ± 0.2 

IFNβ-1b 1.6 MIU:

3.3 ± 0.1 

1) Recombinant interferon β-1b (IFNβ1b), 8 MIU selfadministered by SC injection every other day for duration of study (n = 124) 2) Recombinant IFNβ1b, 1.6 MIU selfadministered by SC injection every other day for duration of study (n = 125) 3) Placebo (n = 123) 

1) Physical functioning: A secondary endpoint, progression in disability, was defined as a persistent increase of one or more EDSS points confirmed on t

wo consecutive evaluations 

separated by at least 3 months Results: Median time to progression (yr)  Placebo – 4.18 1.6 MIU – 3.49 8 MIU – 4.79Time to progression (placebo vs. 8 MIU)  P = 0.096 2) Relapse frequency:Definition of “relapse”: Appearance of a ne

w

sy

mptom or worsening of an old symptom, 

attributable to M

S; accompanied by an 

appropriate ne

w neurological abnormality;

lasting at least 24 hours in the absence of fever; and preceded by stability orimprovement for at least 30 daysAnnual relapse rate: Year 1 Placebo – 1.44 

1.6 MIU – 1.22

8 MIU – 0.96 

Placebo vs. 8 MIU: p < 0.001 

Year 2 Placebo – 1.18 

1.6 MIU – 1.04

8 MIU – 0.85 

Placebo vs. 8 MIU: p ≤ 0.03 

Year 3 Placebo – 0.92 

1.6 MIU – 0.80

8 MIU – 0.66 

Placebo vs. 8 MIU: p = 0.084 

Year 4 Placebo – 0.88 

1.6 MIU – 0.68

8 MIU – 0.67 

Placebo vs. 8 MIU: p = 0.166 

Year 5 Placebo – 0.81 

1.6 MIU – 0.66

These of IFNexacediseasdemonof any 

Q

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Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Placebo: 3.6 ± 0.1 8 MIU – 0.57 

Placebo vs. 8 MIU: p = 0.393 

3) Cognitive functioning: Immediate and delayed recall memory and visual reproduction subtests of the Wechsler Memory Scale, forms 1 and 2, attention/mental speed (Trailmaking Test part B; Stroop Color-Word Test), dominant and nondominant morot function (Purdue Pegboard), and Beck Depression Inventory were administered to patients in all groups during the course of the study. No baseline measurements were made. Results: A significant main effect for time (F = 15.75 [2, 27], p < 0.001) and an interaction effect between treatment condition and time of testing (F = 4.15 [2, 27], p < 0.03) were found for WMS VRDelayed Recall. Follow-up pairwise comparisons indicated an improvement in delayed visual reproduction between the second and fourth years of treatment in the high-dose group (WMS VR-Delayed Recall; p < 0.003). The placebo and low-dose groups did not change significantly. No other neuropsychological parameters demonstrated a significant difference between the groups during the study.

Jacobs, Cookfair, Rudick, et al., 1996 and Rudick, Goodkin, Jacobs, et al., 1997 and 

Inclusion: DefiniteMS for ≥ 1 yr; EDSS 

1.0-3.5; relapsing disease course, with ≥ 2 documented exacerbations in previous 3 yr and no exacerbations for at least past 2 mo; age 18-55 Exclusion: Prior 

RCT (parallelgroup, doubleblind, multicenter)Duration of study treatment/followup: Variable (enrollment date varied, but endof-study date same for all patients) 

No. of patients randomized: 301 Dropouts: Not completely clear; 23 earlywithdrawals,variable treatment durations Completed: 287 followed up through 1 yr; 172

1) Interferon β-1a

(IFNβ-1a) 6 million 

units by IM injection weekly for up to 3 yr (n = 158) 2) Placebo for up to 3 yr (n = 143) 

1) Physical functioning: Definition of “improvement”: ≥ 0.5- or 1.0-point improvement on EDSS Proportion of patients with “improvement”:  Placebo IFNβ-1a Improved Unsustained 

≥ 1.0 10 (11.5%) 16 (19.3%) 

 0.5 10 (11.5%) 13 (15.7%) Improved 

The stdemonwith reas merelapsvariouparamIFNβ-

of the treatmdata oSome the nu
70 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Fischer, Priore, Jacobs, et al., 2000 and Jacobs, Rudick, and Simon, 2000 and Rudick, Fisher, Lee, et al., 2000 

immunosuppressant or interferon therapy;adrenocorticotropic hormone orcorticosteroidtreatment in previous 2 mo; pregnancy or nursing; unwilling to practice contraception; chronic progressive MS; any disease other than MS compromising organ function 

Provider specialty:Neurologists Location: 4 sites in US 

through 2 yr; 31 through 3 yr Age (mean ± SE): IFNβ-1a: 36.7 ±

0.57 Placebo: 36.9 ±

0.64 Baseline EDSS (mean ± SE):IFNβ-1a: 2.4 ±

0.06 Placebo: 2.3 ±

0.07 Baseline relapse rate (mean ± SE,time frame not specified): IFNβ-1a: 1.2 ±

0.05 Placebo: 1.2 ±

0.05 

Sustained ≥ 1.0 5 (8.9%) 10 (18.2%)  0.5 9 (16.1%) 14 (25.5%) Other (non-improvement) outcomes: Time to sustained progression of disability,the primary outcome measure, was significantly greater in IFNβ-1a-treated 

patients than in placebo-treated patients (p = 0.02) 2) Relapse frequency:Definition of “relapse”: Appearance of newneurological symptoms or worsening of preexisting neurological symptoms lasting at least 48 hours in a patient who had been neurologically stable or improving for the previous 30 days accompanied by objective change on neurological examination 

(worsening of 0.5 point on the EDSS or a worsening by ≥ 1.0 point on the pyramidal, 

cerebellar, brainstem, or visual functional system scores)Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Annual relapse rates:  Placebo IFNβ-1a P value 

All patients 0.82 0.67 0.04 104 week patient subset 0.90 0.61 0.002 3) Cognitive functioning: The Comprehensive NP Battery is a broadspectrum battery comprising measures from the core battery recommended by the National MS Society Cognitive Function Study Group as well as additional measures covering cognitive domains of theoretical 

EDSS QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
71 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

interest Definition of “improvement”: Not defined for individual patients Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Relapsing MS patients treated with IFNβ-1a 

for 2 yr performed significantly better than placebo patients on a composite of information processing and learning/recent memory measures (set A from the Comprehensive NP Battery). A similar trend was observed on a composite measure of visuospatial abilities and executive functions (set B) but not on the set C composite (verbal abilities and attention span).

Johnson, Brooks, Cohen, et al., 1995 and Weinstein, Schwid, Schiffer, et al., 1999 and Liu, Blumhardt, and the Copolymer 1 Multiple Sclerosis StudyGroup, 2000 and 

Inclusion: Clinicallydefinite or laboratorysupported MS; relapsing-remittingcourse; ambulatory,with EDSS 0-5.0; ≥ 2 

clearly documented relapses in 2 yr prior to entry; onset of first relapse ≥ 1 yr before 

randomization; neurological stabilityand freedom fromcorticosteroid therapyfor ≥ 30 days prior to 

entry; age 18-45Exclusion: Previous Copolymer 1 therapy;previous immunosuppressive therapywith cyctotoxic chemotherapy or

RCT (parallelgroup, doubleblind, multicenter)Duration of study treatment/followup: 2 yr Provider specialty:Neurologists Location: 11 sites in the US 

No. of patients randomized: 251 Dropouts: 36 Completed: 215Age (mean ± SD):Cop 1: 34.6 ± 6.0 Placebo: 34.3 ±

6.5 Baseline EDSS (mean ± SD): Cop 1: 2.8 ± 1.2Placebo: 2.4 ± 1.3

Baseline relapse rate (mean ± SD for prior 2 yr): Cop 1: 2.9 ± 1.3Placebo: 2.9 ± 1.1

1) Glatiramer acetate = Copolymer 1 (Cop 1) by SC injection; 20 mg self-injected daily for 2 yr (n = 125) 2) Placebo (n = 126) 

1) Physical functioning: Definition of “improvement”: ≥ 1.0-point 

EDSS reduction Proportion of patients with “improvement”: Original 2-yr trial: Cop 1 – 24.8% Placebo – 15.2%Extension study:Cop 1 – 27.2% Placebo – 12.0%Other (non-improvement) outcomes: Mean change in EDSS, Ambulation Index, proportion of progression-free patients, area under curve analyses of EDSS progression 2) Relapse frequency:Definition of “relapse”: Appearance or reappearance of one or more neurological 

This sCopolrelapspatienon EDQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
72 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Johnson, Brooks, Cohen, et al., 1998 

lymphoid irradiation; need for aspirin or chronic NSAIDs during trial; [othergeneric exclusions] 

abnormalities persisting for at least 48 hours 

and immediately preceded by a relativelystable or improving neurological state of at least 30 days. A relapse was confirmed onlywhen a patient’s symptoms wereaccompanied by objective changes on the neurological examination consistent with an increase of at least a half a step on the EDSS, two points on one of the seven functional systems, or one point on two or more of the functional systems. Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Relapse rate:  Cop 1 Placebo P-value Relapse rate 24 months 1.19 1.68 0.007 Annual relapse rate 0.59 0.84 Relapse free 33.6% 27.0% 0.098 Extension Relapse rate 1.34 1.98 0.002 Extension Annual relapse rate 0.58 0.81 3) Cognitive functioning: Brief Repeatable Battery of Neuropsychological Tests – consisting of 5 tests including measures of sustained attention and concentration (Paced Auditory Serial Addition Test and Symbol Digit Modalities Test), verbal learning and delayed recall (Buschke Selective Reminder Test), visuospatial learning and delayed recall (10/36 Spatial Recall Test), and semantic retrieval (Word 
73 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

List Generation Test) Definition of “improvement”: Not defined Proportion of patients with “improvement”: Mean neuropsychologic test scores were improved at 12 and 24 months compared with baseline for placebo and glatiramer groups. No differences were detected between the treatment groups for any of the neuropsychologic test results. Other (non-improvement) outcomes: 

Kappos, Polman, Pozzilli, et al., 2001 and Freeman, Thompson, Fitzpatrick, et al., 2001 

Inclusion: Clinicallyor laboratory supported definite diagnosis of secondaryprogressive MS; EDSS 3.0-6.5; ≥ 2 relapses or ≥ 1.0-point increase in EDSS in previous 2 yr; age 18-55Exclusion: None specified 

RCT (parallelgroup, doubleblind, multicenter)Mean duration oftreatment/followup: Treatment lasted up to 36 mo; article reports results at study termination;mean follow-up time 1068 ± 176 days for IFNβ-1b

and 1054 ± 199 days for placeboProvider specialty: NR (presumably neurologists) Location: 32 sites in Europe 

No. of patients randomized: 718 Lost to follow up:88Withdrew from treatment: 132 Completed treatment and follow up: 498 Age (mean ± SD):IFNβ-1b: 41.1 ±

7.2 Placebo: 40.9 ±

7.2 Baseline EDSS (mean ± SD): IFNβ-1b: 5.1 ± 1.1

Placebo: 5.2 ± 1.1

Baseline relapse rate (% of patients without relapse in 2 yr preceding study): 

1) Interferon β-1b

(IFNβ-1b) by SC 

injection; initial dose 0.5 mL (4 MIU) everyother day, increased after 2 wk to 1.0 mL (8 MIU) every other dayfor up to 3 yr (n = 360)2) Placebo (n = 358) 

1) Physical functioning: Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Time to confirmed progression in EDSS favored IFNβ-1b, p = 0.007 Percent of patients progression-free Placebo – 46.1%IFNβ-1b – 54.7%

P = 0.031 2) Relapse frequency:Definition of “relapse”: Previously defined Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not assessed Other (non-improvement) outcomes: Percent of patients relapse-free: Placebo – 36.3%IFNβ-1b – 42.5%

P = 0.083 

These analysfrom tconduGroup ProgreSignifrelapsparamstudy improvrates.QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
74 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

IFNβ-1b: 31.9%

Placebo: 28.2%

Percent of patients relapse-free or decrease in relapse rate: Placebo – 45.0%IFNβ-1b – 53.1%

P = 0.031 3) Quality of life: The SIP is a generic self-report questionnaire of health-related quality of life, which examines the individual’s perception of the impact of the disease process on behavior in everyday life. The total score ranges from 0 (best) to 100 (worst). The GEMS scale was developed specificallyfor this study and provides a global evaluation of the neurologist’s perception of change in terms of disease status and disability. The scale provides 7 points ranging from “very much better” to “verymuch worse.” No published information is available determining its measurement properties. Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: The difference in total SIP score for the twogroups shows a non-statistically significant trend in favor of IFNβ-1b. 

The SIP physical dimension score demonstrates a statistically significant benefit in favor of IFNβ-1b therapy at 6 and 

12 months. A significant treatment effect of IFNβ-1b was 

demonstrated in the psychosocial dimension scores at 18 months but not at the end of the study.
75 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Khatri, McQuillen, Harrington,et al., 1985 

Inclusion: Clinicallydefinite MS; chronic progressive disease course (continuous worsening on serial neurological exams during previous 12mo); patient insured, and insurance company would payfor plasma exchange Exclusion: None specified 

RCT (parallelgroup, doubleblind, singlecenter) Duration of study treatment/followup: 18 mo Provider specialty:Neurologists Location: 1 site in Milwaukee, WI

No. of patients randomized: 59Dropouts: 4 Completed: 55 Age (mean, completers): Genuine: 37.8 Sham: 42.2 Baseline EDSS (mean, completers): Genuine: 6.6 Sham: 6.3 Baseline relapse rate: NR 

1) Plasma exchange (n = 30); during each exchange, plasmavolume equivalent to 5% of patient’s bodyweight exchanged for 5% albumin solution and normal saline in equal ratios; exchanges performed once per week for 20 wk2) Sham plasmaexchange (patient’s plasma returned after it had been separated) (n = 29); exchanges performed once per week for 20 wkPatients in both groups also received: a) Oral cyclophosphamide (1.5 mg/kg per day, rounded tonearest 50 mg); b) prednisone (1 mg/kg every other day,gradually decreasing doses after 15th wk);

and c) pooled human immune serum globulin (40 ml in 4 divided IM injections over 2 days after each exchange) 

1) Physical functioning: Two scoring scales were used in measuring clinical change, the Kurtzke DSS and the Canter Scale, which measures changes in activities of daily living Definition of “improvement”: ≥ 1-point improvement on DSS Proportion of patients with “improvement”: At 5 mo, 14 plasmapheresis patients improved and 8 sham pheresis patients improved with details as follows: 5-mo evaluation: PP Sham 3 or more 5 0 points 2 points 5 4 1 point 4 4 11-mo evaluation: PP Sham 3 or more 3 0 points 2 points 4 1 1 point 4 4 Other (non-improvement) outcomes: Not delineated 2) Relapse frequency:Definition of “relapse”: Not definedDefinition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Not delineated 3) Cognitive functioning: Standard 

This sthe treThe replasmmeasuObserimprovalthouQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
76 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

neurological examination Definition of “improvement”: Not defined Proportion of patients with “improvement”: 4 patients with cognitive deficits improved in these functions at the 15th PP treatment, but 

this did not occur in similar patients in the sham group 

Leary,Miller, Stevenson, et al., 2003 

Inclusion: Primaryprogressive MS (progressive historywithout relapse orremission, ≥ 2 typical lesions on MRI brain or spinal cod, and oligoclonal bands in the CSF not present in parallel serum orabnormal visual evoked potentials); disease duration ≥ 2 

yr; EDSS 2.0-7.0;age 18-60 Exclusion: Interferon, immunosuppressant, or chronic steroidtherapy in previous 3 mo; pregnancy orlactation; seizure in previous 3 mo; history of severe depression 

RCT (parallelgroup, doubleblind, singlecenter) No. of patients randomized: 50 Dropouts: 7 

withdrew fromtreatment; all but 1 of these followedup for 2 yr Completed: 43 completed treatment; 49followed up for 2 yrAge (mean [with range]):

Duration of study treatment/followup: 2 yr Provider specialty: NR (presumably neurologists) Location: 1 site in London, UK 

IFNβ-1a 60: 47 

(25-59) IFNβ-1a 30: 46.5 

(29-58) Placebo: 43 (30-59) Baseline EDSS (median [with range]):IFNβ-1a 60: 5.5 

(2.0-6.5) IFNβ-1a 30: 5.5 

(3.5-7.0) Placebo: 4.5 (2.0-7.0) Baseline relapse 

1) Interferon β-1a

(IFNβ-1a) 60 μg 

weekly by IM injection for 2 yr (n = 15) 2) IFNβ-1a 30 μg

weekly by IM injection for 2 yr (n = 15) 3) Placebo for 2 yr (n = 20) 

1) Physical functioning: Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Primary endpoint was time to sustained progression in disability, and there was no statistically significant difference among the treatment arms 

This sIFNβ-

progreof time found treatmregardimprovQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
77 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

rate: NA 

Milanese, La Mantia, Salmaggi, et al., 1988 

Inclusion: Clinicallydefinite MS bySchumacher’s criteria; relapsingremitting (with ≥ 2 

relapses in previous 3 yr) or progressive (with continuous worsening of neurological status over previous 1 yr) disease course Exclusion: Conditions which did not permit regular examination or which hampered patient’s reliability (e.g., DSS > 7 or psychic disturbances); contraindications to immunosuppressive treatment; previous use of immunosuppressive therapy;pregnancy 

RCT (parallelgroup, doubleblind, singlecenter) Duration of study treatment/followup: 1 yr (see “Comments”) Provider specialty:Neurologists Location: 1 site in Milan, Italy

No. of patients randomized: 23 included in 1-yranalysis reportedhere (13 relapsingremitting, 10 progressive) Dropouts: 0 (though 2 droppedout after 1 yr; see “Comments”) Completed: 23 Age (mean): AZA-relapsing: 33.1 Placebo-relapsing: 34.1 AZA-progressive: 38.1 Placeboprogressive: 42.4 Baseline EDSS (mean): AZA-relapsing: 2.17 Placebo-relapsing: 2.43 AZA-progressive: 5.00 Placeboprogressive: 3.86Baseline relapse rate (mean per yr): AZA-relapsing: 1.144 Placebo-relapsing: 0.890 

1) Azathioprine (AZA) PO 2-2.5 mg/kg per day for 1 yr (n = 9) 2) Placebo for 1 yr (n = 14) 

1) Physical functioning: Definition of “improvement”: Not delineated Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: No statistically significant difference at 1 yr2) Relapse frequency:Definition of “relapse”: Schumacher criteria Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Relapse rate – Progressive MS: 

Pre- Final

AZA 0.5 0.42 Placebo 0.32 0.42 Relapse rate – Relapsing-remitting MS: 

Pre- Final

AZA 1.14 0.98 Placebo 0.89 0.92 No statistically significant differences in relapse rates 

This sazathiremittstatistdetecttrial. ApatienresultiregardinformindividQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
78 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

AZA-progressive: 0.500 Placeboprogressive: 0.318

Millefiorini, Gasperini, Pozzilli, et al., 1997 

Inclusion: Clinicallydefinite or laboratorysupported relapsingremitting MS; disease duration 1-10 yr; EDSS 2-5; at least 2 exacerbations in previous 2 yr; age 18-45 Exclusion: HIVpositive; previouscardiovasculardisease; left ventricular ejection fraction < 50%; renal, liver, and/or respiratory dysfunction; diabetes; malignancy;psychiatric illness; pregnancy; women not using contraception; use of steroids in previous 3 mo; previous immunosuppressant therapy 

RCT (parallelgroup, doubleblind [patients and assessors, not treating physicians], multicenter)Duration of study treatment/followup: Treatment lasted 1 yr; patients followedfor total of 2 yr Provider specialty:Neurologists Location: 8 sites in Italy

No. of patients randomized: 51 (all relapsingremitting) Dropouts: 9 Completed: 42 completed all assessments (including MRIs) Age (mean ± SD):MTX: 30.9 ± 6.0 Placebo: 28.7 ±

6.5 Baseline EDSS (mean ± SD): MTX: 3.6 ± 0.9 Placebo: 3.5 ± 1.2

Baseline relapse rate (mean ± SD in previous 2 yr): MTX: 2.8 ± 1.2 Placebo: 2.8 ± 1.1

1) Mitoxantrone (MTX), 30-min IVinfusion (8 mg/m2) 

ever month for 1 yr (n = 27) 2) Placebo (n = 24) 

1) Physical functioning: Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: % of patients who progressed by 1.0 point on EDSS – found statistically significant benefit of mitoxantrone at 2 yr 2) Relapse frequency:Definition of “relapse”: Appearance of a newsymptom or worsening of an old symptom, attributable to MS, accompanied by a documented new neurological abnormality,lasting more than 48 hours and preceded bystability or improvement for at least 30 daysDefinition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Number of exacerbation (mean ± SD): MTX: 0.89 ± 2.1 Placebo: 2.62 ± 1.9 

p = 0.0002 Exacerbation-free patients: MTX: 17 (63%) Placebo: 5 (21%) p = 0.006 

This smitoxaremittisignifiregard rate rewith reimprovQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of No – a
79 

Evidence Table 3a. Disease modifying therapies and long-term impro

vement (continued) 

Stu

d

y

S

electe

d

Inclusion/ Exclusion Criteria

Study Design Patients Interv

entions Outcomes/Results Com

MultipleSclerosis StudyGroup, 1990 

Inclusion: Clinicallydefinite MS for ≥ 1 yr; EDSS 3.0-7.0; age 18-55; chronic and progressive clinical deterioration of ≥ 1 grade, but not > 3 grades, on EDS

S in 

previous 12 mo, 

with 

some decline in last 6 mo; no acute relapse in previous 3 mo; no immunosuppressive drugs in previous 3 mo; no unproventherapies for MS (e.g., hyperbaric oxygen, gangliosides, snake venom [!]) in previous 1 mo; noprior treatment with cyclophosphamide or radiation; no uncontrolled hypertension (SBP > 170 mmHg or DBP > 110 mmHg),malignancy, recent myocardial infarction, chronic pulmonary disease, active infection, hepatic or renal dysfunction, or other neurological disorders; not using medications kno

wn to 

interfere with studydrugs Exclusion: Known sensitivity or adverse reactions to immunosuppressive 

RCT (parallelgroup, doubleblind, multicenter)Duration of study treatment/follo

w

up: 2 yr Provider specialty:Neurologists Location: 12 sites in US 

No. of patients randomized: 547 Dropouts: 120 (cyclosporine) + 87 (placebo) = 207 Completed: 340 Age (mean ± SD):Cyclosporine: 40.5 ± 7.7 Placebo: 40.6 ±

8.2 Baseline EDSS (mean ± SD): Cyclosporine: 5.4 ± 1.2 Placebo: 5.4 ± 1.2

Baseline relapse rate: NR 

1) Cyclosporine PO (liquid suspension); initial dose of 6 mg/kg diluted in milk ororange juice and taken each morning 

with

breakfast; dose adjusted to achieve whole-blood cyclosporine trough level of 400-600 ng/mL, later reduced to 300-500 ng/mL; maximum dose permitted was 10mg/kg/day (n = 273) 2) Placebo (n = 274) 

1) Physical functioning: Extensive evaluations performed including EDSS, incapacity status scales, functional system scores of the Multiple Sclerosis Minimal Record of Disability, standardized neurological exa

mination, quantitative 

examination of neurological functional, Ambulation Index, physical exa

mination, and 

clinical evaluation Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Mean change in EDSS – found benefit of cyclosporine therapy with p = 0.006 in patients completing study, and p = 0.002 in all patients. 2) Relapse frequency:Definition of “relapse”: Not definedDefinition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: 

This stherappatienhigh ddemonbenefprogrenot primprovQ

UAL

DescrMethodescriConceDescrPatienInvestOutcoNo. of Yes – withdrnecesprimamodifianalys56% ocycloscontinthose succe(p=0.0
80 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

drug; severe dementia; paraplegia or gait ataxia sufficient to prevent walking; severeupper extremityataxia preventing independent feeding or dressing 

Noseworthy,O’Brien, Petterson, et al., 2001 

Inclusion: One ormore episodes ofdemyelinating optic neuritis occurring in the setting of clinically definite orlaboratory-supported definite MS or in the presence of cranial MRI changes consistent with MS; first episode of optic neuritis between ages of 18 and 45; age < 50 at enrollment; fixed,apparentlyirreversible loss of visual acuity in at least one eye thatmet following criteria: a) visual acuity worse than 20/40 for a period of at least 6 mo and unchanged on at least 2 exams separated by at least 1 mo; b) optic disc pallor as detected bystudy neuroophthalmologist; c) abnormal visual field measured on Humphrey Field 

RCT (parallelgroup, doubleblind, singlecenter) Duration of study treatment/followup: Treatment lasted 12 wk + 5 days; patients followed for total of 12 mo Provider specialty:Ophthalmologists and neurologists Location: 1 site in Rochester, MN

No. of patients randomized: 55 (42 relapsingremitting, 13 secondaryprogressive) Dropouts: 2 (both between 6 and 12mo) Completed: 53 Age (mean ± SD):IV IgG: 38.0 ± 7.2 

Placebo: 39.2 ±

6.7 Baseline EDSS (mean ± SD, excluding visual functional status scores): IV IgG: 3.6 ± 2.5

Placebo: 3.0 ± 2.5

Baseline relapse rate: NR 

1) IV immunoglobulin (IV IgG) 0.4 g/kg dailyfor 5 days, then once per month for 3 months (total of 8 infusions) (n = 27) 2) Placebo (n = 28) 

1) Physical functioning: Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Several measures of visual function were assessed, as well as EDSS. No measures demonstrated statistically significant benefit from therapy.2) Relapse frequency:Definition of “relapse”: Not defined

Definition of “improvement”: Not assessed Proportion of patients with “improvement”: Not assessed Other (non-improvement) outcomes: 

This sIgG in patienterminNo daindividQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
81 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Analyzer with a mean deviation ≤ -4.00 and a pattern of defect consistent with optic neuritis; no adrenocorticotropic hormone orcorticosteroids inprevious 2 mo Exclusion: Primaryprogressive MS; nondemyelinating cause for visual loss; preexisting ocular abnormalities; serious intercurrent medical illness; concomitant use of experimental drug for MS or other disease; serum creatinine > 1.5 times normal;pregnancy or unwillingness to use contraception; known antibody deficiencysyndrome; need for IV IgG administration 

Patti, L’Episcopo, Cataldi, et al., 1999 

Inclusion: DefiniteMS; disease course relapsing-remitting(with ≥ 2 documented 

relapses in previous 2 yr and EDSS ≤ 3.5) 

or secondary progressive (withdeterioration of ≥ 1.0 point on the EDSSover previous 2 yr and EDSS ≤ 7.0); emotionally stable; 

RCT (parallelgroup, doubleblind, singlecenter) Duration of study treatment/followup: 2 yr Provider specialty:Neurologists 

No. of patients randomized: 98 (58 relapsingremitting, 40 secondaryprogressive) Dropouts: 0 Completed: 98 Age (mean): Relapsing1) Natural interferon-β (nIFNβ) 6 MIU by IM injection three times per wk for 2 yr (n = 49) 2) Placebo for 2 yr (n = 49) 1) Physical functioning: Definition of “improvement”: Decrease of 0.5 or 1.0 in EDSS Proportion of patients with “improvement”: Relapsing-remitting patients: Placebo – 1 of 29 patients (3.4%) improved nIFNβ – 15 of 29 patients (52%) improved P = 0.002 Secondary progressive patients: Placebo – 1 of 20 patients (5%) improved nIFNβ – 8 of 20 patients (40%) improved This s

nIFNβ 

seconsignifitreatmpropoor 1.0 propoQUALDescrMethodescri
82 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

negative for HIV,HbsAg, and Borreliosis; free of other immune orneurological diseases; clinicallystable for ≥ 30 days; no ACTH orcorticosteroids inprevious 30 days; age 18-45 Exclusion: Pregnancy; prior treatment with azathioprine or cyclophosphamide (in previous 1 yr) 

Location: 1 site in Catania, Italy

remitting (RR)patients: 36.6 Secondaryprogressive (SP)patients: 36.9 Baseline EDSS (mean): RR-nIFNβ: 3.06RR-placebo: 3.1SP-nIFNβ: 5.8 SP-placebo: 6.0Baseline relapse rate (mean over previous 2 yr): RR-nIFNβ: 1.8 RR-placebo: 1.9SP-nIFNβ: 0.4 SP-placebo: 0.6

P = 0.006 2) Relapse frequency:Definition of “relapse”: Rapid onset of newsymptoms or a worsening of preexisting symptoms persisting for 48 hours or more and were accompanied by objective changes on the neurologic examination – an increase of at least one grade in the score for at least one of the functional groups of EDSS Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: The probability of remaining exacerbationfree was significantly higher in the nIFNβtreated group (presented in graphical form; 

p < 0.001) 

ConceDescrPatienInvestOutcoNo. of Yes

Patzold, Hecker, and Pocklington, 1982 

Inclusion: Confirmed MS; resident in district of study site Exclusion: None specified 

RCT (parallelgroup, openlabel, singlecenter) Duration of study treatment/followup: 2 yr Provider specialty:Neurologists Location: 1 site in Hanover, Germany

No. of patients randomized: 142 Dropouts: 27 before completing1 yr; 17 more before completing2 yrCompleted: 115 completed 1 yr (53 intermittent, 52 intermittentprogressive, 10 progressive); 98 completed 2 yr (47 intermittent, 43 intermittentprogressive, 8 progressive) 

1) Azathioprine PO, daily dose of 2 mg/kg for 2 yr (n = 74) 2) No azathioprine (n = 68) 

1) Physical functioning (EDSS notassessed): Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not assessed Other (non-improvement) outcomes: Patients were evaluated clinically and the severity of disease was calculated by means of an objective weighting scale corresponding to the data recorded by the examiner. In the untreated group on average MS deteriorated three times as rapidly as in the treated group. 2) Relapse frequency:

This sazathiThis trissues validaThe suncleadata rimprovQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of 
83 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Age: NR Baseline EDSS: NR Baseline relapse rate: NR 

Definition of “relapse”: Definite worsening of condition lasting for 24 hr or more, or the occurrence or recurrence of symptoms and signs after a period of 4 wk in which these had either disappeared or improvedDefinition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: No. of relapses: Azathioprine: 2.4 ± 2.0 Control: 1.9 ± 1.3 

Yes

PRISMS StudyGroup and the Universityof British Columbia MS/MRI AnalysisGroup, 1998 and Liu and Blumhardt, 1999 and Liu and Blumhardt, 2002 and Patten and Metz, 2001 

Inclusion: Clinicallydefinite or laboratorysupported definite MS of at least 1 yr duration; relapsingremitting MS with ≥ 2 relapses in preceding 2 yr and EDSS score 0-5.0; adult Exclusion: Any previous systemictreatment with interferons, lymphoid irradiation, or cyclophosphamide; other immunomodulatory or immunosuppressive treatment in previous 12 mo 

RCT (parallelgroup, doubleblind, multicenter)Duration of study treatment/followup: 2 yr Provider specialty:Neurologists Location: 22 sites in Canada, Australia, and 7 European countries 

No. of patients randomized: 560 Lost to follow up:27 Withdrew from treatment: 31Followed up to 2 yr: 533 Completed treatment to 2 yr:502 Age (median withIQR):IFNβ-1a 44 μg: 

35.6 (28.4-41.0)IFNβ-1a 22 μg: 

34.8 (29.3-39.8)Placebo: 34.6 (28.8-40.4) Baseline EDSS (mean ± SD): 

1) Interferon β-1a

(IFNβ-1a) by SC 

injection, 44 μg (12 MIU), 3 times weekly(n = 184) 2) IFNβ-1a by SC

injection, 22 μg (6 MIU), 3 times weekly(n = 189) 3) Placebo (n = 187) 

1) Physical functioning: Definition of “improvement”: In the categorical disability trend analysissustained improvement was defined as a decrease of at least 1.0 EDSS point confirmed at 3 months and sustained until the end of the study

Proportion of patients with “improvement”: Not stated – in the categorical disabilitytrend analysis data were not reported on the number of patients with sustained improvement. 31% of treated patients and 20% of placebo patients attained stable course. Other (non-improvement) outcomes: 22-mcg dose and 44-mcg dose patients both had mean reduction in EDSS compared with placebo of 0.25 2-yr change in EDSS: 

Mean AUC 

Placebo +0.48 +0.48 22-mcg dose +0.23 +0.05 44-mcg dose +0.24 +0.06 

This sregardplacebEDSS are reno datpatienstatusQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
84 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

IFNβ-1a 44 μg: 

2.5 ± 1.3 

IFNβ-1a 22 μg: 

2.5 ± 1.2 

Placebo: 2.4 ± 1.2

Baseline relapse rate (mean relapses in previous 2 yr [±SD]: IFNβ-1a 44 μg: 

3.0 ± 1.1 

IFNβ-1a 22 μg: 

3.0 ± 1.1 

Placebo: 3.0 ± 1.3

2) Relapse frequency (primary outcome measure): Definition of “relapse”: As defined bySchumacher criteria, required theappearance of a new symptom or worsening of an old symptom over at least 24 hr that could be attributed to MS activity and was preceded by stability or improvement for at least 30 daysDefinition of “improvement”: Proportion of patients with “improvement”: - Not stated Other (non-improvement) outcomes: Relapses per patient:  Placebo – 2.56 22 mcg dose – 1.82  44 mcg dose – 1.73 % reduction in relapses vs. placebo:  22 mcg dose – 29  44 mcg dose – 32 % relapse free over 1 year:  Placebo – 22 22 mcg dose – 37  44 mcg dose – 45 % relapse free over 2 years:  Placebo – 16 22 mcg dose – 27  44 mcg dose – 32 Moderate or severe relapses - % with no relapses:  Placebo – 42 22 mcg dose – 61  44 mcg dose – 62 % with no admissions for MS: 
85 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

 Placebo – 75 22 mcg dose – 77  44 mcg dose - 82 3) Cognitive functioning [describe scale/ instrument used]:Definition of “improvement”: Not assessed Proportion of patients with “improvement”: Not assessed 5) Quality of life: Center for Epidemiological Studies Depression Rating Scale was used to assess whether treatment with IFNβ-1a was associated with depression Other (non-improvement) outcomes: Proportion of patients exceeding cut-point did not vary significantly across treatment groups 

Rice, Filippi, and Comi, 2000 

Inclusion: Clinicallydefinite or laboratorysupported MS according to Schumacher or Poser criteria; chronic progressive disease course (slowprogression of signs and symptoms over preceding 12 mo); EDSS 3.0-6.5; serum creatinine < 1.5 mg/dL and creatinine clearance ≥ 80% of 

age-adjusted normal; aspartate and alanine transaminase and alkaline phosphatase levels < twice the normal upper limit; 

RCT (parallelgroup, doubleblind, multicenter)Duration of study treatment/followup: 12 mo Provider specialty: NR (presumably neurologists) Location: 6 sites in Canada and the US 

No. of patients randomized: 159 (111 secondary progressive, 48 primaryprogressive) Dropouts: 4 Completed: 155Age (mean): High-dose: 43.8Low-dose: 44.6 Placebo: 44.2 Baseline EDSS (mean): High-dose: 5.6 Low-dose: 5.6 Placebo: 5.6 

1) Cladribine by SC injection, 6 monthlycourses of 0.07 mg/kg/day for 5 consecutive days (total dose 2.1 mg/kg),followed by 2 monthlycourses of placebo (n = 52) 2) Cladribine by SC injection, 2 monthlycourses of 0.07 mg/kg/day for 5 consecutive days (total dose 0.7 mg/kg),followed by 6 monthlycourses of placebo (n = 53) 3) Placebo, 8 monthlycourses (n = 54)

1) Physical functioning: Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Primary outcome measure was mean change in EDSS – no statistical difference in treatment groups observed 2) Relapse frequency:Definition of “relapse”: Not assessed Definition of “improvement”: Not delineated Proportion of patients with “improvement”: Not assessed 

This sof cladsignifioutcomregardimprovQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of No – 9study
86 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

neutrophil count > 1600/μL; plateletcount > 130,000/μL; clinically normal ECGand chest X-ray; age 21-60 Exclusion: Significant history of medical disease in previous 2 yr; use of corticosteroids or other immunosuppressants in previous 3 mo; total lymphoid irradiation; persistent leukopenia or thrombocytopenia after treatment with immunosuppressive agents; alcohol or drug abuse orattempted suicide in previous 1 yr; malignancy in previous 5 yr; pregnancy or nursing; HIV+; use of experimental drug or device in last 60 days; previous participation in cladribine trial 

Baseline relapse rate: NR 

Romine, Sipe, Koziol, et al., 1999 

Inclusion: Clinicallydefinite relapsingremitting MS for at least 1 yr; ≥ 2 relapses in previous 2 yr; EDSS ≤ 6.5Exclusion: Treatment with immunosupRCT (parallel- group, double- blind, single- center) Duration of study treatment/follow up: Treatment lasted 8 mo; 

patients followed

No. of patients randomized: 52Dropouts: 2 before 12 mo, plus 6 more before 18 moCompleted: 50 to12 mo, 44 to 18mo 

1) Cladribine by SC injection; 5 consecutive daily injections of 0.07 mg/kg/day given monthly for 6 mo for total cumulative dose of 2.1 mg/kg; during remaining 2 mo of 8-mo treatment period, placebo given unless 

1) Physical functioning: Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not assessed Other (non-improvement) outcomes: No significant differences between the two groups with regard to EDSS or SNRS scores over the 18-mo period 

This scladribpatienstatistregard benefwith reThe dto clinpatien
87 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

pressive drugs in previous 3 mo; serum creatinine > 1.5 mg/dL; serum glutamic-oxaloacetic transaminase/serum glutamic-pyruvic transaminase or alkaline phosphatase elevated to twice the upper limit of normal; neutrophil counts of < 1600/μL or platelet counts < 130,000/μL; previous total lymphoid irradiation or extensive myelosuppressive chemotherapy 

for total of 18 moProvider specialty:Neurologists Location: 1 site in La Jolla, CA 

Age (mean, with range): Cladribine: 43.4 (30-52) Placebo: 39.8 (31-52) Baseline EDSS (mean, with range): Cladribine: 3.9 (2.0-6.5) Placebo: 3.8 (2.0-6.5) Baseline relapse rate (number inprevious 1 yr): Cladribine: 1: 5 (19%) 2: 16 (59%) 3-4: 6 (22%) Placebo: 1: 13 (52%) 2: 5 (20%) 3-4: 7 (28%) 

investigators had had to substitute placebo for a monthly dose earlier due to blood count inadequacy, in which case active drug could be given during mo 7 or 8 (n = 27) 2) Placebo (n = 25) 

2) Relapse frequency:Definition of “relapse”: Appearance of newsymptoms or worsening of an existing symptom, attributable to MS and accompanied by objective worsening of neurological findings and must have been preceded by disease stability or improvement lasting for at least 30 days, and the worsening must have lasted at least 24 hours and occur in the absence of fever Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Relapse rate: Cladribine – 0.77 (95% CI, 0.37 to 1.41) Placebo – 1.67 (95% CI, 1.02 to 2.57) 

QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes

Schwartz, CoulthardMorris, Cole, et al., 1997 

Inclusion: Relapsingremitting MS Exclusion: None specified 

RCT (see under“Comments”) Duration of study treatment/followup: 1 yr Provider specialty: NR Location: NR; patients had applied to lotteryto gain access to experimental drug 

No. of patients randomized: NRDropouts: NRCompleted: 79 Age (mean): IFNβ-1b: 43.9 

Control: 43.3 Baseline EDSS: NR Baseline relapse rate: NR 

1) Recombinant interferon β-1b (IFNβ1b); dose, route of administration, and treatment regimen not described (n = 34) 2) Usual care (n = 45)

1) Physical functioning: Not assessed 2) Relapse frequency: Not assessed 3) Cognitive functioning: Multiple scales used as belowDefinition of “improvement”: Improvement was defined as population mean change Proportion of patients with “improvement”: Not assessed Other (non-improvement) outcomes: Wechsler Memory Scale delayed visual recall demonstrated improvement in the 

As recsamplfinding of the functioStudy advan

1b in a controand fosurvey responQUALDescr
88 

Evidence Table 3a. Disease modifying therapies and long-term improvement (continued) Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

high-dose group compared with placebo (p < 0.003). Other measures failed to reach statistical significance. Individual patient data and percentage of patients improving not reported. 

MethodescriConceDescrPatienInvestOutcoNo. of Yes

Sipe, Romine, Koziol, etal., 1994 

Inclusion: Clinicallydefinite or laboratorysupported definite chronic progressive MS for more than 2 yrExclusion: Serum creatinine ≥ 132 

μmol/L or creatinine clearance < 80% of age-adjusted normal; serum transaminases or hepatic alkaline phosphatase more than twice the upper limit of normal; neutrophil count < 1600 μL or platelet count < 130,000/μL; inadequate birth control; plans to father a child during study; treatment with corticosteroids or other immunosuppressive medications in previous 6 mo; decreased marrowreserve asmanifested byleukopenia or thrombocytopenia for > 6 wk after 

RCT (designed as 2-yr crossovertrial, but analyzedas parallel-grouptrial after 1 yr; double-blind [examining physicians and patients, not treating physicians], single-center, matched-pair design) Duration of study treatment/followup: 1 yr Provider specialty:Neurologists Location: 1 site in La Jolla, CA 

No. of patients randomized: 51 (49 initially entered + 2 replacements for dropouts) Dropouts: 3 cladribine patients (2 of whom werereplaced), 1 placebo patient (included in analyses) Completed: 47 (48 analyzed) Age (mean, with range): Cladribine: 43.0 (28-53) Placebo: 42.7 (21-54) Baseline EDSS (mean ± SE):Cladribine: 4.7 ±0.3 Placebo: 4.6 ± 0.3

Baseline relapse rate: NR 

Central venous access device surgicallyimplanted in all patients for study drug administration 1) Cladribine administered bycontinuous 7-day IV infusion at the rate of 0.1 mg/kg daily; total of 4 monthly courses given (n = 24) 2) Placebo infusion (n = 24) 

1) Physical functioning: Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Paired differences in the two groups were significant in favor of cladribine: 

EDSS SNRS

Cladribine 4.4 ± 2.0 74.8 ± 10.3 

Placebo 5.6 ± 1.5 62.6 ± 11.3 

P-value p < 0.01 p < 0.001 2) Relapse frequency:Definition of “relapse”: Not definedDefinition of “improvement”: Not defined Proportion of patients with “improvement”: Not assessed Other (non-improvement) outcomes: None 

This scladribprogresignifiwith reprogreSNRSregard patienQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
89 

Evidence Table 3a. Disease modifying therapies and long-term impro

vement (continued) 

Stu

d

y

S

electe

d

Inclusion/ Exclusion Criteria

Study Design Patients Interv

entions Outcomes/Results Com

conclusion of immunosuppressive treatment 

SPECTRIMS StudyGroup, 2001 

Inclusion: Clinicallydefinite secondary progressive MS (defined as progressive deterioration of disability for ≥ 6 mo, 

with increase of ≥ 1 EDSS point over the last 2 yr [or 0.5 point bet

ween EDSS 6.0 

and 6.5], 

with or

without superimposed exacerbations, following an initial relapsing-remittingcourse); EDSS 3.0-6.5; pyramidal functional score ≥ 2; 

age 18-55 Exclusion: Immunosuppressive or immunomodulatorytreatments during previous 3-12 mo(depending on drug); corticosteroid use or disease exacerbation in previous 8 wk;severe concurrent illness; pregnancy or lactation; unwillingness to use contraception 

RCT (parallelgroup, doubleblind, multicenter)Duration of study treatment/follo

w

up: 3 yr Provider specialty:Neurologists Location: 22 sites in Europe, Canada, and Australia 

No. of patients randomized: 618 Dropouts: 112 withdrew fromtreatment; 65 of these were followed up for 3 yrCompleted: 506 completed treatment; 571 were follo

wed up

for 3 yr Age (mean ± SD):IFNβ-1a 44: 42.6 

± 7.3 IFNβ-1a 22: 43.1 

± 7.2 Placebo: 42.7 ±

6.8 Baseline EDSS (mean ± SD): IFNβ-1a 44: 5.3 ±

1.1 IFNβ-1a 22: 5.5 ±

1.1 Placebo: 5.4 ± 1.1

Baseline relapse rate (mean ± SD in 

previous 2 yr): IFNβ-1a 44: 0.9 ±

1.3 IFNβ-1a 22: 0.9 ±

1.4 Placebo: 0.9 ± 1.2

1) Interferon β-1a

(IFNβ-1a) 44 μg by SC 

injection three times weekly for 3 yr (n = 204) 2) IFNβ-1a 22 μg by

SC injection three times weekly for 3 yr(n = 209) 3) Placebo (n = 205) 

1) Physical functioning: Definition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: The primary outcome, time to sustained progression, revealed no statisticallysignificant difference among treatment arms.2) Relapse frequency:Definition of “relapse”: Appearance of a ne

w

sy

mptom or worsening of an old symptom 

attributable to M

S, accompanied by an 

appropriate ne

w neurologic abnormality or

focal neurologic dysfunction lasting at least 24 hours in the absence of fever and preceded by stability or improvement for at least 30 daysDefinition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Mean annual relapse rate: IFN 22 mcg Placebo IFN 44 mcg  0.50 0.71 0.50  p < 0.001 p < 0.001 

This s

1a in tprogresignifiprimaconfirmbenefito relaimprovpatienQ

UAL

DescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
90 

Evidence Table 3a. Disease modifying therapies and long-term impro

vement (continued) 

Stu

d

y

S

electe

d

Inclusion/ Exclusion Criteria

Study Design Patients Interv

entions Outcomes/Results Com

van deWyngaert,Beguin, D’Hooghe, et al., 2001 

Inclusion: Definiteclinical diagnosis of MS by Poser criteria; relapsing, secondaryprogressive disease course; at least partial recovery from last relapse at least 1 mo before study entry; E

DSS 3.0-6.0; 

worsening of EDSS by 1 point in previous 12 mo; effective birth control; normal isotopic cardiac ventriculography and routine blood analysis at entry; age 18-50 Exclusion: Remittent disease course, primary progressive disease, or secondaryprogressive disease without relapses; major illness otherthan MS or immunosuppressive drugs other than corticosteroids inprevious 3 yr

RCT (parallelgroup, doubleblind, singlecenter) Duration of study treatment/follo

w

up: Treatment lasted 32 mo; patients followedup for an additional 4 mo Provider specialty:Neurologists Location: 1 site in Belgium 

No. of patients randomized: 49Dropouts: 25 Completed: 24 Age (mean ± SD):MTX: 38.3 ± 6.9 MP: 39.2 ± 7.8 

Baseline EDSS (mean, with range): MTX: 5.1 (3.0-6.0)MP: 5.0 (3.0-6.0) Baseline relapse rate (mean inprevious 12 mo ±SD): MTX: 2.3 ± 1.0 MP: 2.2 ± 1.2 

1) Mitoxantrone (MTX) 12 mg/m2

initially given intravenously over one hour once per month for 3 mo; then given once every 3 mo, 10 times, until month 32; each treatment preceded by IV administration of 3 vials of alizapride (anti-emetic) (n = 28) 2) Methylprednisolone (MP) 1 g initially given intravenously over one hour between 8 and 10 a.m. once permonth for 3 mo; then given once every 3 mo, 10 times, until month 32 (n = 21) 

1) Physical functioning: Definition of “improvement”: Not defined Proportion of patients with “improvement”: 35% of patients receiving MTX improved clinically compared 

with 22% receiving 

placebo – difference not statisticallysignificant Other (non-improvement) outcomes: 2) Relapse frequency:Definition of “relapse”: Not definedDefinition of “improvement”: Not defined Proportion of patients with “improvement”: Not delineated Other (non-improvement) outcomes: Mean number of relapses/patient/year was significantly lower in the MTX group after 2 and 3 years of treatment (p = 0.016 and 0.029, respectively) 

This scladribprogredemonfavor onumbeprecisnot givhave csignifiQ

UAL

DescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
Evidence Table 3b. Symptom manag

ement and improvement 

91 

Stu

d

y

S

electe

d

Inclusion/ Exclusion Criteria

Study Design Patients Interv

entions Outcomes/Results Com

Bass, Weinshenker, Rice, et al., 1988 and Rice, 1989 

Inclusion: Clinicallydefinite MS; spasticityinterfered with activities of dailyliving; spasticitystable for ≥ 2 moExclusion: None specified 

RCT (crossover, double-blind, single-center) Duration of study treatment/follo

w

up: 9 

wk with 

each treatment, 22 

wk total (2-wk

run-in, t

wo 9-

wk

treatment periods, 2-

wk

washout)Provider specialty:Neurologists andphysiotherapists Location: 1 site in London, Ontario, Canada

No. of patients randomized: 66Dropouts: 4 excluded for protocol violations/ non-compliance; 14 more failed tocomplete both treatment periods Completed: 48 completed both treatment periods and were analyzed (MS diagnoses NR; of 62 not excluded for protocol violations/ non-compliance, 1 was “remitting” atentry, 19 were “progressive,” and 42 were “stable”)Age (mean, 

with 

range; n = 62 notexcluded for protocol violations/ non-compliance):51.1 (30-74) Baseline EDSS: NR 

1) Tizanidine PO initiated at dose of 2 mg on the first day and 6 mg daily for the next three days; then increased by 6 mgevery four days to a maximum of 32 mg/day (increaseduntil spasticitycontrolled, AEs intolerable, or maximum dose reached); maintenance dose taken for 5 

wk; tapered 

withdrawal during wk 9 of treatment 2) Baclofen PO initiated at dose of 5 mg on the first day and 15 mg daily for the next three days; then increased by 15 mg every four days to a maximum of 80 mg/day (increaseduntil spasticitycontrolled, AEs intolerable, or maximum dose reached); maintenance dose taken for 5 

wk; tapered 

withdrawal during wk 9 of treatment 2-

wk washout period 

bet

ween treatments (in 

addition to 1-

wk

tapered withdrawal) 

1) Symptom-specific functional status/ quality-of-life outcomes: Muscle strength (7-point ordinal scale); muscle tone (6-point ordinal scale) Definition of “improvement”: ≥ 1-point change from baseline in right or left side Proportion of patients with “improvement”: Similar percentages of patients improved, remained the same, and 

worsened on 

tizanidine compared to baclofen (p = NS) Other (non-improvement) outcomes: NR 

2) Physical functioning (EDSS): Definition of “improvement”: Decrease of ≥

1 point from baseline Proportion of patients with “improvement”: Tizanidine 9/48 (18

%) 

Baclofen 6/48 (12

%) (P = NS) 

Other (non-improvement) outcomes: NR 3) Cognitive functioning: NR 4) Work or e

mployment outcomes: NR 

5) Generic quality-of-life outcomes: NR 6) Adverse events: Tizanidine (daytime somnolence, insomnia, xerostomia) 46% required dosage reduction; 4 withdrew (weakness) Baclofen (muscle weakness) 61% required dosage reduction; 7 

withdre

w (weakness) 

Non-sassesshown Q

UAL

DescrMethodescriConceDescrPatienInvestOutcoNo. of YesCrossPeriod discusWashNo. of descriWere of the analys
92 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Brar, Smith, Nelson, et al., 1991 

Inclusion: Clinicallydefinite MS; EDSS ≤5.5; clinically stable for past 3 mo; mild to moderate spasticity in one or both lower extremities; age 24-54 Exclusion: Systemic disorders; impaired mentation; previous intolerance to baclofen 

RCT (crossover, partially doubleblind, singlecenter) Duration of study treatment/followup: 10 wk total: 2 wk each with baclofen, stretching, and combination; 4 wk with placebo (after each period involving baclofen; included tapering of baclofen) Provider specialty:Neurologists andphysical therapists Location: 1 site in Denver, CO

No. of patients randomized: 38Dropouts: 8 Completed: 30 Age: NR Baseline EDSS: NR 

1) Baclofen alone; titrated according to a predetermined schedule of 5-mgincrements or decrements every day for 5 days to maximum of 20 mg/day; maximum dose then maintained for seven days2) Stretching exercises + placebo; exercise instruction given by physical therapist; program included stretches for hamstrings, quadriceps, adductor, and plantarflexor muscles 3) Stretching exercises (as above) + baclofen (as above) 4) Placebo alone Placebo periods followed each period in which baclofen was used and included a period for tapering off baclofen 

1) Symptom-specific functional status/ quality-of-life outcomes: Quadriceps hypertonicity; muscle tone (Ashworth scale); self-rated questionnaire of functional abilitiesDefinition of “improvement”: Not given Proportion of patients with “improvement”: Ashworth Improved Baclofen 9 (30%) Stretch 5 (17%) Comb 12 (40%); p=0.10 v placebo Placebo 6 (20%)  100-yd Stair Household  walk climb activities Baclofen 10% 20% 17% Stretch 30% 7% 23% Comb 10% 23% 23% Placebo 17% 13% 20% Other (non-improvement) outcomes: Quadriceps spasticity was significantlyimproved after both baclofen and combination treatment when compared to placebo (p < 0.05) 2) Physical functioning: NR 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: None reported

QUALDescrMethodescriConceDescrPatienvs. plaInvestbaclofOutcoNo. of No CrossPeriod discusWashNo. of descriWere of the analys
93 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Canadian MS Research Group, 1987 

Inclusion: At least 6-mo history of definite MS according to Schumacher criteria; ≥ 3-mo history ofchronic, persistent, moderate to severe, daily fatigue (confirmed during 2-wk run-in) Exclusion: Pregnancy;hypersensitivity to amantadine; CHF or peripheral edema; hepatic or renal impairment; epilepsy; history of depression or other psychiatric disorders; acute anemia; thyroid disorders; diabetes; gastric or duodenal ulcers; alcohol or drug abuse 

RCT (crossover, double-blind, multicenter)Duration of study treatment/followup: 3 wk with each treatment, 10 wk total (2-wkplacebo run-in, two 3-wktreatment periods, 2-wkplacebo washout)Provider specialty: NR (presumably neurologists) Location: 11 sites in Canada 

No. of patients randomized: 115 (57 relapsingremitting, 33 relapsingprogressing, 22 chronic progressing, 3 benign) Dropouts: 6 Completed: 109Excluded from allanalyses: 2 (protocolviolations) Excluded from some analyses: 21 (discovered post-randomization to have had insufficient baseline fatigue) “Efficacyanalyzable” population: 86 (41 relapsing-remitting, 28 relapsingprogressing, 15 chronic progressing, 2 benign) Age (mean ± SE; n = 86): 40.1 ± 1.0

Baseline EDSS (mean ± SE; n = 86): 4.3 ± 0.2 

1) Amantadine PO 100 mg twice per dayfor 3 wk2) Placebo for 3 wk2-wk placebo washout period between treatments 

1) Symptom-specific functional status/ quality-of-life outcomes: VAS fatigue score Definition of “improvement”: None

Proportion of patients with “improvement”: NA Other (non-improvement) outcomes: Change in VAS fatigue score baseline to end: Amantadine: 29 to 25 (23 to 26), -4.3 mm Placebo: 30 to 27 (25 to 29), -2.6 mm p = NS 2) Physical functioning: most affected activity VAS; effect on activities of dailyliving total score Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: Most affected activity VAS favoredamantadine p < 0.05 ADL total score amantadine 27 (SE 1.13) baseline to 24 (SE 1.06) end, change of -2.5compared to placebo 26 (SE 0.74) baseline to 26 (SE 0.74) end; change of -0.3 (p = 0.09) 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: 66/115 (57%) reported AEs on amantadine; 62/115 (54%) reported AEs on placebo; 1 dropout for acute confusional state on amantadine 

QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of YesCrossPeriod WashNo. of descriWere of the analys
94 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Cartlidge, Hudgson, and Weightman,1974 

Inclusion: Spasticity; Ashworth score of 3-4 in at least one lower limb Exclusion: None specified 

RCT (crossover, double-blind, single-center) Duration of study treatment/followup: 4 wk with each treatment, 9 wk total (two 4-wk treatment periods, 1-wkwashout)Provider specialty:Neurologists Location: Newcastle, UK 

No. of patients randomized: 40 (34 MS “in remission but withsevere residual neurological deficits,” 2 hereditary spastic paraplegia, 1 spondylotic myelopathy, 1 traumatic paraplegia) Dropouts: 3 Completed: 37 Age (range): 22-61 Baseline EDSS: NR 

1) Baclofen PO 30 mg per day for 2 wk, then 60 mg per day for 2 wk2) Diazepam PO 15 mg per day for 2 wk, then 30 mg per day for 2 wk1-wk washout between treatment periods 

1) Symptom-specific functional status/ quality-of-life outcomes: Spasticity score (Ashworth scale) Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: Low-dose Baclofen Diazepam N 37 37Before/after 2.87/2.38 2.87/2.16 Change (SE) 0.49 (0.163) 0.71 (0.159)p-value < 0.01 < 0.001 High-dose N 26 23Change (SE) 1.31 (0.227) 1.13 (0.202)p-value < 0.001 < 0.001 No differences between baclofen and diazepam. No period effect or treatmentperiod interaction2) Physical functioning: NR 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: Daytime sedation, weakness, gustatorydisturbances (loss of taste and smell) 11 withdrew on high-dose baclofen 14 withdrew on high-dose diazepam 

AdverresulteQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of YesCrossPeriod Wash

No. of descriWere of the analys
95 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Cohen and Fisher, 1989 

Inclusion: Definite or probable MS according to Posercriteria; diagnosis established at least 6 mo prior to study entry; dailysymptomatic fatigue for ≥ 3 mo 

Exclusion: EDSS > 6; moderate or major depression on Beck Depression Inventory; pregnancy;CHF; renal or hepatic impairment; epilepsy; anemia; thyroid disorders; diabetes; active gastric or duodenal ulcer; psychiatric disorder; alcohol or drug abuse; current use of stimulants, sedativehypnotics, antidepressants, major tranquilizers, betablockers, immunosuppressants, or steroids 

RCT (crossover, double-blind, single-center) Duration of study treatment/followup: 4 wk with each treatment, 10 wk total (two4-wk treatment periods, 2-wkwashout)Provider specialty: NR Location: 1 site in Worcester, MA 

No. of patients randomized: 29 (16 benign orrelapsing-remitting, 13 chronicdeteriorating orrelapsingdeteriorating) Dropouts: 7 Completed: 22 Age (mean ± SD):44.5 ± 9.3 

Baseline EDSS (mean ± SD, n = 22 completers): 4.0 ± 1.4 

1) Amantadine PO 100 mg twice per dayfor 4 wk2) Placebo for 4 wk2-wk washout between treatment periods 

1) Symptom-specific functional status/ quality-of-life outcomes: Fatigue (dailyratings; point scale 1-5) Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: Amantadine mean fatigue score 3.2 ± 0.04 

SE versus placebo 3.0 ± 0.03 SE (p = 0.58) 

2) Physical functioning: NR 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: 4 amantadine and 4 placebo patients reported AEs. At least 1 amantadine-treated patient withdrew due to nausea and anxiety; 1 placebo patient with constipation mayhave withdrawn.

QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of YesCrossPeriod WashNo. of descriWere of the analys

Crawford and McIvor, 1985 

Inclusion: Primarydiagnosis of MS; mental status optimal or only mildly to moderately deficient Exclusion: None specified 

RCT (parallelgroup, openlabel, singlecenter) Duration of study treatment/followup: 6 mo Provider 

No. of patients randomized: 32Dropouts: NRCompleted: NR Age: Mean, 47.25; range, 20-63 

1) Traditional, insightoriented group psychotherapy (IOT; n = NR); two 1-hrsessions per wk for approximately 6 mo (50 sessions total) 2) Current events discussion group (CE, 

1) Symptom-specific functional status/ quality-of-life outcomes: 2) Physical functioning: NR 3) Cognitive functioning: MMPI Depression30 Scale (D-30); Anxiety Scale Questionnaire (ASQ); Internal-External Control Scale (IECS); Rosenberg SelfEsteem Scale (SES) 

Little aimportpsychQUALDescrMethodescriConceDescr
96 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

specialty: NR (presumably psychologists) Location: 1 site in New York, NY

Baseline EDSS: NR; patients described as “moderately to severely disabled physically”

active control; n = NR); two 1-hr sessions per wk for approximately 6 mo (50 sessions total) 3) No treatment (n = NR) 

Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes:  IOT CE Control p-value D-30 19.3 23.5 23.5 0.025 IECS 28.3 30.7 37 0.005 ASQ NR NR NR NS SES NR NR NR NS 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: NR 

PatienInvestOutcoNo. of No 

Cutter, Scott, Johnson, et al., 2000 

Inclusion: Laboratory-supported diagnosis of chronic progressive MS (MRI and/or CSF); clinical evidence of spasticity; veteran eligible for care at study site (Denver VAMC); age 18-85 Exclusion: Lack of clinically significant spasticity; inability to travel to study site for evaluations; potential to become pregnant during study;significant renal dysfunction 

RCT (crossover, double-blind, single-center) Duration of study treatment/followup: 26 days (6 days treatment with each intervention + 14-day washout period) Provider specialty: NR Location: Denver, CO (1site)

No. of patients randomized: 22Dropouts: 1 Completed: 21 Age: Range, 34-67 Baseline EDSS: Range, 6.0-9.0 

1) Gabapentin PO; 300 mg three times per day for 2 days, then 600 mg three times per day for 2 days, finally 900 mg three times per day for 2 days (n = 22) 2) Placebo (n = 22) 14-day washout between treatment periods 

1) Symptom-specific functional status/ quality-of-life outcomes: Spasm frequency scale; spasm severity scale, interference with function scale, painful spasm scale, global assessment scale Definition of “improvement”: Spasm frequency – no spasms Interference with function – not defined Global assessment – not defined Proportion of patients with “improvement”: Spasm frequency (p = 0.0001)  Gabapentin Placebo 

 B/l Post B/l Post 

None 0 (0%) 6 (28%) 0 (0%) 0 (0%)Mild 5 (24%) 12 (57%) 5 (24%) 7 (33%)Mod 11 (52%) 2 (9%) 11 (52%) 12 (57%)Sev 5 (24%) 1 (5%) 5 (24%) 2 (9%)Interference with function (p = 0.02)  Gabapentin Placebo  B/l Post B/l Post None 2 (9%) 10 (48%) 4 (19%)4 (19%)Difficult 13 (62%) 10 (48%) 11 (52%) 12 

Some but noQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of YesCrossPeriod WashNo. of descriWere of the analys
97 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

(57%) Imposs 6 (29%) 1(5%) 6 (29%) 5 (24%)Global assessment (p = 0.003)  Gabapentin Placebo  Post PostLot better 11 (52%) 1 (5%)Little better 4 (19%) 4 (19%) Unchanged 6 (27%) 12 (57%) Worse 0 (0%) 4 (19%) Other (non-improvement) outcomes: Modified Ashworth Scale (p = 0.0005) 2) Physical functioning (EDSS): Definition of “improvement”: Proportion of patients with “improvement”: “No significant change in...EDSS with eithergabapentin or placebo? Other (non-improvement) outcomes: 3) Cognitive functioning: Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: Digit Span, Digit Symbol, adjective generation technique 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: Falls in 2 patients, 1 gabapentin, 1 placebo 
98 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Eyssette, Rohmer, Serratrice, et al., 1988 

Inclusion: Chronic spasticity due to MS; age 18-70 Exclusion: None specified 

RCT (parallelgroup, doubleblind, multicenter)Duration of study treatment/followup: Treatment lasted 8 wk; preceded by 3-day run-in Provider specialty: NR (presumably neurologists) Location: 6 sites in France 

No. of patients randomized: 100 Dropouts: 14 Completed: 86 Age (mean ± SE): Tizanidine: 46.8 ±

1.6 Baclofen: 47.5 ±1.7 Baseline EDSS: NR (60/100 patients were bedridden at entry) 

1) Tizanidine (n = 50); initiated at 2 mg three times per day; dailydose then increased, if tolerated, by 2 mgevery 2 days for first 2 wk, up to maximum dose of 24 mg/day; maximum dose then taken for 6 wk2) Baclofen (n = 50); initiated at 5 mg three times per day; dailydose then increased, if tolerated, by 5 mgevery 2 days for first 2 wk, up to maximum dose of 60 mg/day; maximum dose then taken for 6 wk

1) Symptom-specific functional status/ quality-of-life outcomes: Muscle tone (5-point scale); flexor spasms, clonus, strength, locomotor function Definition of “improvement”: Flexor spasms & muscle tone – none described; clonus – no longer detectable Proportion of patients with “improvement”: Flexor spasms 2 wk 8 wkTizanidine (n = 36) 47% 55% Baclofen (n = 33) 48% 43% P = NS Muscle tone by muscle group improved in between 40% to 67% of patients; no statistically significant difference between tizanidine and baclofen for any muscle group or time point Clonus 2 wk 8 wkTizanidine 8/35 (23%) 8/28 (29%) Baclofen 8/30 (27%) 6/28 21%) Other (non-improvement) outcomes: In ambulatory patients (40/100) there was no significant change in walking distance for tizanidine or baclofen 2) Physical functioning: NR 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: Tizanidine: daytime drowsiness (n = 15), dry mouth (n = 14), fatigue (n = 8), orthostatic hypotension (n = 6), and insomnia (n = 7). Discontinued in 6: daytime drowsiness (n = 

QUALDescr

MethodescriConceDescrPatienInvestOutcoNo. of Yes
99 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

2); weakness and drowsiness (n = 2), syncope (n = 1) and bradycardia (n = 1). Baclofen (daytime drowsiness (n = 10), fatigue (n = 12), muscular weakness (n = 10), disturbances of affect (n = 9), and vomiting (n = 8). Discontinued in 4: rash (n = 1), vomiting (n = 1), disturbed affect (n = 1), and muscular weakness and syncope (n = 1). 

Feldman, Kelly-Hayes,Conomy, et al., 1978 

Inclusion: Adults with an established diagnosis of MS; spontaneous flexor contractions or spasticity for ≥ 3 mo; free of infections, peripheral vascular disease, contractures, advanced arthritis, or other conditions that might hinder evaluation of joint movement Exclusion: Women of childbearing age;patients with bleeding tendencies, GI disease, or liver and renal impairment

RCT (crossover, double-blind, single-center) Duration of study treatment/followup: 4 wk with each treatment; 10 wk total (1-wkplacebo run-in, two 4-wktreatment periods, 1-wkplacebo washout) Provider specialty: NR Location: Boston, MA 

No. of patients randomized: 33Dropouts: 10 Completed: 23 Age: Mean, 43; range, 38-53 Baseline EDSS: NR; disability said to have varied “from being ambulatory with a spastic gait to functional quadriplegia” 

1) Baclofen; initiated at 5 mg three times per day for 3 days; increases then made at intervals not less than 3 days up to a maximum dose of 80 mg/day (or less if AEsoccurred or maximum benefit achieved at lower dose) 2) Placebo (with dose adjustments as above)1-wk placebo washout between treatment periods 

1) Symptom-specific functional status/ quality-of-life outcomes (spasm frequency,clonus [knee], resistance to passive movement, functional assessment): Definition of “improvement”: Not defined Proportion of patients with “improvement”:  ROM Spasm exercises frequency Baclofen 15/23 (65%) 9/16 (56%) Placebo 4/23 (17%) 1/16 (6%)  P < 0.05 p < 0.05  Clonus Barthel Baclofen 12/15 (80%) 8/16 (50%) Placebo 1/15 (7%) 7/16 (46%)  P < 0.01 p = NS Other (non-improvement) outcomes: 2) Physical functioning: NR 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: Dry mouth (baclofen n = 5; placebo n = 1). Also observed: drowsiness, dizziness, anorexia, nocturia and constipation. 

QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of No CrossPeriod 

discusWashNo. of descriWere of the analys
100 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Foley, Bedell, LaRocca, et al., 1987 

Inclusion: Confirmed diagnosis of MS; DSS ≤ 8; no major cognitive deficits Exclusion: None specified 

RCT (parallelgroup, openlabel, singlecenter) Duration of study treatment/followup: 5 wk (6-mo follow up included only 10 patients and only patientsin experimental group) Provider specialty:Experimental group: Advancedclinical psychology graduate student, supervised by 2 licensed clinicalpsychologists Control group: “Hospital staff who utilized standard methods in treating patients”Location: 1 site in Bronx, NY

No. of patients randomized: 41 (type of MS not specified; 60% of patients were experiencing a relapse at start oftrial, 58% at end)Dropouts: 5 (missing data) Completed: 36 Age: Mean, 38.8Baseline DSS: Mean, 6; range, 1-8 

1) Stress inoculation therapy (SIT) (n = NR); combination of cognitive-behavioral therapy (focused on relieving affective distress and preventing maladaptive psychological responses to stress) and progressive muscle relaxation (shortened version); total of 6 sessions over 5 wk (length of individual session NR) 2) Current available care (CAC) (n = NR); patients received a variety of psychotherapeutic and medical interventions (including minimum of 2 hr of supportive psychotherapy) for 5 wk

1) Symptom-specific functional status/ quality-of-life outcomes (BDI; STAI-S; STAIT; Hassles scale; PFC): Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: MANOVA showed significant treatment effect for composite of all outcome measures (p < 0.002):  SIT CAC p-valueBDI 13.2 ± 10.5 21.6 ± 14.2 < 0.05 

STAI-S 37.2 ± 13.8 50.5 ± 13.0 < 0.05 

STAI-T 46.2 ± 13.1 51.9 ± 13.4 NS 

Hassles 57.5 ± 37.6 89.2 ± 67.1 < 0.05 

WCC 16.2 ± 4.8 11.8 ± 4.6 < 0.05 

2) Physical functioning: NR 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: NR 

QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of No 

Francabandera, Holland, WieselLevison, et al., 1988 

Inclusion: DefiniteMS; followed at studysite; EDSS 6.0-9.0; evidence of ability to benefit from rehabilitation (at least 3 specific rehabilitation goals); not institutionalized 

RCT (parallelgroup, openlabel, singlecenter) Duration of study treatment/followup: 3 mo 

No. of patients randomized: 84Dropouts: 11 did not enter treatment or were lost to follow up Completed: 73 

1) Inpatient rehabilitation (n = 42); daily physical (two 45-min sessions per day)and occupational therapy (1 session per day); bladder management, speech therapy, and social 

1) Symptom-specific functional status/ quality-of-life outcomes: Incapacity Status Scale (ISS) (part of Minimal Record of disability [16-item self-report inventoryreflecting ambulation status and level of independence in self-care); need for home assistance (number of hours of assistance in ADLs) 

QUALDescrMethodescriConceDescrPatienInvestOutco
101 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

and able to returnhome after inpatient treatment; insurance or other resources to pay for inpatient or outpatient treatment Exclusion: None specified 

Provider specialty:Neurologists, physical therapists, occupational therapists, nursesLocation: 1 site in Bronx, NY

Age: NR Baseline EDSS: NR 

services provided as needed; equipment needs assessed and addressed; individual care plan for each patient; coordinated, multidisciplinaryapproach 2) Outpatient rehabilitation (n = 42); physical and occupational therapy;bladder management, speech therapy, and social services asneeded; equipment needs assessed and addressed; treatment administered through community-basedvisiting nurse services or public health nurse services Treatment of both groups supervised byneurologist at studysite 

Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes:  Entry 3-mo 3-mo p-value ISS adjusted  Inpt 28± 9 26± 9.4 24.3 < 0.05 

 Opt 24± 7.2 26± 8.5 27.2 

Assistance  Inpt 62± 52 73± 62 76.9 0.17 

 Opt 71± 56 77± 56 73.1 

2) Physical functioning: NR 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: NR 

No. of No 

Fredrikson, 1996 

Inclusion: Clinicallydefinite MS; increased daytime frequency of voiding/ incontinence episodes; had previously testedanticholinergic drugs with unsatisfactoryeffect on bladdersymptoms Exclusion: Hypertension, coronary 

RCT (crossover, double-blind, single-center) Duration of study treatment/followup: 2 wk with each treatment; 6 wk total (2-wk run-in, two 2-wktreatment periods, no washout)

No. of patients randomized: 27Dropouts: 0 premature withdrawals; 1patient excluded from analyses (appendectomy); 4 provided incomplete data for main outcome Completed: 22 

1) Desmopressin nasal spray 20 μgdaily2) Placebo nasalsprayNo washout between treatment periods 

1) Symptom-specific functional status/ quality-of-life outcomes: Number of voidings and incontinence episodes (a) during 6 hr after drug intake, (b) during 24 hrDefinition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: Voidings Mean ± SD  6 hr 24 hr 

QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of YesCrossPeriod discus
102 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

artery disease; diabetes; hepatic disease 

Provider specialty: NR (presumably neurologists) Location: 1 site in Huddinge, Sweden 

included in analysis of main outcome Age: Mean, 51; range, 24-69 Baseline EDSS: NR 

Baseline 3.1± 1.0 10.7± 2.5 

Placebo 3.1± 1.0 8.6± 2.3 

Desmopressin 2.6± 1.0 8.4± 2.6 

p-value < 0.05 NS 2) Physical functioning: NR 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: NR 

WashNo. of descriWere of the analys

Freeman, Langdon, Hobart, et al., 1997 

Inclusion: Clinicallyor laboratorysupported definite MS; in progressive phase of the disease as established by neurologist; considered appropriate for inpatient rehabilitation Exclusion: Current or recent (within 1 mo) relapse; use of steroids in previous mo; required urgent admission on clinical grounds; other diseases; cognitive impairment such that unable to give informed consent

RCT (parallelgroup, openlabel, singlecenter) Duration of study treatment/followup: Active treatment lasted average of 20 days; patients followed for total of 6 wkProvider specialty: Multidisciplinary teamLocation: 1 site in London, UK 

No. of patients randomized: 70Dropouts: 4 Completed: 66 (60 secondaryprogressive, 6 primaryprogressive) Age (mean ± SD; n= 66 completers):Rehab: 43.2 ±10.8 Wait-list: 44.6 ±

9.7 Baseline EDSS (median, with range): Rehab: 6.5 (5.0-9.0) Wait-list: 6.5 (6.0-8.5) 

1) Comprehensive, short-term (mean, 20 days; range, 17-31), inpatient rehabilitation program; not described in detail, but said to involve multidisciplinary teamapproach, interventions tailored to individual’s needs, and patient-centered functional goal-setting approach (n = 32) 2) Wait-list control (n= 34) 

1) Symptom-specific functional status/ quality-of-life outcomes: NR 2) Physical functioning (EDSS): Definition of “improvement”: Proportion of patients with “improvement”: EDSS – No statistically significant difference between the two groups in ... EDSS change scores (p = 0.42)...“with change scores clustering closely around zero” FIM motor scores - 72% of people in the treatment group improved their overall level of disability, 3% stayed the same, and 25% deteriorated. In contrast, 29% of people in the control group improved their overall level of disability, 9% stayed the same, and 62% deteriorated (p < 0.001) Other (non-improvement) outcomes: LHS – 53% of the treatment group improved their total handicap score, 3% remained the same, and 44% deteriorated. In contrast 23% of the control group improved, 12% stayed the same, and 65% deteriorated (p = 0.01) 

No diftreatmwho wwas a 

wheelQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
103 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: NR 

From and Heltberg, 1975 

Inclusion: Spasticitydue to MS; inpatients Exclusion: None specified 

RCT (crossover, double-blind, single-center) Duration of study treatment/followup: 4 wk with each treatment, 10 wk total (two4-wk treatment periods, 1-wkwashout, 1-wkfollow up)Provider specialty:Neurologists Location: 1 site in Copenhagen,Denmark 

No. of patients randomized: 17Dropouts: 1 Completed: 16 Age: Mean, 51; range, 38-68 Baseline EDSS: NR; only 2 patients had significant walking ability

1) Baclofen PO 10-mg tablets; dose titrated to optimal level during first 2 wk, thencontinued for 2 wk; mean optimal dose, 61.2 mg (range, 30-120 mg) 2) Diazepam PO 5-mg tablets; dose titrated to optimal level during first 2 wk, then continued for 2 wk; mean optimal dose, 26.8 mg (range, 10-40 mg) 1-wk washout between treatment periods 

1) Symptom-specific functional status/ quality-of-life outcomes (flexor spasm, clonus): Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes:  Baclofen Diazepam Flexor spasm 10/12 (83%) 12/14 (86%) Clonus 16/26 (62%) 18/28 (64%) 2) Physical functioning: NR 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: Baclofen 8 (sedation [n = 5], weakness, depression, nausea) Diazepam 12 (sedation [n = 11], weakness) One patient discontinued treatment with baclofen due to AE (sedation). 

No sigbaclofQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of YesCrossPeriod discusWashNo. of descriWere of the analys
104 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Gambi, Rossini, Calenda, et al., 1983 

Inclusion: Spinal spasticityExclusion: None specified 

RCT (crossover, double-blind, single-center) Duration of study treatment/followup: 5 wk with each treatment, 13 wk total (2-wkrun-in, two 5-wktreatment periods, 1-wkwashout)Provider specialty: NR (presumably neurologists) Location: 1 site in Milan, Italy

No. of patients randomized: 24 (12 MS, 12 degenerative myelopathies) Dropouts: 2 (both MS) Completed: 22 (10 MS, 12 degenerative myelopathies) Age (mean ± SE,MS patients only): 38.2 ± 2 

Baseline EDSS: NR 

1) Dantrolene sodium PO; initiated at 25 mg twice per day and increased by slowweekly increments until therapeutic goal achieved (maximum dose permitted = 350 mg per day); treatment lasted 5 wk2) Placebo, with dose adjustments as above, for 5 wk1-wk washout between treatment period

1) Symptom-specific functional status/ quality-of-life outcomes: NR 2) Physical functioning: Hip flexor movement (degrees); degree of spasticity (6-point scale); muscular strength (6-point scale); clonus (6-point scale); knee and ankle tendon reflexes (6-point scale) Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: Change in hip flexor movement (degrees)  Dantrolene Placebo p-value CrossLeft hip 8.5± 3.7 1.5± 3.9 NS 

Right hip 9.5± 2.7 -1± 2.9 NS 

No influence on knee joint movements Dantrolene reduced spasticity of both lower limbs (p < 0.05; data not shown)No significant difference for muscular strength, clonus and tendon reflexes (data not shown) 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: 13/24 (59%) reported AEs (headache drowsiness, nausea, vomiting, gastric pain, malaise, muscular weakness). 2/24 (9%) on dantrolene and 3/24 (14%) on placebo withdrew due to AEs. 

Few dSmall subgroQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of YesPeriod discusWashNo. of descriWere of the analys
105 

Evidence Table 3b. Symptom manag

ement and improvement (continu

e

d)

Stu

d

y

S

electe

d

Inclusion/ Exclusion Criteria

Study Design Patients Interv

entions Outcomes/Results Com

Geisler, Sli

winski, 

Coyle, et al., 1996 

Inclusion: Clinicallyor laboratorysupported definite MS according to Poser criteria; severefatigue (FatigueSeverity Scale score≥ 4.0); ambulatory; EDSS ≤ 6.5; age 18-

50 Exclusion: EDSS > 6.5; severe depression (score > 35 on Center for Epidemiologic Studies Depression Scale); severe dementia (score < 15 on Mini-Mental State Examination); current or recent (

within 2 

mo) MS relapse; current or recent (within 2 mo) use of fatigue-producing medication (e.g., tricyclic antidepressants, benzodiazepines) 

RCT (parallelgroup, doubleblind, singlecenter) Duration of study treatment/follo

w

up: 6 

wk

treatment, 10 wktotal (2-wk run-in, 6 wk treatment, 2wk follow up)Provider specialty:Neurologists Location: 1 site in Stony Brook, NY

No. of patients randomized: 45 (38 relapsingremitting, 7 chronic progressive) Dropouts: N

R

(implied 0) Completed: NR(implied 45) Age (mean ± SD):Amantadine: 40 ±6.4 Pemoline: 41 ±

6.2 Placebo: 40 ± 5.6 Baseline EDSS (mean ± SD): Amantadine: 3.1 ±2.1 Pemoline: 2.6 ±

0.9 Placebo: 2.2 ± 1.7

1) Amantadine PO 100 mg t

wice daily for 

6 wk (n = 16) 2) Pemoline PO 18.75 mg, once daily for 1st

wk, t

wice daily for 2nd

wk, then three times per day during 

weeks 

3-6 (n = 13) 3) Placebo (doubledummy technique used) (n = 16) 

1) Symptom-specific functional status/ quality-of-life outcomes: NR 2) Physical functioning: NR 3) Cognitive functioning: Attention (Digit Span, Trail Making Test, Symbol Digit Modalities Test); verbal memory (

Selective 

Reminding Test); nonverbal memory(Benton Visual Retention Test), and motor speed (Finger Tapping Test) Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: All three treatment groups sho

wed

significant improvement on cognitive measures; ho

wever, only written SDMT (a 

measure of attention and visual search) showed a significant difference between treatment groups, with amantadine-treatedgroup sho

wing the greatest improvement. 

For other measures, the change scores were nearly identical between groups with no significant differences bet

ween the active 

drug groups and the placebo group. 4) Work or e

mployment outcomes: NR 

5) Generic quality-of-life outcomes: NR 6) Adverse events: NR 

Study patienDoschQ

UAL

DescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
106 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Gillson, Richards, Smith, et al., 2002 

Inclusion: Diagnosis of MS confirmed byneurologist exam and the presence of CNS sclerotic lesions on MRI; EDSS 5.0-6.5; Modified Fatigue Impact Scale (MFIS) score > 40; no relapse in previous 3 mo; age ≥ 18 Exclusion: Current or previous use of studydrug; current use of antispasmodic agents, corticosteroids, chemotherapeutic agents, MAOIs, or histamine blockers; started antidepressants, interferons, orglatiramer acetate in past 3 mo; serious renal, hepatic, endocrine, cardiac, or pulmonary disease 

RCT (parallelgroup, doubleblind, singlecenter) Duration of study treatment/followup: 12 wkProvider specialty: NR Location: 1 site in Seattle, WA 

No. of patients randomized: 29 (10 relapsingremitting, 16 secondaryprogressive, 3 primaryprogressive; significant difference between treatment groupsat baseline) Dropouts: 3 Completed: 26 Age: Mean, 47.4Baseline EDSS: NR 

1) Transdermal cream containing histamine diphosphate 1.65 mg + caffeine citrate 100 mg per 0.2 mL (ProkarinTM); applied twice per day using a skin patch (n = 22) 2) Placebo cream (n = 7) 

1) Symptom-specific functional status/ quality-of-life outcomes: Modified Fatigue Impact Scale (MFIS); timed walk test (25-foot); 9-hole peg test Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: MFIS p-valueWeek 0 4 8 12 within groupPK 58±8.9 38± 18 38± 16 37± 15 < 0.001

Pl 61±7.5 NR NR 53± 11 NS 

p-value (between-group) < 0.02 No significant differences between the ProkarinTM group and the placebo group for secondary endpoints (25-foot timed walk, 9-hole peg test) 2) Physical functioning: NR 3) Cognitive functioning: Paced AuditorySerial Additions Test (PASAT) Definition of “improvement”: None

Proportion of patients with “improvement”: NA Other (non-improvement) outcomes: No significant differences between the ProkarinTM group and the placebo group for PASAT 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: All AEs observed were mild – specific AEs included skin irritation, 

Authodiffereremittgroup QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
107 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

itching, and headache 

Hauser, Doolittle, LopezBresnahan, et al., 1992 

Inclusion: Clinicallydefinite MS of either inactive (relapsingremitting MS that had been clinically stable for > 2 yr) or veryslowly progressive (chronic MS without change for ≥ 1 yr as

assessed byAmbulation Index and EDSS) form; spasticity or spontaneous flexor spasms sufficient in degree to interfere with functional activities for ≥ 3 mo; ambulatory, with EDSS ≤ 6 and 

Ambulation Index ≤ 5; 

reasonable functional use of arms; good general health; age 18-55 Exclusion: Cancer or serious underlying medical illness; advanced arthritis, contractures, or other conditions hindering evaluation of joint movement; use ofpsychoactive drugs; antispasticitytreatment within previous 1 mo; use of chemotherapeutic agents within previous 6 mo

RCT (crossover, double-blind, single-center) Duration of study treatment/followup: 8 wk each treatment, 18 wktotal (two 8-wktreatment periods, 2-wkwashout)Provider specialty:Neurologists Location: 1 site in Boston, MA 

No. of patients randomized: 26Dropouts: 5 Completed: 21 Age (mean ± SE): 41 ± 6.5 

Baseline EDSS (mean ± SE):4.7 ± 1.5 

1) Threonine (naturally occurring amino acid), 5 capsules three times per day for a total dailydose of 7.5 mg for 8 wk2) Placebo for 8 wk2-wk washout between treatment periods Patients also instructed to consume “a standard 75-g protein diet” during the study

1) Symptom-specific functional status/ quality-of-life outcomes: Ashworth Scale; Clinician Spasticity Scale (upper extremity muscle tone, lower extremity muscle tone, reflexes and spontaneous flexor spasms each graded improved [+1]/same[0]/worse [-1] then summed); Patient Spasticity Scale Definition of “improvement”: Not described Proportion of patients with “improvement”: Spasticity Clinician Scale Patient Scale Threonine 11/21 (52%) 8/21 (38%) Placebo 5/21 (24%) 4/21 (19%) p-value 0.04 0.18 Other (non-improvement) outcomes: 2) Physical functioning: EDSS; Ambulation Index Definition of “improvement”: Proportion of patients with “improvement”: Other (non-improvement) outcomes: 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life utcomes: NR 6) Adverse events: None reported

QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of YesCrossPeriod WashNo. of descriWere of the analys
108 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Hilton, Hertogs, and Stanton, 1983 

Inclusion: Women with MS who complained of nocturia (waking to void on two or more occasions each night) Exclusion: History of impaired renal function, ischemic heart disease, hypertension, or urinary infection 

RCT (crossover, double-blind, single-center) Duration of study treatment/followup: NR (1-wk run-in, but lengthof treatment not specified) Provider specialty:OB/GYNsLocation: 1 site in London, UK 

No. of patients randomized: 16Dropouts: 0 Completed: 16 Age: NR Baseline EDSS: NR 

1) Desmopressin nasal spray 20 μgdaily at bedtime 2) Placebo nasalspray at bedtimeNo washout period described 

1) Symptom-specific functional status/ quality-of-life outcomes: Subjective benefit in nocturia Definition of “improvement”: Not described Proportion of patients with “improvement”: Desmopressin 9/16 (56%) Placebo 1/16 ( 6%) P = 0.008 Other (non-improvement) outcomes:  DesmoUrinary freq pressin Placebo p-value Daytime 8.7± 3.4 8.6± 2.5 ns 

Nighttime 1.3± 1.0 2.0± 0.9 < 0.001

2) Physical functioning: NR 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: Headache (n = 3), nasal congestion (n = 1) No patients stopped treatment due to AEs 

Treatmapparanalyseffects QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of YesCrossPeriod discusWashNo. of descriWere of the analys

Hoogstraten, van der Ploeg, Burg, et al., 1988 

Inclusion: Spasticitydue to MS; spasticitystable for ≥ 2 mo; EDSS 4-7 Exclusion: Severe cardiac insufficiency;marked hypertension (DBP > 110 mmHg); severe hypotension; chronic alcoholism; history of mental illness; pretreatment 

RCT (crossover, open label [onlyassessors of selected outcomes wereblinded], singlecenter) Duration of study treatment/followup: 6-7 wk with each treatment, 13.5-15.5 wk+ 

No. of patients randomized: 16Dropouts: 5 Completed: 11 Age (mean ± SD):54.9 ± 8.3 

Baseline EDSS (mean ± SD): 6.1 ± 0.8 

1) Tizanidine PO; dose titrated to optimal level (range, 12-24 mg daily) over first 2-3 wk, then continued for 4 wk2) Baclofen PO; dose titrated to optimal level (range, 15-60 mgdaily) over first 2-3 wk, then continued for 4 wk

1) Symptom-specific functional status/ quality-of-life outcomes: NR 2) Physical functioning: Spasticity (7-point scale); spasms (7-point scale); mobility (7-point scale) Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: 

Small Unclemeasuand vaQUALDescrMethodescriConceDescrPatien
109 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

with diazepam ordantrolene 

total (two 6- to 7-wk treatment periods, 1.5-wk+ washout period)Provider specialty: NR (presumably neurologists) Location: 1 site in Groningen,The Netherlands

Washout betweentreatment periods: taper off of study meds over 1-2 wk, followed by drug-free period of at least 3 days

Data not provided for spasticity. Overall efficacy variable showed nosignificant difference whether completers of both periods analyzed as cross-over (n = 11) or first-period only data (n = 14) analyzed. 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: AEs reported on baclofen (muscle weakness (n = 11), somnolence (n = 4), dry mouth, nausea (n = 3), urine incontinence (n = 3), dizziness) and on tizanidine (muscle weakness (n = 4), somnolence (n = 8), dry mouth (n = 5); flushed (n = 3); Severe AEs on baclofen (muscle weakness (n = 6); nausea (n = 1)) and tizanidine (somnolence (n = 1), depression (n = 1)) 3 patients discontinued treatment due to AEs on baclofen 

InvestOutcoNo. of YesCrossPeriod WashNo. of descriWere of the analys

Hoverd and Fowler, 1998 

Inclusion: MS and neurogenic bladder dysfunction (≥ 8 episodes of voiding per day); sufficient lower limb power to stand; cognitively unimpaired Exclusion: Diabetes; heart disease; hypertension; renal disease; use of diuretic therapy 

RCT (crossover, double-blind, single-center) Duration of study treatment/followup: 2 wk with each treatment; 6 wk total (2-wk run-in, two 2-wktreatment periods, no washout)Provider specialty: NR Location: 1 site 

No. of patients randomized: 28Dropouts: 4 (3 before treatment started) Completed: 24 Age: Mean, 43; range 18-65 Baseline EDSS: NR 

1) Desmopressin nasal spray 20 μg at same time each day(between 8:00 AM and 2:00 PM) 2) Placebo nasalsprayNo washout between treatment periods 

1) Symptom-specific functional status/ quality-of-life outcomes [describe scale/instrument used]: Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes:  DesmoUrinary freq pressin Placebo p-value Day (6 hr) 2.4± 0.9 3.1± 1.4 0.008 

Nighttime 1.5± 1.2 1.4± 1.1 0.26 

Vol (6 hr) 246± 99 342± 166 0.006 

Vol (24 hr) 1218± 455 1272 ± 482 0.052 

No wacarry-QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of YesCrossPeriod discusWash
110 

Evidence Table 3b. Symptom manag

ement and improvement (continu

e

d)

Stu

d

y

S

electe

d

Inclusion/ Exclusion Criteria

Study Design Patients Interv

entions Outcomes/Results Com

in London, UK 

2) Physical functioning: NR 3) Cognitive functioning: NR 4) Work or e

mployment outcomes: NR 

5) Generic quality-of-life outcomes: NR 6) Adverse events: Hyponatremia, malaise, headache nausea (required withdra

wal from desmopressin) 

No. of descriWere of the analys

Hyman,Barnes, Bhakta, et al., 2000 

Inclusion: Definite or probable MS; disabling spasticityaffecting the hip adductor muscles of both legs (EDSS ≥ 7), which had been stable for ≥ 6 mo and which caused moderate pain ordifficulty in nursing(hygiene score ≥ 2); age ≥ 18 

Exclusion: Acute exacerbation of MS; contracture of the hip; hypersensitivity to botulinum toxin; myasthenia gravis; other neuromuscular junction diseases; pregnant; premenopausal and unwilling to use contraception; recent treatment with botulinum toxin (4mo), phenol injection (4 mo), intrathecal 

RCT (parallelgroup, doubleblind, multicenter)Duration of study treatment/follo

w

up: Single treatment; patients followedup for 12 

wk

Provider specialty: NR Location: 8 sites in Europe (6 UK, 1 Ger

many, 1 

Austria) 

No. of patients randomized: 74Dropouts: 14 Completed: 60 Age (mean ± SD):BTX 1500: 46.8 ±

10.3 BTX 1000: 54.0 ±

9.9 BTX 500: 47.0 ±12.2 Placebo: 50.7 ±

10.9 Baseline EDSS (median): BTX 1500: 7.50BTX 1000: 7.50BTX 500: 8.00 Placebo: 7.75 

1) Botulinum toxin (Dysport®) IM 1500 

units, one injection to hip adductor muscles of both legs (n = 17) 2) Botulinum toxin IM 1000 units, one injection, as above (n = 20) 

3) Botulinum toxin IM 

500 units, one injection, as above (n = 21) 4) Placebo, one injection, as above (n = 16) 

1) Symptom-specific functional status/ quality-of-life outcomes: Hygeineassessment Definition of “improvement”: Overall investigator and patient opinion at end of study – excellent, good or fair on 5-point scale where lowest categories are poor, no benefit Proportion of patients with “improvement”: 

Overall opinion

Outcome Invest Patient Placebo 7(44%) 7 (44

%) 

BTX 500 14 (67

%) 13 (62

%) 

BTX 1000 9 (48

%) 10 (53

%) 

BTX 1500 6 (36

%) 8 (47

%) 

Other (non-improvement) outcomes: Outcome

Hygiene assessment (median) 

Placebo 2.0 BTX 500 2.0 BTX 1000 1.0 BTX 1500 1.0 2) Physical functioning: Passive hip abduction; active hip abduction; modified Ashworth score; spasm frequency Definition of “improvement”: Hip abduction - Not described 

Q

UAL

DescrMethodescriConceDescrPatienInvestOutcoNo. of No 
111 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

baclofen (14 days), or any investigational drug (3 mo) 

Proportion of patients with “improvement”:  ActiveOutcome Hip abd Placebo 2 (13%) BTX 500 1 (5%)BTX 1000 1 (6%)BTX 1500 2 (12%) Other (non-improvement) outcomes: 

Hip abduction

 Passive Active  Deg (SD) possible (%) Placebo 54 (20) 4 (27) BTX 500 56 (25) 5 (26) BX 1000 63 (24) 5 (31) BTX 1500 61 (25) 7 (41) p-value NS NS  Ashworth Muscle Spasm  Score Tone Frequency Max Max (median) n (%) n (%) Placebo 8.0 13 (87) 3 (20) BTX 500 4.0 13 (68) 3 (16) BTX 1000 12.0 13 (76) 7 (41) BTX 1500 8.0 10 (59) 4 (24) p-value NS NS NS 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: AEs reported by 32/58 (55%) BTX; 10/16 (62%) placebo Hypertonia (22%), weakness of non-injected muscles (14%), fatigue (7%), UTI (5%), headache (5%), micturition frequency (5%). back pain (5%), diarrhea (5%). Twice as many AEs reported by 1500 Unit group (mean 2.7/pt) compared with the 500 Unit group (mean 1.2/pt) Six patients had serious AEs;2 on BTX, 4 on 
112 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

placebo; none was believed to be drug related. 

Killestein, Hoogervorst, Reif, et al., 2002 

Inclusion: Progressive MS; disease duration > 1 yr; severe spasticity(mean Ashworth spasticity score ≥ 2 in at least one limb); EDSS 4-7.5 Exclusion: Otherdisease of clinicalimportance; use of other investigational drug; MS exacerbation; steroid treatment or use of cannabinoids in previous 2 mo; history of alcohol or drug abuse, depression, psychosis, or schizophrenia 

RCT (crossover, double-blind, single-center) Duration of study treatment/followup: 4 wk with each treatment; 20 wk total (three4-wk treatment periods and two 4-wk washouts) Provider specialty: NR (presumably neurologists) Location: 1 site in Amsterdam, The Netherlands

No. of patients randomized: 16 (10 secondary progressive, 6 primaryprogressive) Dropouts: 0 Completed: 16 Age (mean ± SD):46 ± 7.9 

Baseline EDSS (mean ± SD): 6.2 ± 1.2 

1) Synthetic delta-9-tetrahydrocannabinol (THC) PO; initiated at 2.5 mg twice daily for 2 wk; if well tolerated, then increased to 5 mg twice daily for 2 more wk2) Cannabis sativa plant extract with delta-9-THC and cannabidiol PO; initiated at 2.5 mg twice daily for 2 wk; if well tolerated, then increased to 5 mgtwice daily for 2 more wk3) Placebo (with dose escalation after 2 wk, as above) 4-wk washout between treatment periods 

1) Symptom-specific functional status/ quality-of-life outcomes: Multiple Sclerosis Functional Composite (MSFC) score; 9-hole Peg Test Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: Compared to placebo, MSFC (p = 0.09) and 9-hole peg test (p = 0.02) scores were worse on delta-9-THC treatment 2) Physical functioning: EDSS, muscle tone (Ashworth score)Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: 

Compared with placebo, active treatment did not result in significant differences of muscle tone or EDSS score 3) Cognitive functioning: Fatigue SeverityScale (FSS) Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: No significant changes in FSS scores 4) Work or employment outcomes: NR 

QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of YesCrossPeriod discusWashNo. of descriWere of the analys
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Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

5) Generic quality-of-life outcomes: SF-36 Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: Mental Health subscale (p = 0.02) and Psychological status domain (p = 0.02) improved during delta-9-THC treatment. Other SF-36 data not given. 6) Adverse events: AEs more common during plant-extract treatment than placebo (p = 0.01).Increased spasticity (n = 5). One serious AE (brief acute psychosis). 

Kinn and Larson, 1990 

Inclusion: MS for > 5 yr; advanced urgencyand urinary leakage due to detrusor hyperreflexia; normal liver and renal function tests Exclusion: Diabetes; heart disease; hypertension 

RCT (crossover, double-blind, single-center) Duration of study treatment/followup: 3 wk with each treatment, no washout period; trial preceded by a 7-day run-in periodand a 12-daydesmopressin dose-titration phase (doses increased every 3 days from 0.1 mgto 0.2, 0.4, and 0.8 mg per day) Provider specialty:Urologists 

No. of patients randomized: 13Dropouts: 1 Completed: 12 Age: Mean, 48; range, 28-68 Baseline EDSS: NR 

1) Desmopressin PO at optimal daily dose (established during dose-titration phase) for 3 wk2) Placebo for 3 wkNo washout period described 

1) Symptom-specific functional status/ quality-of-life outcomes: Micturition frequency within 6 hr Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: Micturition frequency decreased significantlyfor desmopressin compared to run-in and placebo (p < 0.05) No. of voidings in 24 hr did not showdifference (p = NS) Urine volume in 6 hr lower for desmopressin than run-in and placebo (325 mL vs 440 mL; p < 0.05) 2) Physical functioning: NR 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 

QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of No CrossPeriod discusWashNo. of descriWere of the analys
114 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Location: 1 site in Malmö, Sweden 

5) Generic quality-of-life outcomes: NR 6) Adverse events: 1 withdrawal during run-in (on desmopressin) – tachycardia and pruritis 

Krupp, Coyle, Doscher, et al., 1995 

Inclusion: Clinicallyor laboratorysupported definite MS; severe fatigue (Fatigue SeverityScale score ≥ 4.0), persisting as a problem after a 2-wkpre-trial monitoring phase; ambulatory;EDSS ≤ 6.0; age 18-

52 Exclusion: Current or recent (within 2 mo) use of benzodiazepines, antidepressants, azathioprine, or cyclophosphamide; severe depression (score of ≥ 36 on the Center for Epidemiologic Studies Depression scale)

RCT (parallelgroup, doubleblind, multicenter)Duration of study treatment/followup: 6 wktreatment, 10 wktotal (2-wk run-in, 6 wk treatment, 2wk follow up)Provider specialty:Neurologists Location: 3 sites in metropolitan New York Cityarea 

No. of patients randomized: 119 Dropouts: 26 Completed: 93 (83 relapsing-remitting)Age (mean ± SD, n= 93 completers):Amantadine: 40.7 ± 7.1 Pemoline: 40.2 ±8.2 Placebo: 41.4 ±

5.9 Baseline EDSS (mean ± SD; n = 93 completers): Amantadine: 2.7 ±1.8 Pemoline: 3.1 ±

1.7 Placebo: 2.1 ± 1.2

1) Amantadine PO 100 mg twice daily for 6 wk (n = 31) 2) Pemoline PO 18.75 mg, once daily for 1st

wk, twice daily for 2nd

wk, then three times per day during weeks 3-6 (n = 27) 3) Placebo (doubledummy technique used) (n = 35) 

1) Symptom-specific functional status/ quality-of-life outcomes: MS-FS; FSS Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: MS-FS Baseline End Change Aman 4.9 ± 0.24 4.4 ± 0.29 -0.5 

Pemoline 4.7 ± 0.20 4.7 ± 0.18 -0.03 

Placebo 4.7 ± 0.14 4.7 ± 0.20 +0.1 

Aman vs. placebo; p = 0.04 Pemoline vs. placebo; p = 0.394 FSS Baseline End Change Aman 5.6 ± 0.17 5.2 ± 0.22 -0.45 

Pemoline 5.7 ± 0.18 5.4 ± 0.27 +0.3 

Placebo 5.6 ± 0.15 5.4 ± 0.20 -0.22 

Aman vs. placebo; p = NS Pemoline vs. placebo; p = 0.845 2) Physical functioning: NR 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: 5 AEs reported on amantadine (2withdrawals for rash, anxiety); 6 AEs reported on pemoline (2 withdrawals for irritability, anxiety); 3 AEs reported on placebo (1 withdrawal due to sleep 

QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
115 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

disturbance) 

Larcombe and Wilson, 1984 

Inclusion: Diagnosis of MS by a neurologist; selfreported duration of depression ≥ 3 mo; 

no current or prior treatment with major tranquilizers or lithium; score of ≥ 20 

on Beck Depression Inventory; definite or probable depression according to Feighner criteria; no other major psychological disorders; low suicide risk, as assessed byBeck criteria; scorewithin normal range on revised version of the Paired Associate Learning sub-test of the Wechsler Memory Scale and on the Simpson Memory Pictures Test; age 20-65 Exclusion: None specified 

RCT (parallelgroup, openlabel, singlecenter) Duration of study treatment/followup: 6 wktreatment; 1-wkrun-in and 1-wkpost-treatment follow up Provider specialty:Psychologists Location: 1 site in Australia 

No. of patients randomized: 20 Dropouts: 1 Completed: 19 Age (mean, with range, overall only): 42.5 (26-61)Baseline EDSS: NR; 8 patients required wheelchair for mobility

1) Cognitivebehavioral therapy(n = 9); weekly group sessions lasting 1.5 hr each for 6 wk2) Wait-list control (n = 10) 

1) Symptom-specific functional status/ quality-of-life outcomes: BDI; HRSD; Significant-Other Rating; Best Mood; Worst Mood; Average Mood Definition of “improvement”: Proportion of patients with “improvement”: Subjects in the cognitive-behavioral therapy condition improved significantly more than subjects in the waiting list control condition on each of: BDI p < 0.01 27± 5.6 to 8.1 ± 5 vs. 29 ± 8.7 to 33 ± 9.7 

Hamilton Rating Scale p < 0.01 16± 5 to 2± 1.5 vs. 16.9± 6.4 to 17.4± 8.3 

Significant-Other Rating Scale p < 0.01 10.7 ± 4.4 to 5.9 ± 2.8 vs. 12 ± 2.7 to 11.7±

2.8 Worst Mood Rating p < 0.05 25 ± 5.7 to 37 ± 6.5 vs. 20.9 ± 7.2 to 19.6 ±

5.4 No significant effect for: Best Mood 39.8 ±7 to 44.4 ± 6.0 vs. 30.8 ± 8.0 to 30 ±

6.8 Average Mood 34.7± 6.2 to 42.2 ± 5 vs. 27.3 ± 8.3 to 26.1±

5.8 Other (non-improvement) outcomes: 2) Physical functioning: NR 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: NR 

Differewere nalso cfollow benefalthouQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of No 
116 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Lee and Patterson, 1993 

Inclusion: Spasticityand a clinical picture of predominant spinal cord involvement; increased lower extremity tone associated with upper motor neuron signs such as weakness, hyperreflexia, orextensor plantar responses; spasticityscore (Ashworth Scale) ≥ 15 and stable over 4-wk runin period Exclusion: Suspicion of an extra-pyramidal contribution to their increased tone 

RCT (crossover, double-blind, single-center) Duration of study treatment/followup: 2 wk with each treatment; 10 wk total (4-wkrun-in, two 2-wktreatment periods, 2-wkwashout)Provider specialty: NR (presumably neurologists) Location: 1 site in Belfast, Northern Ireland

No. of patients randomized: 41? Dropouts: 8 (4 during 4-wk run-in, 4 during treatment)Completed: 33 (26 MS, 5 spinal cord injury, 1 syringomyelia, and 1 spinal tumor) Age (range; n = 33 completers): 17-70 Baseline DSS (mean, with range; n = 33 completers): 7.4(2-9) 

1) L-threonine PO 6 g per day (four 500-mg capsules 3 times per day on an empty stomach) for 2 wk 2) Placebo for 2 wk2-wk washout between treatment periods 

1) Symptom-specific functional status/ quality-of-life outcomes: Spasticity Score – sum of 6 highest scoring lower extremitymuscle groups according to Ashworth Scale; Spasm score (not described); Barthel Index Definition of “improvement”: 10% reduction in Spasticity score Proportion of patients with “improvement”: Only a few patients reported a symptomatic benefit. 16/33 “responded” to L-threonine; 3/33 to placebo; 8 had no response to either treatment; 2 responded to both treatments; 4 dropped out. Spasticity score 21.5 baseline; 18.9 post threonine; 20.6 post placebo (p = NR) Spasm score 3.8 to 2.6 on L-threonine and 3.4 to 3.0 on placebo (p = NR) No change in Barthel Index ...was seen with either treatment.Other (non-improvement) outcomes: 2) Physical functioning: Kurtzke DSS Definition of “improvement”: Proportion of patients with “improvement”: No change in ... Kurtzke DSS in either treatment Other (non-improvement) outcomes: 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: 4 patients dropped out; 2 for medical reasons (urosepsis, chest infection) believed to be unrelated to treatment. 2 dropped out 

QUALDescrMetho

descriConceDescrPatienInvestOutcoNo. of YesCrossPeriod discusWashNo. of descriWere of the analys
117 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

for non-medical reasons. Two other patients reported minor side-effects on L-threonine (indigestion and diarrhea); 1 reported headache on placebo. 

Levine, Jossmann,and DeAngelis, 1977 

Inclusion: Spasticitycaused by MS orspinal cord injury; severely disabled (confined to bed or bed and wheelchair) Exclusion: None specified 

RCT (parallelgroup, doubleblind, singlecenter) Duration of study treatment/followup: 5 wktreatment; 11 wktotal (3-wk run-in, 5 wk treatment, 3wk post-treatmentfollow up)Provider specialty: NR (presumably neurologists) Location: 1 site in Boston, MA 

No. of patients randomized: 19Dropouts: 1 Completed: 18 (12 MS, 6 spinal cord injury)Age (mean overall, n = 18 completers): 42.5 Baseline EDSS: NR “The patients being reported wereseverely disabled and were either bed or bed and wheelchair confined” 

1) Baclofen (Lioresal) PO given in evenlydivided daily doses for 5 wk as follows: wk 1, 15 mg; wk 2, 30 mg; wk 3, 45 mg; wk 4, 60 mg; wk 5, 80 mg (n = NR) 2) Placebo for 5 wk (n= NR) 

1) Symptom-specific functional status/ quality-of-life outcomes: Ashworth scale Definition of “improvement”: 10% drop in spasticity scoreProportion of tests with “improvement”: Dose Baclofen Placebo 15 mg 1/17 (6%) 1/15 (7%) 30 mg 4/16 (25%) 2/16 (13%) 45 mg 4/15 (25%) 4/17 (25%) 60 mg 8/15 (50%) 8/15 (50%) 80 mg 8/15 (50%) 6/15 (40%) p-value NR at any dose Other (non-improvement) outcomes: Avg change in spasticity scores Dose Baclofen Placebo 15 mg -2 -5 30 mg -7 -3 45 mg -11 -6 60 mg -13 -9 80 mg -12 -10 p-value NR at any dose 2) Physical functioning: NR 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: Baclofen “ was for the most part tolerated quite well. Side effects included occasional mild drowsiness and infrequent complaints of vertigo, weakness and fatigue.”

Resulpresen“was 1SCI; owas 3“Cliniclackinskeletby moof inteQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of 

Yes
118 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Lincoln, Dent, Harding, et al., 2002 

Inclusion: Clinicallydefinite, laboratorysupported, orclinically probable MS; resident within 20-mile radius of study site; able to undergo 30-min assessments Exclusion: None specified 

RCT (parallelgroup, singleblind [assessorsonly], singlecenter) Duration of study treatment/followup: Onlyextended intervention (cognitive rehabilitation program) lasted 6 wk; all patients followed up for 8 mo Provider specialty:Psychologists Location: 1 site in Nottingham, UK 

No. of patients randomized: 240 (107 relapsingremitting, 94 secondaryprogressive, 19 primaryprogressive, 20 unknown) Dropouts: 17 Completed: 223Age (mean ± SD):43 ± 10 

Baseline EDSS: NR; baseline Ambulation Index (median): Rehab: 4 Assessment: 4 Control: 3 

1) Detailed cognitive assessment + cognitive rehabilitation program (n = 79); 3-hr assessment session using multiple instruments selected according to nature of patient’s problems; results communicated to GP, hospital staff, patients, and families; cognitive rehabilitation program designed and implemented for anydeficits identified 2) Detailed cognitive assessment, as above, but no subsequent intervention (n = 79); results of assessment communicated to GP, hospital staff, patients, and families 3) No psychological/ cognitive assessment beyond screening tests; results of screening tests not communicated to medical or rehabilitation staff, patients, or families (n= 82) 

1) Symptom-specific functional status/ quality-of-life outcomes: Extended Activities of Daily Living Scale (EADL) Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: EADL Control Assess Inter- p-value  vention4-month 48.0 43.0 45.0 0.23 8-month 47.5 44.5 42.0 0.21 2) Physical functioning: NR 3) Cognitive functioning: General Health Questionnaire-28 (GHQ-28); Dysexecutive 

Syndrome Questionnaire (DEX); EverydayMemory Questionnaire (EMQ); Memory Aids Questionnaire (MAQ) Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: GHQ-28 Control Assess Inter- p-value  vention4-month 21.0 21.0 22.0 0.73 8-month 18.0 18.5 21.0 0.59 DEX 4-month 17.0 16.0 20.0 0.77 8-month 16.5 18.0 18.0 0.98 EMQ 4-month 16.5 18.5 17.0 0.69 8-month 14.0 15.0 15.0 0.76 MAQ 4-month 10.0 11.0 10.0 0.92 

Althouproblereportno sigtestingcarried Heteroleads measutreatmQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
119 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

8-month 10.0 9.0 10.0 0.80 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: SF-36 physical and mental composite scores Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: SF-36 Control Assess Inter- p-value  vention4-month Physical 25.6 27.1 31.4 0.45 Mental 44.7 44.7 46.9 0.55 8-month Physical 30.0 32.1 30.7 0.55 Mental 47.3 49.3 46.9 0.76 6) Adverse events: NR 

Livesley, 1992 

Inclusion: Spasticityas a component of a chronic neurological disease (stable for ≥ 6 mo); high level of cognitive awareness; inpatient or outpatient Exclusion: None specified 

RCT (parallelgroup, singleblind [patients only], singlecenter) Duration of study treatment/followup: 6 wkProvider specialty:Physiotherapist Location: 1 site in Nottingham, UK 

No. of patients randomized: 40 (37 MS, 2 spinal injuries, 1 stroke) Dropouts: 1 Completed: 39 Age (mean ± SD):ENS: 48 ± 8.8 

Sham ENS: 47 ±

11.2 Baseline EDSS: NR 

1) Electrical neuromuscular stimulation (ENS); quadriceps and hamstrings treated for 12 min every working day for 6 wk; frequency graduallyincreased from 3 Hz (2 min) to 10 Hz (5 min) to 35 Hz (5 min) during each treatment session (n = 20) 2) Sham ENS; asabove, but stimulator deactivated (n = 20) 

1) Symptom-specific functional status/ quality-of-life outcomes: Functional ambulation classification appendix; Spasticity self-rating Definition of “improvement”: Rated better onscale of worse, same, or better Proportion of patients with “improvement”: Treatment 9/20 (45%) Sham 4/19 (21%) Other (non-improvement) outcomes: Functional ambulation (median) Treatment Sham Entry Exit Entry Exit p-value 4 4 5 5 NS 2) Physical functioning: Rivermead motor assessment; Range of movement at hip, 

QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
120 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

knee and ankle (degrees) Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: Rivermead motor assessment (median)  Treatment Sham  Entry Exit Entry Exit p Gross 8 9 11 11 NS Leg 8 8 7 9 NS Joint ROM (degrees)  Treatment Sham  Entry Exit Entry Exit p Hip flex 98± 19 102±21100±17 100±18 NS 

Hip ext 8.5± 6 8.5± 6 7± 6 7.5± 7 NS

Hip abd 33± 11 35± 10 29± 13 34± 13 NS 

Knee fl 121±25 126±19 122±18 120±24 NS 

Knee ex 1± 3 2.5±5.5 0.5± 2 0.5± 2 NS

Ank dor 18±6.5 26±6 21±12 18±4 NS

Ank pla 21±17 14±5 12.5±7 19±8 NS

3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: NR 

Mendoza, Pittenger, and Weinstein, 2001 

Inclusion: Advanced MS; resident in a skilled nursing facilityspecializing in the treatment of patients with advanced MSExclusion: Primaryadmitting diagnosis not MS; unable to

RCT (parallelgroup, openlabel, singlecenter) Duration of study treatment/followup: 2 mo Provider 

No. of patients randomized: 20Dropouts: 0 (though post-studydata not collected from 1 patient because of a medical complication) 

1) Active treatment (n = 10); extendedbattery of cognitive tests, plus specific problem-solving strategy: Individual CNA assigned to each patient, provided with special training, and charged with keeping 

1) Symptom-specific functional status/ quality-of-life outcomes: NR 2) Physical functioning: NR 3) Cognitive functioning: Beck Depression InventoryDefinition of “improvement”: Change score greater than 2 SD

QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of 
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Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

read test stimuli; comorbid major mental disorder; unable to answer test questions at a sufficiently high verbal level; performance on Kaufman Short Neuropsychological Assessment Procedure MentalStatus Subtest in the impaired range 

specialty:Certified nursing assistants (CNAs), social workers, and psychologists Location: 1 site in Dorchester, MA 

Completed: 20 Age (mean): Active: 54.6 Control: 64.7 Baseline EDSS: NR; 2 groups “equivalent in terms of general physical status” 

a notebook, attached to patient’s chair, in which information was recorded on patient’s comments or concerns, special assistance required, etc. 2) Control (n = 10); no change to previous treatment routine

Proportion of patients with “improvement”: Treatment 6/10 (60%) Control 1/9 (11%) Other (non-improvement) outcomes: BDI Pre Post Treatment 11.3 5.5 Control 9.3 8.6 p-value NS 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: NR 

Yes

Mohr, Boudewyn, Goodkin, et al., 2001 

Inclusion: Confirmed diagnosis of MS (Poser criteria); relapsing-remitting or secondaryprogressive disease course confirmed bya neurologist; diagnosis of major depressive disorder based on Structured Clinical Interview forthe DSM-IV; score ≥ 16 on 17-item Hamilton Rating Scale for Depression; score ≥ 16 on Beck Depression Inventory; willingness to abstain from psychological or pharmacological treatment for depression other than that provided as part of study

(Pseudorandomized, parallelgroup, openlabel, singlecenter) Patients allocated to group therapy based on threshold number during 4-week period; if fewer than 6 pts enrolled, then they were randomized to CBT or sertraline.Duration of study treatment/followup: 16 wk; 43 patients also followed up at 6 mo Provider specialty:Neurologists andpsychologists 

No. of patients randomized: 63Dropouts: 11 Completed: 52 Age (mean ± SD, overall only): 43.9 ± 10.0 Baseline EDSS (mean, with range, overall only): 2.4(0 to 8.0)

1) Cognitivebehavioral therapyfocused on improving coping skills (in relation to both depression and MS); individual sessions (50 min each) once weeklyfor 16 wk (n = 20 at start, 19 at end) 2) Supportiveexpressive group therapy, focused on facilitating expression and providing social support; sessions involved 5-9 patients and 2 therapists; weekly 90-min sessions for 16 wk (n= 22 at start, 18 at end) 3) Sertraline PO, initiated at 50 mg per day, increased by 50 mg every 4 wk until 

1) Symptom-specific functional status/ quality-of-life outcomes: BDI, HRSD (Hamilton) Definition of “improvement”: 50% decrease in symptoms and symptoms severity on HRSD Proportion of patients with “improvement”: CBT 10 (50%) SEG 3 (14%) Sertraline 5 (24%) Other (non-improvement) outcomes: ITT BDI – SEG significantly less effective than CBT (P = 0.003) and sertraline (p = 0.047) BDI-18 – SEG less effective than CBT (p = 0.0007) and marginally less effective than sertraline (p = 0.84) HRSD - CBT more effective than SEG (p = 002); no significant differences between SEG and sertraline (p = 0.45) or between CBT and sertraline (p = 0.13) 2) Physical functioning: EDSS Definition of “improvement”: None

QUALDescrMethodescriConce

DescrPatienInvestOutcoNo. of Yes
122 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Exclusion: Otherserious psychological disorders; dementia (below 5th percentile 

in 3 or 6 areas ofneuropsychological functioning); severe suicidality; treatment with corticosteroids in previous 14 days; initiation of treatment with interferon in previous 2 mo; current MS exacerbation; other disorders of CNS; current or planned pregnancy; current psychological or pharmacological treatment for depression 

Location: 1 site in San Francisco, CA 

dosage of 200 mg was reached or until full remission achieved as judged by treating clinicians; patient visitslasting 10-15 min every 4 wk; treatment lasted 16 wk (n = 21 at start, 15 at end) 

Proportion of patients with “improvement”: NR Other (non-improvement) outcomes: 3) Cognitive functioning: Symbol Digit Modalities Test, Digit Span; Ret AuditoryVerbal Learning Test, 7/24, Controlled Oral Word Association, California Card Sort Test Definition of “improvement”: NoneProportion of patients with “improvement”: NR Other (non-improvement) outcomes: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: NR 

Mohr, Likosky,Bertagnolli, et al., 2000 

Inclusion: Diagnosis of a relapsing form of MS; score of ≥ 15 on 

the DepressionDejection scale of the Profile of Mood States; treatment for depression (if any) initiated at least 3 mo before start of studywith continuationintended Exclusion: Dementia (score < 5th percentile 

on the Short WordList); other neurological disorder 

RCT (parallelgroup, openlabel, singlecenter) Duration of study treatment/followup: 8 wkProvider specialty:Neurologists andpsychologists Location: 1 managed care program in northern California 

No. of patients randomized: 32 (all relapsing) Dropouts: 9 Completed: 23 Age: Mean, 42.4Baseline EDSS: NR; 56% walked without aids, 34% walked with aids,and 9% used a wheelchair 

1) Telephoneadministered cognitive-behavioral therapy (n = 16); eight weekly 50-min sessions; included training in thought monitoring, increasing pleasant events, and managing fatigue, as needed for individual patients 2) Usual care (n = 16)

1) Symptom-specific functional status/ quality-of-life outcomes: Profile of Modd States Depression-Dejection scale Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: Completers Pre Post CBT 34.8± 13.5 13.8± 12.8 

Usual 26.0± 8.1 24.3± 10.7 

P = 0.003 ITT Pre PostCBT 33.1± 12.4 18.7± 13.8 

Usual 27.9± 12.1 26.7± 13.7 

P = 0.01 2) Physical functioning: NR 

No chwk, butreatmscores upper QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
123 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: NR 

Mondrup and Pedersen, 1984a and Mondrup and Pedersen, 1984b 

Inclusion: Spastic paresis in a stable phase for ≥ 2 moExclusion: Markedlyimpaired liver or renal function; severe hypertension (DBP > 110 mmHg);orthostatic hypotension; chronic alcoholism; diabetes; cardiac disease; overt psychopathology; epilepsy;disease with dominating cerebellar symptoms; pregnancy 

RCT (crossover, double-blind, single-center) Duration of study treatment/followup: 2 wk with each treatment, 4 wk total (no washoutdescribed) Provider specialty:Neurologists Location: 1 site in Aarhus, Denmark 

No. of patients randomized: 17Dropouts: 1 Completed: 16 (14 MS, 2 hereditaryspastic paraplegia)Age (completers): Median, 45.5; range, 30-62 Baseline EDSS: NR 

1) Progabide PO administered three times per day;maximum dose reached after 3-5days; treatment lasted 2 wk; median dailydose 24.3 mg/kg (range, 14.3-32.7mg/kg) 2) Placebo, with dose adjustments as above, for 2 wkNo washout described 

1) Symptom-specific functional status/ quality-of-life outcomes: Overall therapeutic effect (includes evaluation of gait and other ADLs; 4-point scale) Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: Overall therapeutic effect  Investigator p < 0.01 

Patient p < 0.01 

2) Physical functioning: Spastic hypertonia (angle at which stretch reflex appears bymobilization of limb at gravity speed in steps of 15 degrees); tendon reflexes-patellar (4-point scale) Achilles (3-point scale); flexorspasms frequency (5-point scale) and discomfort (4-point scale); flexor reflex (4-point scale); muscle strength (6-point scale);Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes:  p-valueSpastic hypertonia < 0.01 Tendon reflexes Patellar < 0.01  Achilles NS 

No wano teswas dcarry-QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of 

YesCrossPeriod discusWashNo. of descriWere of the analys
124 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Clonus  Patellar NS 

Foot NS 

Flexor reflex NS Flexor spasms  Frequency < 0.05  Discomfort NS Muscle strength 

Upper NS Lower NS

3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: “No side-effects were registered” 

Mueller, Gruenthal, Olson, et al., 1997 

Inclusion: Laboratory-supported definite MS, including characteristic MRI findings; spasticityand leg cramps severe enough tointerfere with daily activities, including sleep; age 18-50Exclusion: Pregnancy;significant renal disease 

RCT (crossover, double-blind, single-center) Duration of study treatment/followup: 2 days with each treatment; 15 days total (two 2-hr run-ins [on 1st day of 

treatment during each period], two2-day treatment periods, 11-day washout)Provider specialty: NR (neurologists andothers?) Location: 1 site in Louisville, KY

No. of patients randomized: 15Dropouts: 0 Completed: 15 Age (mean, with range): 42.2 (31-59) Baseline EDSS (median): Prior to gabapentin: 12 Prior to placebo: 13 

1) Gabapentin PO400 mg three times per day for 2 days 2) Placebo threetimes per day for 2 days11-day washout between treatment periods 

1) Symptom-specific functional status/ quality-of-life outcomes: Visual Faces Scale, Ashworth Scale; clonus; reflexes; Response to Noxious Stimuli Definition of “improvement”: NoneProportion of patients with “improvement”: NR Other (non-improvement) outcomes:  VFS Ashworth ClonusPlacebo b/l 2 22 1 Gabapentin b/l 2 23 1 Placebo 2 23 1 Gabapentin 1 22 1 p-value 0.008 0.007 0.1  Reflexes Noxious Placebo b/l 14 2 Gabapentin b/l 14 2 Placebo 14 2 Gabapentin 13 2 p-value 0.28 0.25 

ImprovstatistdramaQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of YesCrossPeriod WashNo. of descriWere of the analys
125 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

2) Physical functioning: EDSS Definition of “improvement”: NoneProportion of patients with “improvement”: NR Other (non-improvement) outcomes:  EDSSPlacebo b/l 13 Gabapentin b/l 12 Placebo 12.5 Gabapentin 10 p-value 0.03 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: NR 
126 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Newman, Nogues, Newman, et al., 1982 

Inclusion: Disabled by spasticity; neurologically stable Exclusion: None specified 

RCT (crossover, double-blind, single-center) Duration of study treatment/followup: 6 wk with each treatment, 13 wk total (two6-wk treatment periods, 1-wkwashout)Provider specialty:Neurologists Location: 1 site in Newcastle, UK 

No. of patients randomized: 36 (32 MS, 4 syringomyelia) Dropouts: 10 Completed: 26 Age (mean ± SD, completers): 45.9 ± 9.4 Baseline EDSS: NR 

1) Tizanidine PO in 2-mg capsules; dose increased over 2 wk to 8 capsules daily (16 mg), then maintained at this level for a further 1 mo (dose could be lowered if not tolerated) 2) Baclofen PO in 5- mg capsules; dose increased over 2 wk to 8 capsules daily (40 mg), then maintained at this level for a further 1 mo (dose could be lowered if not tolerated) 1-wk washout between treatment periods 

1) Symptom-specific functional status/ quality-of-life outcomes: NR 2) Physical functioning: Muscle tone (Ashworth); EDSS; Pedersen scoreDefinition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: Overall score of lower limb muscle tone: Tizanidine 9/26 (35%) p < 0.02 Baclofen 8/26 (31%) p > 0.05 Difference between treatments p = NS No significant difference in muscle power Flexor, extensor, and adductor spasms in the lower limbs were improved more in baclofen group (p = NS) No significant change in Kurtzke scores or Pedersen scores 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: AEs experienced by 17/26 (65%) on tizanidine and 17/26 (65%) on baclofen. Drowsiness, muscle pains, dizziness, weakness, abdominal pain, bowel or bladder disturbance, sleeplessness, depression. Similar AE profiles for both drugs. 

QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of No CrossPeriod WashNo. of descriWere of the analys
127 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Nielsen, Sinkjaer, and Jakobsen, 1996 

Inclusion: Clinicallydefinite or laboratorysupported definite MS by Poser criteria; EDSS < 7.0; stable neurological condition for ≥ 6 mo; lower limb 

spasticity ≥ 2 on Ashworth score for at least one joint; preserved walking performance for 10 m Exclusion: Epilepsy; other neurological disorders; pregnancy;implanted spinal metal, drug infusion pump, or pacemaker; previous exposure to magnetic stimulation 

RCT (parallelgroup, doubleblind [patients and assessors, not treating clinicians], singlecenter/ multicenter)Duration of study treatment/followup: 7 daystreatment; followup evaluations 1, 8, and 16 days after last treatment Provider specialty: NR (neurologists?) Location: 1 site in Aarhus, Denmark 

No. of patients randomized: 38Dropouts: 3 Completed: 35 Age (median, withrange): Active: 44 (34-67) Sham: 44 (26-66) Baseline EDSS: NR 

1) Repetitive magnetic stimulation twice daily for 7 consecutive days(n = 21); magnetic coil place in midline of back at mid-thoracic level; subjectsstimulated in supine position for 25 min with repeated periods of stimulation for 8 sec at 25 Hz, followed by22 sec of repose;magnetic field strength gradually increased to 0.7 Tesla within a fewminutes 2) Sham stimulation twice daily for 7 consecutive days(n = 17) 

1) Symptom-specific functional status/ quality-of-life outcomes: Clinical score = muscle tone (Ashworth score) + reflex activity; self-scoreDefinition of “improvement”: NoneProportion of patients with “improvement”:  Mag stim Sham Self-score 9/18 (50%) 10/17 (59%) Clin score 14/18 (78%) 10/17 (59%) p-values NR Other (non-improvement) outcomes:  Mag stim Sham p-value OutcoSelf-score 1.1± 1.6 1.5± 1.8 NS 

Clinical 1d -3.3± 4.7 0.7± 2.5 0.003 Improvements in clinical score extinguished at 8 and 16 days after treatment 2) Physical functioning: NR 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 

5) Generic quality-of-life outcomes: NR 6) Adverse events: NR 

TreatitreatmNo de“improQUALDescrMethodescriConceDescrPatienInvestNo. of Yes

O’Hara, Cadbury,De Souza, etal., 2002 

Inclusion: Diagnosis of MS confirmed byGPExclusion: None 

RCT (parallelgroup, single blinded [assessors only,not treating clinicians or patients], multicenter)Duration of study treatment/follow

No. of patients randomized: 183 Dropouts: 14 Completed: 169 (80 relapsingremitting, 82 chronic progressive, 7 unknown) 

1) Professionallyguided self-care program (n = 73); two 1- to 2-hr group or individual discussions of self-care strategies during 1st mo; 

supported by an information booklet developed for the study in line with 

1) Symptom-specific functional status/ quality-of-life outcomes: Standard DayDependency Record (SDDR) subscales SDDRO & SDDRE Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: 

QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
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Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

up: 6 mo Provider specialty: NR Location: Multiple local sites in London, UK 

Age (mean ± SD):Active: 52.5 ± 11.2Control: 50.4 ±10.4 Baseline EDSS: NR 

consumer priorities; information covered physical, social, and psychological domains of life 2) No-treatment control (n = 96) 

Change from baseline to follow up:  Intervention Control p-value SDDRO 0.5 0.8 0.6 SDDRE -0.3 0.6 0.04 2) Physical functioning: Barthel Index Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes:  Intervention Control Barthel 0 (0,0) 0 (-1,0) 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: SF-36 Change from baseline to follow up:  Intervention Control p-value Mental hlth 3.7 -1.2 0.04 Pain 2.4 -1.1 0.32 Phys role -6.4 -6.2 0.31 Phys fn 0.6 -1.4 0.5 Role emo -4.2 -3.1 0.9 Social fn 0.8 -3.3 0.33 Vitality 1.5 -4.2 0.05 Gen hlth 7.4 4.8 0.32 6) Adverse events: NR 

Ørsnes, Sørensen, Larsen, etal., 2000 

Inclusion: clinicallydefinite MS; stable disease for ≥ 1 mo; 

increased stretch reflexes and hyperreflexia;moderate functional deficits; able to walk unaided and without 

RCT (crossover, double-blind, single-center) Duration of study treatment/followup: Approximately 24 days with each treatment; 

No. of patients randomized: 14 (5 relapsingremitting, 4 primaryprogressive, 5 secondaryprogressive) Dropouts: 0 

1) Baclofen PO; dose initiated at 5 mg three times per day andincreased by 5 mgevery 3 days to maximum of 15 mg three times per day or maximum tolerated dose; after 11 days at 

1) Symptom-specific functional status/ quality-of-life outcomes: Ashworth index Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: 

QUALDescrMethodescriConceDescrPatienInvestOutco
129 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

support for at least 1 min Exclusion: Use of drugs that could affect spasticity

approximately 62days total (no run-in described,two 24-daytreatment periods, 2-wkwashout)Provider specialty: NR (presumably neurologists) Location: 1 site in Copenhagen,Denmark 

Completed: 14 Age (median, withage): 42 (24-57)Baseline EDSS (median, with range): 5 (3.5-6.0)

this dose, treatment tapered over “about 1 wk”2) Placebo, dosing schedule as above, for approximately 24 days2-wk washout between treatment periods 

 Tendon Muscle tone  Reflexes Ashworth Baclofen  Before 13.6 (2.8) 1.9 (1.5)  During 11.7 (4.1) 2.8 (2.4) Placebo  Before 13.7 (3.5) 3.1 (2.1)  During 13.1 (3.1) 3.2 (2.3) p-value 0.14 0.33 2) Physical functioning: EDSS, Ambulation Index (AI), Neurologic Rating Scale (NRS),MS-impairment scale (MSIS) Definition of “improvement”: Not defined Proportion of patients with “improvement”: EDSS & AI: Baclofen 1/14 (7%) Placebo 3/14 (21%) Other (non-improvement) outcomes: No significant differences between baclofen and placebo in EDSS, AI, NRS or MSIS 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: NR 

No. of YesCrossPeriod WashNo. of descriWere of the analys

Patti, Ciancio, Reggio, et al., 2002 

Inclusion: Clinicallydefinite or laboratorysupported MS; primary or secondaryprogressive form of MS; EDSS 4.0-8.0; age 18-65 Exclusion: One or more exacerbations 

RCT (parallelgroup, singleblind [assessorsonly], singlecenter) Duration of study treatment/followup: 12 wk

No. of patients randomized: 111 Dropouts: 5 Completed: 106Age: Mean, 45.6;range, 25-60 

1) Comprehensive outpatient rehabilitation program for 6 wk + selfexercise treatment for 6 wk (n = 58); rehabilitation program included physiotherapy, occupational therapy,

1) Symptom-specific functional status/ quality-of-life outcomes: Fatigue Impact Scale (FIS) Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: 

QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of 
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Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

in previous 3 mo; cognitive impairment (Mini-Mental State Examination score≤ 24); history of cardiovascular,respiratory, orthopedic, psychiatric, or other medical condition precluding participation; pregnancy; treatment with immunosuppressives, interferons, copolymer, 4-amminopyridine, or experimental drugs in preceding 6 mo; rehabilitation therapyin previous 3 mo 

Provider specialty: NR (presumably neurologists) Location: 1 site in Catania, Italy

Baseline EDSS: Mean, 6.2; range, 4-8 

speech therapy (if needed), and complementary and alternative therapies 2) Control = 12-wkself-exercise treatment (n = 53) 

Change from T0 to T1 

 Treatment Control p-value FIS -18.8± 14.3 0.6± 0.9 < 0.0012) Physical functioning: EDSS Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: “Changes in EDSS scores clustered nearlyaround 0 in both groups at weeks 6 and 12.”3) Cognitive functioning: Tempelaar Social Experience Checklist (SET); Beck Depression Inventory (BDI) Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: 

Change from T0 to T1 

 Treatment Control p-value SET -2.6± 6.0 -0.3± 0.8 < 0.001

BDI -2.2± 3.4 0.1± 1.0 < 0.0014) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: SF-36 Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: SF-36 Change from T0 to T1  Treatment Control p-value PF 6.9± 18 -0.1± 0.3 < 0.001

RP 14± 24 -0.2± 0.5 < 0.001

Yes
131 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

BP 15± 20 -0.1± 0.6 < 0.001

GH 5.8± 10 -0.2± 0.5 < 0.001

VT 7.4± 12 -0.1± 0.5 < 0.05 

SF 12± 15 -0.1± 0.3 < 0.001

RE 6.2± 24 -0.1± 0.3 < 0.05 

MH 7.7± 16 -0.1± 0.5 < 0.05 

6) Adverse events: NR 

Penn, Savoy,Corcos, et al., 1989 

Inclusion: Severe, disabling spasms caused by MS orspinal-cord injury; not responsive to oraldoses of anti-spastic medication; agreed to implantation of drug pump after pre-trial test dose of intrathecal baclofen Exclusion: None specified 

RCT (crossover, double-blind, single-center) Duration of study treatment/followup: 3 days with each treatment; pre-trial test with bolus intrathecal dose; no washoutProvider specialty:Physiatrists, motor physiologists, and neurosurgeons Location: 1 site in Chicago, IL 

No. of patients randomized: 20 (10 MS, 10 spinalcord injury)Dropouts: 0 Completed: 20 Age (mean, with range): 41.5 (23-62) Baseline EDSS: NR; 9/10 MS patients wheelchair-bound; all 10 “functionally dependent” 

1) Baclofen byintrathecal infusion via surgically implanted pump; daily dose 1.5-2 times the effective bolus intrathecal dose (typically 100-150 μg per day) given bycontinuous infusion over 3 days2) Placebo by same route for 3 daysNo washout between treatment periods 

1) Symptom-specific functional status/ quality-of-life outcomes: Ashworth score; Spasm score Definition of “improvement”: Not defined Proportion of patients with “improvement”: 9/10 patients had clinically important improvement – 1 had no improvement during dbl blind trial, but did showimprovement at higher dosage during open trial Other (non-improvement) outcomes: Ashworth  Placebo 4.0± 1.0 

 Baclofen 1.2± 0.4 

 Change 2.8 (p < 0.0001) Spasm score  Placebo 3.3± 1.2 

 Baclofen 0.4± 0.8 

 Change 2.9 (p < 0.0005) 2) Physical functioning: NR 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: During 26 mo follow up, 2 catheters dislodged, 1 pump failed at 4 mo, pain at 

Study the effgiven patienQUALDescrMetho

descriConceDescrPatienInvestOutcoNo. of YesCrossPeriod discusWashNo. of descriWere of the analys
132 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

implantation site

Petajan, Gappmaier,White, et al., 1996 

Inclusion: Confirmed diagnosis of clinicallydefinite MS; EDSS ≤ 6.0; not involved in any form of regular physical activity for previous 6 mo; nohistory of cardiovascular, respiratory,orthopedic, metabolic, or other medical condition that would preclude participation in exercise program Exclusion: None specified 

RCT (parallelgroup, openlabel, singlecenter) Duration of study treatment/followup: 15 wkProvider specialty:Neurologists (andphysical therapists/ exercise physiologists) Location: 1 site in Salt Lake City,UT 

No. of patients randomized: 54Dropouts: 8 Completed: 46 Age (mean ± SE): Exercise: 41.1 ±

2.0 Control: 39.0 ± 1.7Baseline EDSS (mean ± SE):Exercise: 3.8 ± 0.3

Control: 2.9 ± 0.3 

1) Exercise program (n = 21); 3 supervised training session per week for 15 wk; each session consisted of 5-min warm-up at 30% VO2max, 30 min at 

60% VO2max, 5-min 

cool-down, and 5-10 min stretching focusing on posterior muscles of lower leg, thigh, and back 2) No treatment (patients agreed not to alter their level of physical exercise) (n = 25) 

1) Symptom-specific functional status/ quality-of-life outcomes: Fatigue SeverityScale (FSS); Sickness Impact Profile (SIP) Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: “No changes were observed for exercise or non-exercise groups on the FSS”Significant improvement in exercise group compared to non-exercise group for physical dimension subscale of the SIP. In other dimensions (ambulation, mobility,and body care and movement) exercise patients improved compared to baseline, but not significantly compared to non-exercise group. No changes for psychosocial dimension subscale. 2) Physical functioning: EDSS; ISS; VO2maxDefinition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: EDSS Exercise Non-exercise Baseline 3.8± 0.3 2.9± 0.3 

15-week 3.7± 0.3 2.8± 0.3 

p = NS ISS Exercise Non-exercise Baseline 9.0± 0.9 8.1± 0.9 

15-week 6.8± 1.1 8.3± 0.9 

p = NS 

QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
133 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

VO2max Exercise Non-exercise Baseline 24.2± 1.4 26.0± 1.3 

15-week 29.4± 1.3 26.4± 1.4 

p < 0.01 3) Cognitive functioning: Profile of Mood States (POMS) Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: POMS – Lower scores for depression (5,10 wk), anger (5,10 wk), and fatigue (10 wk) subscales from baseline to post-treatment in exercise group; no between-groupdifferences 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: NR 

Pozzilli, Brunetti, Amicosante, et al., 2002 

Inclusion: Clinicallydefinite MS; resident in Rome service area of Italian National Health Service Exclusion: None specified 

RCT (parallelgroup, openlabel, multicenter)Duration of study treatment/followup: 1 yr Provider specialty:Multidisciplinarycare teams forhome-care patients; neurologists for hospital patients 

No. of patients randomized: 201 (40 relapsingremitting, 41 primaryprogressive, 120 secondaryprogressive) Dropouts: 13 Completed: 188Age (mean ± SD):Home: 47.0 ± 10.3Hospital: 46.7 ±

1) Home-based management (n = 133); patients managed through home visits and telephone calls; multidisciplinary careteam designed individualized clinical care plan and coordinated home services; care included observation, administration of IV drugs, nursing care, rehabilitation, 

1) Symptom-specific functional status/ quality-of-life outcomes: SF-36, Fatigue Severity Scale (FSS); Functional Independence Measure (FIM) Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: SF-36 Diff CI p-valuePhys fn 0.27 -0.53 to 1.06 0.55 Role phys 3.67 -1.19 to 8.53 0.09 Bodily pain 3.46 2.4 to 4.5 0.0001 Gen Health 5.01 4.5 to 5.5 0.0001 

QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
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Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Location: Care provided in patients’ homes and at various MS clinics in Rome, Italy

13.3 Baseline EDSS (mean ± SD): Home: 6.0 ± 2.0Hospital: 5.8 ± 2.2

education, psychological support, and social services; treatment continued for 1 yr 2) Traditional hospital care (n = 68); patients followed as usual in their MS referralcenters for 1 yr 

Vitality 0.28 -0.38 to 0.94 0.41 Social fn 1.09 0.51 to 1.67 0.001 Role, emo 12.4 9.8 to 14.9 0.0001 Mental hlth -0.10 -0.25 to 0.05 0.19 Phys component score  1.19 1.04 to 1.34 0.0001 Mental comp score  0.75 0.58 to 0.91 0.0001 No significant differences betweenintervention and control groups for FSS or FIM 2) Physical functioning: EDSS Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: No significant differences betweenintervention and control groups for EDSS 3) Cognitive functioning: MMSE, State-trait Anger Expression Inventory (STAXI); StateTrait Anxiety Inventory (STAI); Clinical Depression Questionnaire (CDQ)Definition of “improvement”: Proportion of patients with “improvement”: No significant differences betweenintervention and control groups for MMSE, STAXI, STAI Trend in favor of intervention group for changes in depression as measured by the CDQ score; intervention (-7.8%); control (+0.7%) (p = 0.11) Other (non-improvement) outcomes: No significant differences betweenintervention and control groups for MMSE 
135 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: NR 

Prasad, Smith, and Wright, 2003 

Inclusion: MS; voiding dysfunction, (such as frequency or urgency) associated with elevated residual volume of > 100 mL and < 500 mL; attending a continence advisoryclinic or a neurorehabilitation clinic; reasonable handdexterity; intact abdominal sensation; able to walk short distances indoors without aids Exclusion: Urinarysymptoms caused byinfection 

RCT (crossover, open-label, twocenter) Duration of study treatment/followup: 2 wk with each treatment; 8 wk total (no run-indescribed, three 2-wk treatment periods, two 1-wkwashouts)Provider specialty: NR (rehabilitation medicine) Location: 2 sites in Edinburgh, Scotland 

No. of patients randomized: 30Dropouts: 2 (postrandomization, but pre-treatment) Completed: 28 Age (mean ± SD):49 ± 9.2 

Baseline EDSS: NR 

1) Abdominal vibration; provided bylow-cost, commerciallyavailable bodymassager (Queen Square Bladder Stimulator); usedagainst supra-pubic region (2.5 cm above public symphysis)during and for 1 min after voiding; treatment continued for 2 wk2) Abdominal pressure; appliedusing same massager as above, but without batteries, for 2 wk3) No treatment for 2 wk1-wk washout between treatment periods 

1) Symptom-specific functional status/ quality-of-life outcomes: Frequency of micturition (per 72 hr); incontinence; frequency of incontinence; post-void residual urine volume (ml) Definition of “improvement”: No incontinence/72 hr Proportion of patients with “improvement”: Vibration 20/28 (71%) Abd pressure 12/28 (43%) No treatment 16/28 (57%) Other (non-improvement) outcomes:  Frequency per 72 hr ± SD Vibration 25± 8.9 Abd pressure 26± 9 No treatment 27± 10.3  Mean episodes of incontinence Vibration 1.3 (0-3) Abd pressure 1.6 (0-20) No treatment 1.9 (0-20)  Post-void residuals (ml) (± SD) 

Vibration 126± 121 (p = 0.002 vs NT) 

Abd pressure 191± 132 (p = 0.059 vs Vib) 

No treatment 231± 119 

2) Physical functioning: NR 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 

QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of YesCrossPeriod discusWashNo. of descriWere of the analys
136 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

6) Adverse events: NR 

Rinne, 1980 Inclusion: Stable

spasticity (≥ 1 yr) due to MS or myelopathyExclusion: None specified 

RCT (parallelgroup, doubleblind, singlecenter) Duration of study treatment/followup: 6 wkProvider specialty: NR (presumably neurologist) Location: 1 site in Turku, Finland

No. of patients randomized: 30 (all MS) Dropouts: 4 Completed: 26 Age (mean ± SD):Tizanidine: 42 ± 3 Diazepam: 40 ± 2 Baseline EDSS: NR 

1) Tizanidine PO 2-mg capsules (n = 15); dose graduallyincreased (at 2-wkintervals) to maximum of nine capsules (18 mg) daily, taken inthree divided doses; treatment lasted 6 wk2) Diazepam PO 2.5-mg capsules (n = 15); dose graduallyincreased (at 2-wkintervals) to maximum of nine capsules (22.5 mg) daily, taken inthree divided doses; treatment lasted 6 wk

1) Symptom-specific functional status/ quality-of-life outcomes: NR 2) Physical functioning: Muscle tone (Ashworth scale) Definition of “improvement”: Marked, moderate or slight improvement on scale including no change and deterioration, based on muscle tone Proportion of patients with “improvement”: Tizanidine 10/16 (63%) Diazapam 9/15 (60%) Other (non-improvement) outcomes: 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: AEs reported by 10/15 (67%) on tizanidine and 12/15 (80%) on diazepam Muscle weakness, drowsiness required withdrawal in 4 patients (diazepam) Overall tolerance was significantly better on tizanidine than diazepam (p < 0.05) 

Article Trials and chreportwith Mfor Triwith MQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes

Rossini, Pasqualetti, Pozzilli, et al., 2001 

Inclusion: Primaryand secondary clinically definite MS; stable neurological deficits for ≥ 2 mo Exclusion: History of previous epileptic 

RCT (crossover, double-blind, single-center) Duration of study treatment/followup: 6 mo with each treatment, 

No. of patients randomized: 54Dropouts: 5 Completed: 49 (43 secondaryprogressive, 6 

1) 4-aminopyridine (4-AP) 8 mg taken orally4 times per day for 6 mo (dose graduallyraised to this level over 1st mo) 

2) Placebo for 6 mo 

1) Symptom-specific functional status/ quality-of-life outcomes: Fatigue SeverityScale (FSS) Definition of “improvement”: NoneProportion of patients with “improvement”: NA 

QUALDescrMethodescriConceDescrPatienInvest
137 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

seizures; EEG

epileptiform activity; treatment with corticosteroids or immunosuppressants in previous 60 days 

12 mo total (no run-in described,no washout between treatments) Provider specialty: NR (presumably neurologists) Location: 1 site in Rome, Italy

primaryprogressive) Age (mean ± SD; n= 49 completers):43.9 ± 8.9 

Baseline EDSS (mean ± SD; n = 49 completers): 6.2 ± 0.8 

No washout between treatment periods 

Other (non-improvement) outcomes: No significant difference in FSS improvements between 4-AP and placebo (p = 0.19) 2) Physical functioning: EDSS Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: EDSS Mean Difference ± SD 

 Placebo -0.05± 0.37 4-AP -0.05± 0.50p = NS Similarly no significant difference for any of the EDSS Functional Systems (FS) 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: None observed 

OutcoNo. of YesCrossPeriod WashNo. of descriWere of the analys

Rudick, Breton, and Krall, 1987 

Inclusion: DefiniteMS by Schumacher criteria; at least grade-3 spasticity(Ashworth Scale) or spasms associated with significant discomfort or functional impairment Exclusion: Epilepsy; significant medical illnesses 

RCT (crossover, double-blind, single-center/ multicenter)Duration of study treatment/followup: 4 wk with each treatment; 12 wk total (two4-wk treatment periods, 2-wkrun-in, 2-wk

No. of patients randomized: 32Dropouts: 7 Completed: 25 Age (mean, with range): 45.3 (24-67) Baseline EDSS (mean ± SD): 6.3 

1) Progabide, dose increased to 30 mg/kg/ day over 10 days, then to 45 mg/kg/day over 10 days of weeks 3-4; treatment lasted total of 4 wk2) Placebo for 4 wk2-wk washout between treatment periods 

1) Symptom-specific functional status/ quality-of-life outcomes: AshworthDefinition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: Ashworth Baseline 10.3 Progabide 8.0 Placebo 9.6 

QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of YesCrossPeriod 
138 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

washout)Provider specialty: NR (presumably neurologists) Location: 1 site in Rochester, NY

± 1.7 P < 0.01 progabide vs placebo 

Measure p-value Timed 8-meter walk 0.62 Zip-a-garment test 0.45 Dial-a-phone test 0.74 Pick-up-coins test 0.25 Spasm count 0.28 Reflex scores 0.20 Arm+leg power 0.77 2) Physical functioning: EDSS Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: No significant change 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: 8 serious AEs included fever and weakness or transaminase elevation (associated with rash, hepatomegaly or fever)

WashNo. of descriWere of the analys

Sachais, Logue, and Carey, 1977 

Inclusion: Spasticitysecondary to MS; inpatients or outpatients; age ≥ 18; no muscle relaxant, anti-hypertensive, or psychoactive drugs for at least 7 days prior to start of trial Exclusion: Evidence 

RCT (parallelgroup, doubleblind, multicenter)Duration of study treatment/followup: 5 wkProvider specialty:Neurologists 

No. of patients randomized: 166 Dropouts: 60 Completed: 106Age (mean [with range], completers): Baclofen: 43 (20-

1) Baclofen PO (n = 85). Dosing for inpatients:Wk 1: 10 mg three times per day for 3 days, 15 mg three times per day for 4 daysWk 2: 20 mg three times per dayWk 3-5: 1-2 10-mg 

1) Symptom-specific functional status/ quality-of-life outcomes: impairment of sexual performance (4-point scale); interference with daily activities (4-point scale); overall disability (6-point scale)Definition of “improvement”: NoneProportion of patients with “improvement”: NA 

Large exclud“disalltreat sQUALDescrMethodescriConceDescr
139 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

or history of renal, hepatic, or active GI disease; clinically evident joint contractures; psychiatric illness unrelated to MS; seizure disorders; drug or alcohol abuse; clinicallysignificant lab abnormalities; pregnant and nursing women and those likely to become pregnant 

Location: 16 sites in US 

64) Placebo: 43 (21-65) Baseline EDSS: NR 

tablets could be added to daily dose as needed; total dailydose not to exceed 80 mg Dosing for outpatients:Wk 1: 5 mg three times per day for 3 days, 10 mg three times per day for 4 daysWk 2: 15 mg three times per day for 3 days, 20 mg three times per day for 4 daysWk 3-5: One or two 10-mg tablets could be added to daily dose as needed; total dailydose not to exceed 80 mg 2) Placebo (n = 81) 

Other (non-improvement) outcomes:  Baclofen Placebo p-value InvestSex perf -0.13 +0.09 NS ADLs -0.16 -0.16 NS Overall disability -0.36 -0.25 NS 2) Physical functioning: MD rated flexor spasm pain, frequency (5-point scale); muscle tone (5-point scale) during flexion and extension at ankle, knee and hip; patellar reflexes, right and left (5-point scale); global severity (6-point scale) Definition of “improvement”: MS assessment Proportion of patients with “improvement”:  Baclofen Placebo p Flexor spasms 17 (42%) 6 (16%) < 0.02 Ankle clonus 12 (27%) 5 (11%) NS Other (non-improvement) outcomes:  Baclofen Placebo p-value Flex spasm 

Pain -1.1 -0.08 < 0.001Freq -0.63 -0.14 < 0.05 

Musc tone  Ank flex -0.39 -0.04 < 0.005 Ank ext -0.45 -0.21 NS 

Knee f -0.46 -0.11 < 0.01 Knee e -0.50 +0.02 < 0.001

 Hip abd -0.34 -0.21 NS  Hip ext -0.33 -0.12 NS Reflexes  L knee -0.60 +0.04 < 0.005  R knee -0.70 -0.02 < 0.001 Global -0.26 -0.19 NS 3) Cognitive functioning: Depression; euphoria, irritability (4-point scale) Definition of “improvement”: None

PatienOutcoNo. of Yes
140 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Proportion of patients with “improvement”: NA Other (non-improvement) outcomes: Mental state Baclofen Placebo p-value  Depression-0.23 -0.21 NS  Euphoria -0.13 -0.37 NS  Irritability -0.26 -0.68 NS 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: Somnolence occurred in 75% of baclofentreated and 36% of placebo-treated patients.Vertigo, weakness, urinary frequency, nausea, vomiting and constipation were other frequent AEs that were more common in baclofen- than placebo-treated patients. 

Sawa and Paty, 1979 

Inclusion: Clinicallydefinite MS or chronic myelopathy(presumed MS); otherwise well Exclusion: Use of drugs that could affect muscle tone (e.g., diazepam or steroids) in previous 7 days

RCT (crossover, double-blind, single-center) Duration of study treatment/followup: 3 wk with each treatment, 7 wk total (no run-indescribed, two 3-wk treatment periods, 1-wkwashout)Provider specialty: NR (presumably neurologists) Location: 1 site in London, Ontario, Canada

No. of patients randomized: 21Dropouts: 3 Completed: 18 Age (mean, reported only bysex): Men (n = 15): 49Women (n = 6):36 Baseline EDSS: NR 

1) Baclofen 10 mg tablets; dose graduallyincreased from 15 mg per day (three 5-mg doses) to 60 mg per day, or until intolerable side effects resulted; treatment continued for 3 wk2) Placebo for 3 wk1-wk washout between treatment periods 

1) Symptom-specific functional status/ quality-of-life outcomes [describe scale/instrument used]: Definition of “improvement”: NoneProportion of patients with “improvement”: 13/18 exhibited an objective improvement in spasticity on baclofen; none on placebo Other (non-improvement) outcomes: 2) Physical functioning: NR 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: Withdrawals 1 due to weakness (baclofen) 

No qustatistQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of YesCrossPeriod discusWashNo. of descriWere of the 
141 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Reported AEs Sedation 6 (29%) Headache 3 (14%) Mood changes 4 (19%) Dizziness 2 (10%) Weakness 3 (14%) Nausea 5 (24%) Vomiting 2 (10%) Abdominal pain 2 (10%) Malaise 2 (10%) 

analys

Schiffer, Herndon, and Rudick, 1985 

Inclusion: Confirmed MS according to Poser criteria; episodes of involuntary laughing or weeping Exclusion: None specified 

RCT (crossover, double-blind, single-center) Duration of study treatment/followup: 30 days witheach treatment; total approximately 6 wk (two30-day treatmentperiods, 1-wkrun-in; 1-wkwashout)Provider specialty: NR (neurologists andpsychiatrists) Location: 1 site in Rochester, NY

No. of patients randomized: 17Dropouts: 5 Completed: 12 (5relapsing, 7 progressive) Age (mean, with range; n = 12completers): 44.3 (22-67) Baseline EDSS: NR; 5/12 completers not ambulatory 

1) Amitriptyline; initial dose 25 mg per day,increased to 75 mg per day over first 5 days; mean dose, 57.8 mg per day, with no patient exceeding 75 mg per day; treatment continued for 30 days2) Placebo for 30days1-wk washout between treatment periods 

1) Symptom-specific functional status/ quality-of-life outcomes: NR 2) Physical functioning: NR 3) Cognitive functioning: No. episodes of pathological laughing or crying; Beck Depression Inventory; Hamilton Rating Scale for Depression Definition of “improvement”: Not reported Proportion of patients with “improvement”: 8/12 (67%) on amitriptyline 1/12 (8%) on placebo Other (non-improvement) outcomes: No significant change in BDI or HRSD 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: Drowsiness and dry mouth requiring reduction of dosage in 4/8 responders 

One-taeffectiQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of No CrossPeriod WashNo. of descriWere of the analys
142 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Schiffer andWineman, 1990 

Inclusion: DefiniteMS according to Poser criteria; definite major depressive disorder (diagnosis made in accordance with the ResearchDiagnostic Criteria and the Schedule for Affective Disorders and Schizophrenia) Exclusion: Depressive episode occurred during period of acute corticosteroidadministration; current use of psychotropic drugs 

RCT (parallelgroup, doubleblind, singlecenter) Duration of study treatment/followup: 30 daysProvider specialty: NR Location: 1 site in Rochester, NY

No. of patients randomized: 32Dropouts: 4 Completed: 28 (completed at least 2 wk of 30-day protocol; mean study duration over 29 days in both groups) Age (mean, with range): Desipramine: 37.8 (22-55) Placebo: 39.1 (22-75) Baseline EDSS (mean ± SD): Desipramine: 4.4 ± 2.1 Placebo: 4.8 ± 2.4

1) Desipramine + psychotherapy (n = 14); desipramine PO 25 mg; dose raised at 2-day intervals over first 7 days to 6 capsules per day (3 twice per day) or to maximum dose permitted by side effects; serum levels checked and dose adjustments made during 2nd week; 

psychotherapy administered in weekly45-min sessions;treatment continued for total of 30 days 2) Placebo + psychotherapy (as above) for 30 days(n = 14) 

1) Symptom-specific functional status/ quality-of-life outcomes: NR 2) Physical functioning: NR 3) Cognitive functioning (BDI, HRSD): Definition of “improvement”: Blind clinical judgment of “sufficient improvement in depressive features so as to permit a definite improvement in psychosocial function” Proportion of patients with “improvement”: 11/13 desipramine6/14 placebo p = 0.05, Fisher’s exact test Other (non-improvement) outcomes: BDI Baseline End Desipramine 18.4± 5.9 11.4± 8.0 

Placebo 18.6± 8.6 15.5± 11.3 

p = 0.16 HRSD Baseline End Desipramine 28.3± 5.8 12.7± 5.8 

Placebo 24.9± 8.6 20.1± 13.6 

p = 0.02 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: 12/14 desipramine patients reported AEs; commonly postural hypotension, dry mouth (n = 5), constipation 7/14 placebo patients reported AEs; drymouth (n = 5)

QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of No 
143 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Schmidt, Lee, and Spehlmann, 1975 and Schmidt, Lee, and Spehlmann, 1976 

Inclusion: MS; moderate or severe spasticity clearlyinterfering with physical function, but relatively less ataxia or weakness; condition stable for ≥ 6 mo; no ACTH or corticosteroids inprevious 6 mo; nomuscle relaxants or sedatives in previous 2 wkExclusion: Severe dementia, ataxia, or tremor 

RCT (crossover, double-blind, single-center) Duration of study treatment/followup: 4 wk with each treatment, 12 wk total (2-wkrun-in, two 4-wktreatment periods, 2-wkwashout)Provider specialty:Neurologists Location: 1 site in Evanston, IL 

No. of patients randomized: 46Dropouts: 4 Completed: 42 Age: NR Baseline DSS: Mean, 5.5 

1) Dantrolene sodium PO; dose graduallyincreased according to a fixed schedule in three increments over a 2-wk period (lowdose); this process then continued over another 2-wk period (high dose); usual doses at end of lowand high-dose titrations were 25 mg and 75 mg four times per day, respectively(reductions permitted for side effects)2) Diazepam PO; gradually increased over two 2-wk periods, as above; usual doses at end of low- and high-dose titrations were 2 mg and 5 mg four times per day, respectively(reductions permitted for side effects)2-wk washout between treatment periods 

1) Symptom-specific functional status/ quality-of-life outcomes: NR 2) Physical functioning: Spasticity, deltoid strength, hip flexor strength, station stability,hand coordination, hand speed, foot speed, stretch reflexes, clonus, and walking speed. Score calculations for each function bysumming individual values from R and L sides and multiple trials. Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: 

Lo DS Hi DS Lo DZ Hi DZ 

Spasticity 10.0 9.54 9.40 9.14 Deltoid str 48.5* 47.4# 49.6 50.2 Hip flex 120 * 122 156 127 Hand coord 145 147 141 134* Stability 43.2 45.9* 39.1 34.1 Hand speed 238 250 239 227 Foot speed 242 240 233 226 Reflexes 20.5* 19.4* 22.5 22.1 Clonus 3.77 3.15 3.50 3.41 Walk speed 11.3 10.6 13.8 17.1 *P < 0.05 compared to corresponding dose of comparator drug #p < 0.10 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 

5) Generic quality-of-life outcomes: NR 6) Adverse events:  Dantrolene Diazepam p Impaired gait 52% 75% NS Drowsiness 31% 67% NS Imbalance 17% 36% NS 

MultipcorrecsignifiQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of No CrossPeriod discusWashNo. of descriWere of the analys
144 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Incoordination 10% 29% NS At least 1 of 4 withdrawals was due to AEs 

Smith, Birnbaum, Carter, et al., 1994 

Inclusion: Stablespasticity secondaryto MS; spasticitysevere enough tocause significant discomfort of functional impairment and to produce score ≥ 2 on AshworthScale for muscle tone or ≥ 2 for muscle 

spasm type and frequency in most severely affected muscle group; age 18-70 Exclusion: Use of any other muscle relaxant or drugs with muscle-relaxant properties; current or recent (within 3 mo) acute MS relapse; fibrous contractures 

RCT (parallelgroup, doubleblind, multicenter)Duration of study treatment/followup: 16 wk total (2-wk run-in, 3-wkdose titration, 9 wk at plateau dose, 1-wk dose tapering, followed by post-treatmentevaluation) Provider specialty:Neurologists Location: 14 sites in US 

No. of patients randomized: 257 Dropouts: 98 Completed: 159 (220 analyzable)Age (mean ± SD; n = 220 analyzable): Tizanidine: 44.5 ±

9.4 Placebo: 46.1 ±

9.6 Baseline EDSS: NR 

1) Tizanidine PO, dose titrated over 3 wkfrom 2 mg/day tomaximum of 36 mg/day (12 mg three times daily); optimal dose continued through plateau phase (9 wk); dose thentapered over 1 wk and discontinued (n = 111)2) Placebo (n = 109) 

1) Symptom-specific functional status/ quality-of-life outcomes: AshworthDefinition of “improvement”: Decrease in total Ashworth Score Proportion of patients with “improvement”: Tizanidine /111 (58%) Placebo /109 (60%) P = 0.83 Other (non-improvement) outcomes: Ashworth adj. mean change (± SD) Tizanidine -2.03 ± 7.22 Placebo -2.73 ± 7.17 P = 0.46 

Spasms & clonus response ratio (% change): Tizanidine -0.44± 0.45 -61.1± 118 

Placebo -0.26± 0.44 -41.0± 102 

 P = 0.028 p = NS 2) Physical functioning: NR 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: 101 (91%) tizanidine 66 (61%) placebo Dry mouth, asthenia, somnolence, dizziness, increased SGOT/AST Serious AE – hepatitis (n = 1), hallucinations (n = 1) Discontinuations:

36 patinadvepatienQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
145 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

14/111 (13%) tizanidine 6/109 (6%) placebo 

Smolenski, Muff, and SmolenskiKautz, 1981 

Inclusion: MS; hospitalized; stable spasticity for ≥ 2 mo Exclusion: History orevidence of cardiac, renal, or hepatic disease; severe hypertension; epilepsy; chronic alcoholism; diabetes; overt psychopathology

RCT (parallelgroup, doubleblind, singlecenter) Duration of study treatment/followup: 6 wkProvider specialty: NR (presumably neurologists) Location: 1 site in Bern, Switzerland 

No. of patients randomized: 21Dropouts: 0 Completed: 21 Age (mean ± SD):Tizanidine: 53 ±11 Baclofen: 55 ± 10

Baseline EDSS: NR 

1) Tizanidine PO 4 mg capsules; dose initiated at 2 capsules per day and graduallyincreased during first few weeks to optimal level (usually between 3 and 6 capsules per day in 3 divided doses); treatmentcontinued for 6 wk (n = 11) 2) Baclofen PO 10 mg capsules; dose initiated at 2 capsules per day and graduallyincreased during first few weeks to optimal level (usually between 3 and 6 capsules per day in 3 divided doses); treatmentcontinued for 6 wk (n = 10) 

1) Symptom-specific functional status/ quality-of-life outcomes: Muscle strength, Ashworth, spasmsDefinition of “improvement”: Not described Proportion of patients with “improvement”: Ashworth (muscle tone) Reported by muscle group  Tizanidine Baclofen Left leg 8/11 9/10 Right leg 6/11 8/10 Left foot 8/11 8/10 Right foot 8/10 8/10 Spasms (reported by muscle group):  Tizanidine Baclofen Flex left leg 6/8 4/7 Flex right leg 5/8 6/8 Ext left leg 7/9 6/8 Ext right leg 7/9 8/9 Abd left leg 4/7 5/8 Abd right leg 4/7 7/9 Other (non-improvement) outcomes: Overall spastic state, spasms and clonus were similarly improved with both medications 2) Physical functioning: NR 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: Tizanidine (tiredness, weakness, dry mouth, 

ataxia) 

MultipQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
146 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Baclofen (weakness, dry mouth, nausea, pyrosis)No withdrawals due to AEs 

Snow, Tsui, Bhatt, et al., 1990 

Inclusion: Stable,chronic MS; chair- or bed-bound (EDSS 8.0-9.5); resident at one of two long-stayinstitutions; spastic contraction of adductor muscles that interfered withsitting, positioning in bed, cleaning, or urethral catheterization; not currently taking antispastic medication (most unresponsive in past) Exclusion: None specified 

RCT (crossover, double-blind, twocenter) Duration of study treatment/followup: Single injections given for each treatment, with follow up at 2 and 6 wk; 3 mobetween two treatment periods/injectionsProvider specialty: NR (presumably neurologists) Location: 2 sites in Vancouver, British Columbia, Canada 

No. of patients randomized: 10Dropouts: 1 Completed: 9 Age (mean, with range): 40.2 (23-61) Baseline EDSS: 8.0 to 9.5 

1) Botulinum-A toxin, single IM injection of 400 mouse units (160 ng) 2) Placebo injection 3 mo betweeninjections 

1) Symptom-specific functional status/ quality-of-life outcomes: Spasticity score = Ashworth (muscle tone)+spasm frequency;Hygiene score. Definition of “improvement”: None defined Proportion of patients with “improvement”: Other (non-improvement) outcomes: Spasticity score @ 6 wkBotulinum 7.9± 4.9 4.7± 4.3 

Placebo 6.8± 5.3 7.1 ± 4.8 

p-value 0.009 Hygiene score @ 6 wk better for botulinum than placebo (p = 0.02) 2) Physical functioning: NR 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: NR 

Small patienQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of 

YesCrossPeriod WashNo. of descriWere of the analys

Solari, Filippini, Gasco, et al., 1999 

Inclusion: Clinicallydefinite or laboratorysupported MS; EDSS 3.0-6.5; age 18-65Exclusion: 1 or more exacerbations in preceding 3 mo; cognitive impairment likely to interfere with 

RCT (parallelgroup, singleblind [evaluating physician only], single-center) Duration of study treatment/followup: Inpatient program lasted 3 

No. of patients randomized: 50 (11 relapsingremitting, 8 primaryprogressive, 31 secondaryprogressive) Dropouts: 5 

1) Inpatient physical rehabilitation program (n = 27); twice dailyexercise periods of 45 min each for 3 consecutive wk; for patients with EDSS ≤4.5, main goals were normalization of postural control, 

1) Symptom-specific functional status/ quality-of-life outcomes: NR 2) Physical functioning: EDSS; Functional Independence Measure (FIM) motor domainDefinition of “improvement”: EDSS – 1-step improvement FIM motor – 2- or more step improvement 

QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of 
147 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

study adherence (Mini-Mental State Examination score≤ 23.8, after adjustment for age and education); history of cardiovascular, respiratory,orthopedic, psychiatric, or other medical conditions precluding participation; pregnancy; treatment with immunosuppressants, interferons, copolymers, 4-aminopyridine, orexperimental drugs in previous 6 mo; rehabilitation therapyin previous 3 mo 

wk; patients followed for total of 15 wkProvider specialty:Neurologists andphysiotherapists Location: 1 site in Milan, Italy

Completed: 45 Age (mean ± SD):Rehab: 44.6 ±10.2 Control: 44.9 ±10.6 Baseline EDSS (median, with range): Rehab: 5.5 (3.0-6.5) Control: 5.5 (3.5-7.0) 

facilitation of normal gait pattern, increasing range of movement, and maximizing muscle power and endurance; for those with EDSS > 4.5,program also included instruction in use of mobility aids and orthoses and refinement of compensatorystrategies. Patients given home exercise program at conclusion of inpatient program. 2) Home exerciseprogram (control)(n = 23) 

Proportion of patients with “improvement”: EDSS 1/27 study group; 0/23 control group FIM motor Intervention Control 3 weeks 13/27 (48%) 2/23 (9%) (p = 0.994) 9 weeks 12/27 (44%) 1/23 (4%) (p = 0.001) Other (non-improvement) outcomes: 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: SF-36 Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: SF-36 component Intervention Control p 3wk  Physical 3.8± 6.7 3.3± 8.4 0.7 

 Mental 5.2± 7.0 -0.77± 7.3 0.008 

9 wk Physical 3.7± 10 1.6± 12 

 Mental 4.8± 9.9 -5.3± 15 

15 wk Physical 3.2± 6.5 0.26± 7.9 

 Mental 2.1± 9.7 -1.8± 7.8 

6) Adverse events: NR 

Yes

Stien, Nordal, Oftedal, et al., 1987 

Inclusion: DefiniteMS (McAlpine 1972); resident at one ofseveral nursing homes for neurological patients; in stable phase of the 

RCT (parallelgroup, doubleblind, multicenter)Duration of study treatment/followup: 6 wk

No. of patients randomized: 40Dropouts: 2 Completed: 38 

1) Tizanidine 4 mg capsules (n = 19); dose graduallyincreased over first 2 wk to maximum of 5 capsules per day (20 mg, given in 3 divided 

1) Symptom-specific functional status/ quality-of-life outcomes: Functional disability (Pedersen)Definition of “improvement”: NoneProportion of patients with “improvement”: 

Study differeQUALDescrMethodescri
148 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

disease for ≥ 3 mo

Exclusion: Mental diseases; overt signs of dementia 

Provider specialty:Neurologists Location: Multiple sites (number NR) in Oslo, Norway

Age (median, withrange; n = 38completers): Tizanidine: 50 (29-70 Baclofen: 45 (26-66) Baseline EDSS: NR 

doses); during last 4 wk, daily dose carefully adjusted for each patient, weighing anti-spastic effect vs. side effects; mean daily dose, 23 mg; range, 4-36 mg 2) Baclofen 10 mg capsules (n = 21); dose graduallyincreased over first 2 wk to maximum of 5 capsules per day (50 mg, given in 3 divided doses); during last 4 wk, daily dose carefully adjusted for each patient, weighing anti-spastic effect vs. side effects; mean daily dose, 59 mg; range, 20-90 mg

NA Other (non-improvement) outcomes: Neither tizanidine nor baclofen induced significant changes in functional disability(Pedersen) [data not shown] 2) Physical functioning: Tendon reflexes; muscle tone (Ashworth scale); provoked or spontaneous spasm activity; muscle strength in extremities; Kurtzke’s scale Definition of “improvement”: Not described Proportion of patients with “improvement”:  Tizanidine Baclofen p-value Clonus 7/18 (39%) 9/20 (45%) NS Musc tone 13/18 (72%) 13/20 (65%) NS Spasms 12/18 (67%) 13/20 (65%) NS Strength 2/18 (11%) 2/20 (10%) NS Other (non-improvement) outcomes: Neither tizanidine nor baclofen induced significant changes in neurological disability(Kurtzke’s scale) [data not shown].3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: AEs were “mild” and dose-dependent Tizanidine n = 6 (tiredness, weakness, sleepiness, dry mouth) Baclofen n = 5 (weakness, tiredness) Withdrawals due to AE: tizanidine (n = 1) subjective stiffness; baclofen (n = 1) gastroenteritis 

ConceDescrPatienInvestOutcoNo. of Yes
149 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Stuifbergen, Becker, Blozis, et al., 2003 

Inclusion: Physiciandiagnosed MS for at least 6 mo; female sex; age 20-70 Exclusion: Pregnancy;concurrent medical conditions for which changes in exercise and diet would becontraindicated 

RCT (parallelgroup, openlabel, multicenter)Duration of study treatment/followup: Active treatment lasted 5 mo; patients followed up for total of 8 mo Provider specialty: Clinical nurse specialist and woman with MS (intervention facilitators), dietician, fitness instructor, nurse practitioner associated with awoman’s wellness center, and a counselor Location: Outpatients recruited from two large metropolitan areas 

No. of patients randomized: 142 Dropouts: 29 failed to provide minimal data needed to beincluded in analysis Completed: 113Age: Mean ± SD, 45.8 ± 10.1; range, 

21-70 Baseline EDSS: NR 

1) Wellness intervention (n = 56); two phases – a) an educational and skillbuilding lifestyle change program (8 sessions over 8 wkthat presented information, guided participants in selfassessment of behaviors, resources, and barriers, andsupported specific strategies aimed at building self-efficacyfor health behaviors; b) supportive telephone follow-up (biweekly calls for 3 mo) 2) Usual care (n = 57)

1) Symptom-specific functional status/ quality-of-life outcomes: NR 2) Physical functioning: NR 3) Cognitive functioning [describe scale/ instrument used]:Definition of “improvement”: Proportion of patients with “improvement”: Other (non-improvement) outcomes: Self-rate [results?] 4) Work or employment outcomes: Proportion employed Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: By month 8, women in the intervention group were more likely to be employed than women in the control group (p < 0.05) 5) Generic quality-of-life outcomes: SelfRated Abilities Scale (measure of selfefficacy); Barriers Scale; Personal Resources Questionnaire (measure of social support); Health Promoting Lifestyle ProfileII (HPLP-II); SF-36 Definition of “improvement”: Proportion of patients with “improvement”: Other (non-improvement) outcomes:  Control Interv p-value Self-efficacy 84± 19 94± 14 < 0.01 

Barriers 32± 8.4 31± 7.5 NS 

PRQ 143± 22 145± 22 NS 

Authowas a reflect represbecauSocietintereswomeQUALDescrMethodescriConceDescrPatienInvestOutcoNo. of No 
150 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

HPLP-II Total 147± 23 158± 22 < 0.01 

SF-36 scales 

PF 40±31 51± 29 NS 

RP 41± 42 47± 44 NS 

BP 64± 28 67± 25 < 0.05 

 GH 60± 24 57± 25 NS 

VT 41± 22 44± 22 NS 

SF 70± 24 70± 26 NS 

RE 66± 42 76± 36 NS 

 MH 71± 20 75± 15 < 0.05 

6) Adverse events: NR 

UnitedKingdom Tizanidine Trial Group, 1994 

Inclusion: Spasticitysecondary to clinically definite, laboratory-supported, or probable MS; stable disease during previous 1 mo; noconcomitant neurological illness likely to alter muscle tone; age 18-75 Exclusion: Use of immunosuppressant drugs during previous 1 mo or corticosteroids during previous 3 mo; uncontrolled hypertension (SBP > 180 mmHg, DBP > 120 mmHg) or hypotension (SBP < 90 mmHg, DBP < 60 mmHg); systemicdisease; abnormalities on routine clinical lab tests; active 

RCT (parallelgroup, doubleblind, multicenter)Duration of study treatment/followup: 12 wktreatment (3 wkdose titration, followed by 9 wkat maximum tolerated dose),plus 1-wktapering period; last follow up visit at 14 wkProvider specialty: NR Location: 16 sites throughout the UK 

No. of patients randomized: 187 (102 clinicallydefinite MS, 58 laboratorysupported, 27 probable) Completed: 155 included in completers’ analysis; 136 completed entire studyAge (mean ± SD):47 ± 9 

Baseline EDSS: NR 

1) Tizanidine PO (n = 94), titrated over a 3-wk period between 2 and 36 mg daily to the maximum tolerated dose; this dose then maintained for 9 more weeks; dose thentapered over 1-wk period 

Dropouts: 32 excluded from completers’ analysis for morethan minor protocol violations; 51 withdrewprematurely

2) Placebo (n = 93) (with dose titration, as above) 

1) Symptom-specific functional status/ quality-of-life outcomes: Intermediate motor skills (turning, lying, and transfer); upper extremity functions; ADL (items from Kurtzke Incapacity Status Scale); impact of spasticityon quality of life (5-point scale) Definition of “improvement”: Not described Proportion of patients with “improvement”:  Tizan Pbop-value Intermed fn 20% 10% NS Upper limb fn 6% 5% NS Impact on PT 40% 21% NS Nursing care 22% 4% 0.09 Other (non-improvement) outcomes: 2) Physical functioning: Muscle tone (Ashworth scale) Definition of “improvement”: Decrease by at least 1 point on Ashworth Proportion of patients with “improvement”: Tizanidine 67/94 (71%) Placebo 46/93 (50%) Other (non-improvement) outcomes: 

Used 

QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
151 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

bedsores, infection, or contractures 

ITT analysis Muscle tone EDSS  Baseline Week 12 change Tizanidine 1.85± 9.4 14.6± 10.1 0.1 

Placebo 16.8± 11.1 15.3± 10 0 

P-value < 0.004 NS Strength Baseline Week 12 change Tizanidine 71± 16 73± 16 +4 

Placebo 72± 14 74± 13 +3 

P-value NSSpasms Baseline Week 12 change (freq)Tizanidine 6.3± 6.6 5.5± 7.0 -13 

Placebo 5.2± 5.8 4.4± 6.0 -15 

P-value NSDTRs Baseline Week 12 change Tizanidine 18± 7.1 16± 7.1 -9 

Placebo 17± 6.5 17± 6.8 -4 

P-value NSTimed walk Baseline Week 12 change (sec for 8m) Tizanidine 20± 20 21± 34 +4 

Placebo 28± 31 25± 26 -10 

P-value NS3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events:  Tizanidine Placebo Total no. AEs 669 261 No. pts with AEs 82 (87%) 57 (61%) Dropouts due to AEs 12 (13%) 5 (5%)Dry mouth; drowsiness, tiredness 
152 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Vahtera, Haaranen, ViramoKoskela, et al., 1997 

Inclusion: Clinicallydefinite MS by Poser criteria; in stable phase of disease; EDSS ≤ 6.5; current 

symptoms of lower urinary tract disorder; post-void residual volume ≤ 100 mL on 

ultrasound Exclusion: Pregnancy; cardiac pacemaker or any metallic implant near the treated area; history of pelvic malignancy;dementia; any nervous system disorder other than MS 

RCT (parallelgroup, openlabel, singlecenter) Duration of study treatment/followup: 6.5 mo Provider specialty: NR Location: 1 site in Masku, Finland

No. of patients randomized: 80Dropouts: 0 lost to follow up; in active group, 25/40 exercising regularly at 6 mo, 12/40 exercising irregularly, and 3/40 not exercising at all Completed: 80 (see immediately above on compliance) Age (mean, with range): Active: 43.4 (25-57) Control: 44.2 (26-68) Baseline EDSS (mean, with range): Active: 4.4 (1.0-6.5) Control: 4.3 (1-6.5) 

1) Pelvic floor rehabilitation (n = 40); consciousness ofaction of pelvic floor muscles stimulated using electrical stimulation at 6 sessions over 2 wk; at final session, patients taught by biofeedback to exercise pelvic floor muscles and advised to continue theseexercises 3-5 times per week for at least 6 mo 2) No-treatment control (n = 40) 

1) Symptom-specific functional status/ quality-of-life outcomes [describe scale/instrument used]: Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: Incontinence and nocturia at week 3 and months 2 and 6 were significantly less frequent in treatment than control group (p < 0.05) No differences in frequency of acute UTIs Urinary symptom related handicap at month 6 lower for treatment than control (traveling, social shame, need of diapers) (p < 0.05) 2) Physical functioning: NR 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: None reported

Uncermultip

tests; QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes

Valiquette, Herbert, and MeadeD’Alisera, 1996 

Inclusion: Clinicallydefinite or laboratorysupported definite MS by Poser criteria; relapsing-remitting or progressive forms of disease; MS in remission for at least 3 mo; 2 or more 

RCT (crossover, double-blind, single-center) Duration of study treatment/followup: 2 wk with each treatment; 6 wk total (2-wk 

No. of patients randomized: 17 (5 relapsingremitting, 4 relapsingprogressive, 8 chronic progressive) 

1) Desmopressin administered as a nasal spray, one 10-μg dose per day at bedtime for 2 wk2) Placebo nasalspray for 2 wk

1) Symptom-specific functional status/ quality-of-life outcomes: Proportion of nights with nocturia; proportion of nights with incontinence; number of episodes of nocturia per night; maximum uninterruptedsleep hours Definition of “improvement”: None

QUALDescrMethodescriConceDescrPatienInvestOutco
153 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

episodes of nocturia in typical night or (for patients with limited mobility) any numberof micturitions or episodes of incontinence per night; age 18-70Exclusion: Evidence or history ofhypertension, thrombotic events, or cardiovascular,thyroid, or renal disease; use of pulsed steroid therapy or short course of immunosuppressive therapyin previous 3 mo 

run-in, two 2-wktreatment periods, no washout)Provider specialty: NR (neurologists?) Location: 1 site in West Haverstraw, NY

Dropouts: 6 Completed: 11 Age (mean, with range): 48.9 (26-70) Baseline EDSS (mean, with range): 6.7 (2.5-8.5) 

No washout between treatment periods 

Proportion of patients with “improvement”: NA Other (non-improvement) outcomes:  Mean diff p-value Nocturia, mean* -0.74 < 0.01 Incontinence -0.36 0.08 Nocturia, freq -2.2 < 0.01 Max uninterrupted 4.28 < 0.01 Sleep (hrs)* *Carry-over effect observed, only period 1 data analyzed. 2) Physical functioning: NR 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: Hyponatremia requiring discontinuation (n = 4) 

No. of No CrossPeriod WashNo. of descriWere of the analys

Wassem and Dudley,2003 

Inclusion: MS Exclusion: None specified 

RCT (parallelgroup, openlabel, singlecenter) Duration of study treatment/followup: Active treatment lasted 4 wk; patients followed up for total of 4 yr Provider specialty:Advance practice nurses 

No. of patients randomized: 27Dropouts: 11 Completed: 16 Age: Mean, 44; range, 18-54 Baseline EDSS: Mean, 3.36; range, 0-9 

1) Intensive outpatient intervention (n = NR); four weekly 2-hr group sessions; included education about MS, instruction in relaxation techniques, and discussion ofdietary concerns, symptom management, psychosocial issues, memory and cognitive problems, etc. 2) Usual care (n = NR) 

1) Symptom-specific functional status/ quality-of-life outcomes: Fatigue, sleep and pain severity (VAS) Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: Fatigue levels were lower for intervention than control at most data collection points (p = 0.09) Sleep disturbance scores were significantlybetter for intervention compared to control (p = 0.07) Pain levels were not significantly different for intervention compared to control (P = NS) 

Study convetesting QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
154 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Location: 1 site in Utah 

Sum of symptom severity scores improved 

for intervention compared to control (p = 0.03) 2) Physical functioning: Modified DSS Definition of “improvement”: Proportion of patients with “improvement”: Other (non-improvement) outcomes: 3) Cognitive functioning: Self-Efficacy for Adjustment Behaviors (SEAB) scale (26 behaviors x 4-point responses ranging from 0 [no confidence in being able to perform the behavior] to 4 [total confidence ...]); 

Psychosocial Adjustment to Illness ScaleSelf-Report (PAIS-SR); Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: SEAB scores were not significantly differentfor intervention compared to control (p = 0.55) PAIS-SR scores were not significantlydifferent for intervention compared to control (p = 0.72) 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: NR 
155 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Weinshenker, Penman, Bass, et al., 1992 

Inclusion: Clinicallydefinite MS; severe fatigue for ≥ 3 mo; age 18-65 Exclusion: Pregnant or not practicing birth control; epilepsy;psychiatric disease; drug abuse; major medical illness 

RCT (crossover, double-blind, twocenter) Duration of study treatment/followup: 5 wk with each treatment, 12 wk total (two5-wk treatment periods, 2-wkwashout)Provider specialty: NR Location: 2 sites in Ontario, Canada 

No. of patients randomized: 46Dropouts: 5 Completed: 41 Age (mean ± SD):42.6 ± 10.6 

Baseline EDSS (mean ± SD): 3.6 ± 2.0 

1) Pemoline PO in 18.75-mg capsules; dose graduallyincreased during first week from 1 capsule (18.75 mg) to maximum of 4 capsules (75 mg) per day; maintenance dose then continued for additional 4 wk 2) Placebo, with dose adjustments as above, for total of 5 wk2-wk washout between treatment periods 

1) Symptom-specific functional status/ quality-of-life outcomes: NR 2) Physical functioning: EDSS; fatigue (50-mm VAS); relief of fatigue (4-point scale) Definition of “improvement”: Excellent/good versus fair/poor rating on relief of fatigue Proportion of patients with “improvement”: Trend toward better relief of fatigue on pemoline than placebo (p = 0.06) Other (non-improvement) outcomes: All patients remained within 1.0 point on the EDSS score during the course of the study(except for patients who were withdrawn due to exacerbations. No significant difference in fatigue (VAS) between pemoline and placebo. 3) Cognitive functioning: Modified Beck self-rating depression inventoryDefinition of “improvement”: Proportion of patients with “improvement”: Other (non-improvement) outcomes: 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: AEs experienced by > 25% while receiving pemoline: Irritability (n = 15); insomnia (12), anorexia (17), and nausea (13). 

QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes

CrossPeriod WashNo. of descriWere of the analys
156 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

Wiles, Newcombe, Fuller, et al., 2001 

Inclusion: Definite or probable MS; difficulty walking, but able to walk 5 meters with or without a mechanical aid; not in a current relapse; free of other major general medical or surgical disorders and pregnancy; age ≥ 18 Exclusion: None specified 

RCT (crossover, single-blind [assessors only], single-center) Duration of study treatment/followup: 8 wk with each treatment, 48 wk total (three8-wk treatment periods, two 8-wkwashouts, one 8-wk follow-upperiod) Provider specialty:Neurophysiotherapists Location: 1 site in Cardiff, UK 

No. of patients randomized: 42Dropouts: 2 Completed: 40 Age: Mean, 47.2;range, 28.2-68.8Baseline EDSS: Mean, 6.0 

1) Home physiotherapy; two 45-min sessions per wk for 8 wk; individualizedproblem-solving approach, focusing on specific functional activities 2) Hospital outpatient physiotherapy, asabove, but focusing on specific facilitationtechniques 3) No physiotherapyfor 8 wk8-wk washout period between treatment periods 

1) Symptom-specific functional status/ quality-of-life outcomes: Rivermead mobilityindex; balance time; Walk A; 9-hole peg Definition of “improvement”: NoneProportion of patients with “improvement”: NA Other (non-improvement) outcomes: 

 Treatment

 None Hosp Home Mobil 9.1 ± 3.9 10.5 ± 3.5 10.6 ± 2.9 

Index p < 0.001 p < 0.001 Bal 15.0 ± 13.8 19.9 ± 13.2 19.7 ± 13.2 

time p = 0.004 p = 0.001 Walk 148 ± 129 138 ± 108 138 ± 110 

A p = 0.003 p = 0.002 9-hole 207 ± 85 190 ± 69 194 ± 70 

peg p = 0.014 p = 0.076 Global 46 ± 11 44 ± 11 44 ± 14 

Mobility p < 0.001 p < 0.001 2) Physical functioning: NR 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: NR 

QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of No CrossPeriod WashNo. of descriWere of the analys

Zajicek, Fox, Sanders, etal., 2003 

Inclusion: Clinicallydefinite or laboratorysupported MS; stable disease for previous 6 mo (in the opinion of the treating physician); problematic spasticity(Ashworth score ≥ 2 

RCT (parallelgroup, doubleblind, multicenter)Duration of study treatment/followup: Treatment lasted 14 wk; patients followed

No. of patients randomized: 657 No. treated and included in ITT analysis: 630 (452 secondaryprogressive, 145 primary

1) Cannabis extract containing delta-9- tetrahydrocannabinol (THC) and cannabidiol PO (n = 211); each capsule contained 2.5 mg of delta-9-THCequivalent, 1.25 mg of cannabidiol, and < 5% 

1) Symptom-specific functional status/ quality-of-life outcomes: NR 2) Physical functioning: Ashworth scale – overall (upper and lower extremity); subjective spasticity (improved, same, deteriorated); mobility (10-m walk time)Definition of “improvement”: None provided 

“There among groupexpecshowifor a seffect, on spa
157 

Evidence Table 3b. Symptom management and improvement (continued)Study Selected

Inclusion/ Exclusion Criteria

Study Design Patients Interventions Outcomes/Results Com

in two or more lower limb muscle groups); age 18-64 Exclusion: Ischemic heart disease; active sources of infection; use of medication that could affect spasticity; not able to avoid driving while on study; fixed-tendon contractures; severe cognitive impairment; history of psychotic illness; other major illness; pregnancy; any previous use of delta-9-tetrahydrocannabinol; use of cannabis in previous 30 days

for an additional (15th) wk

Provider specialty: NR (presumably neurologists) Location: 33 neurology and rehabilitation centers in the UK

progressive, 33 relapsing-remitting)Dropouts (from ITT population): 19 Completed: 611Age (mean ± SD):Cannabis: 50.5 ±

7.6 Delta-9-THC: 50.2 ± 8.2 Placebo: 50.9 ±

7.6 Baseline EDSS: 0-3.5: 3 4-5.5: 23 6-6.5: 299 7-9: 299 NR: 6 

other cannabinoids; initiated at one capsule (2.5 mg delta9-THC equivalent) twice daily, thenincreased by onecapsule twice dailyevery wk, as tolerated, during 5-wk dose titration period; maximum daily dose 25 mg (10 capsules) 2) Synthetic delta-9- tetrahydrocannabinol (THC) PO (n = 206); initiated at one capsule (2.5 mg) twice daily, then increased by one capsule twice daily every wk, astolerated, during 5-wkdose titration period; maximum daily dose 25 mg (10 capsules) 3) Placebo, with dose titration as above (n = 213) 

Proportion of patients with “improvement”: Cannabis extract 61% Delta-9-THC 60% Placebo 46% p = 0.003 Other (non-improvement) outcomes: Ashworth score: No treatment effect overall (p = 0.4); estimated difference in mean reduction in total Ashworth score:Cannabis extract 0.32 (-1.04 to 1.67) Delta-9-THC 0.94 (-0.44 to 2.31) Reduction in 10-m walk time from baseline to visit 7 Cannabis extract 4% (0 to 10%) Delta-9-THC 12% (6 to 21%) Placebo 4% (-2 to 7%) P = 0.015 3) Cognitive functioning: NR 4) Work or employment outcomes: NR 5) Generic quality-of-life outcomes: NR 6) Adverse events: NR 

QUALDescrMethodescriConceDescrPatienInvestOutcoNo. of Yes
E

vidence Table 4. Association of clinical findings 

with 

w

ork abilit

y

158 

Stu

d

y

S

electe

d

Inclusion/ Exclusion Criteria 

Study Design Patients Findings

Considered

R

esults C

o

m

Beatty,Blanco, Wilbanks, etal., 1995 

Inclusion: Clinicallydefinite MS byPoser criteria; adequate vision to read a ne

wspaper; 

judged able to complete a 2.5- to 3-hr battery of neuropsychological tests; age < 65 Exclusion: History of alcohol or drug abuse; serious head injury; learning disability; recent or complicated heart attack; uncontrolled hypertension; metabolic disease; CNS disease other than MS; major psychiatric illness; history ofdepression (if major episode preceded onset of MS-like sy

mptoms); MS 

relapse in previous 1 mo 

Cross-sectional studyLocation/recruitment: Patients recruited from practices of collaborating neurologists (n = 50) and from supportgroups (n = 52) in the areas of Tulsa and Oklahoma City, OK Data collection: Work status self-reported bystudy participants; not clear ho

w clinical data 

(medication use, time since diagnosis, etc.) collected; testingdescribed belo

w

performed in a single 2.5- to 3-hr session, usually (94% of the time) conducted in patient’s home; following tests administered: 1) Beck Depression Inventory2) Brief test of visual acuity3) Ambulation Index 4) Handedness inventory5) Neuropsychological testing in 7 domains: -Verbal ability (

Shipley

Institute of Living Scale Vocabulary Test) -Attention/ 

N = 102 Age (mean ± SD):Overall: 44.2 ± 7.8(range, 29-62) Employed subjects: 39.9 ± 6.1 Retired subjects: 46.8 ±7.8 Baseline measures of physical and mental functioning: Ambulation Index (mean ± SD): Overall: 3.4 ± 2.6 Employed: 1.8 ± 1.8 Retired: 4.3 ± 2.6 Beck Depression Inventory (mean ± SD): Overall: NR Employed: 10.4 ± 7.5 

Retired: 13.4 ± 8.8

Baseline work status: Employed: 38 (33 fulltime, 3 part-time, 2 at least half-time college students; homemakers not considered to be employed) Retired: 64 (all had once worked at full-time jobs and retired prematurely) 

1) Physical: Ambulation Index Visual Acuity2) Mental: Beck Depression InventoryCognitive testing in 7 domains (see under “Study Design” for details; investigators also calculated aglobal measure of the severity of cognitive impairment = number of cognitive domains in which patient “impaired”) 3) Laboratory: None 4) Radiographic: None 5) Other: Age Years of education Age at diagnosis Time since diagnosis SexUse of symptomatic medication 

No direct measure of 

work capacity or 

abilityWork status measured through selfreport 49% of the variance in employment status was explained by walking ability,age, t

wo measures of memory, and 

one test of verbal fluency. Partial R2: 

 Ambulation Index: 0.25  Short Term Memory-Correct: 0.13 Selective Reminding Test-Delay

Recall: 0.04 

 Age (29-62 years): 0.03  Letter fluency: 0.03 

CrosrelatoutcoasseDurawas All paempstatuconsSamtrue Authabsedextemotonot bAmbcontrclericAuthcognat intQ

UA

StudbaseFolloWork wideWork fashiIf subidenta) 

wa

progb) 

wa

NA 
159 

Evidence Table 4. Association of clinical findings with work ability (continued) Study Selected

Inclusion/ Exclusion Criteria 

Study Design Patients Findings

Considered

Results Com

concentration (Digit Span from theWechsler Adult Intelligence ScaleRevised)-Information processing speed (letter fluency,category fluency, and Symbol Digit Modalities Test -Naming (15-itemversion of Boston Naming Test) -Visuospatial perception (Benton Line Orientation Test) -Memory (BrownPeterson Short Term Memory Test, NewMap Test, Selective Reminding Test)-Problem solving/ abstraction (Wisconsin Card Sorting Test, Shipley Institute of Living Scale Abstraction Test, and Conceptual Quotient) 

Beukelman, Kraft, and Freal, 1985 

Inclusion: MS diagnosis from at least one physician; follow-up services from either the University ofWashington MS Clinic, the Puget Sound Chapter 

Cross-sectional studyLocation/recruitment: Survey mailed to“persons diagnosed as having multiple sclerosis and residing in Western Washington [state]” Data collection: 

N = 656 returnedquestionnaires (90% response rate) Age: 1% ≤ 25 23% 25-39 39% 40-54 37% ≥ 55 Baseline measures of 

1) Physical: None 2) Mental: Selfreported expressive communication disorder 3) Laboratory: None 4) Radiographic: None 

No direct measure of work capacity or abilityWork status measured through selfreport Those with communication disorder (n = 149, 23% of total sample) wereasked whether their communication disorder interfered with employment; 3% responded positively. 

ComexclupatieMeasdisorEmponseCrosrelatoutcoasse
160 

Evidence Table 4. Association of clinical findings with work ability (continued) Study Selected

Inclusion/ Exclusion Criteria 

Study Design Patients Findings

Considered

Results Com

of the National MS Society, orthe Neurological Disease Epidemiologic Study; moderate to severesymptoms Exclusion: None specified 

8-page questionnaire requesting information on symptom characteristics and patterns, employment, daily living activities, rehabilitation needs, presence and severityof an expressive communication disorder, and use of communication augmentation equipment 

physical and mental functioning: NR Baseline work status: NR 

5) Other: None Employment patterns of 

communication-disordered group vs. total sample: 1) Full-time employment: Communication-disordered: 7%Total sample: 17% Chi-square p < 0.001 2) “Disabled employment”: Communication-disordered: 56%(“larger percentage . . . as compared to the total sample”) Total sample: NR3) Part-time employment: Communication-disordered: 3%Total sample: 4%

No dauthoand As psubjecommparty objecNo demppopufindinQUAStudbaseFolloWork wideWork fashiIf subidenta) waprogb) waNA 
161 

E

vidence Table 4. Association of clinical findings 

with 

w

ork abilit

y (continued) 

Stu

d

y

S

electe

d

Inclusion/ Exclusion Criteria 

Study Design Patients Findings

Considered

R

esults C

o

m

Canadian Burden ofIllness StudyGroup, 1998a and Canadian Burden ofIllness StudyGroup, 1998b 

Inclusion: Clinically orlaboratorysupported definite MS according to Poser criteria; age ≥ 18 

Exclusion: Treatment with interferon-β; 

pregnancy or delivery in last 3 mo; any major acute or chronic disorder in last 3 mo; other neurological illness; recent participation in a drug trial 

Cross-sectional study(cost analysis designed to estimate annual and lifetime costs of MS from the Canadian societal perspective); some data collected retrospectively for previous 3 mo Location/recruitment: Patients recruited from 14 MS outpatientclinics across Canada Data collection: Patients assessed using EDSS and SF36; other data collected from patients and their families, clinic charts, hospital charts, and sum

maries 

of medical history from other institutions; cost data from various sources 

N = 198 (62 “mild” MS [EDSS ≤ 2.5], 68

“moderate” [EDSS 3.0-6.0], 68 “severe” [EDSS ≥ 6.5]) Types of MS (incomplete data): Mild: 79% relapsingremitting Moderate: 43% relapsing-remitting, 43% secondary progressive Severe: 57% secondaryprogressive, 41% primary progressive Age (mean ± S

D): 

Mild MS: 39.8 ± 9.5 

Moderate: 45.2 ± 10.7 

Severe: 49.6 ± 12.2 Baseline measures of physical and mental functioning: See above for breakdown into EDSS categories; median EDSS scores within each category were: Mild: 2.0 Moderate: 4.5 Severe: 7.5 

Baseline work status: Full-time: 23% Part-ti

me: 12% 

Unemployed: 44% Other: 21% 

1) Physical: EDSS scores 2) Mental: None3) Laboratory: None 4) Radiographic: None 5) Other: None

No direct measure of 

work capacity or 

abilityWork status measured through selfreport 1) Current employment status byEDSS category :EDSS ≤ 2.5: 

23 (37

%) Full-time 

13 (21

%) Part-ti

me 

18 (29

%) Unemployed 

 8 (13

%) Other 

EDSS 3-6: 19 (28

%) Full-time 

 7 (10

%) Part-ti

me 

30 (44

%) Unemployed 

12 (18

%) Other 

EDSS ≥ 6.5: 

 3 (4%) Full-time 4 (6%) Part-ti

me 

39 (57

%) Unemployed 

22 (32

%) Other 

2) Employment change because of MS (self-report): 37% of those 

with EDSS ≤ 2.5 

62% of those 

with EDSS 3.0-6.0 

82% of those 

with ≥ 6.5 

3) Employment status compared to general population: 37% 

with mild M

S were employed fulltime versus 85% in age-matched 

comparator Canadian population4) Lost 

workdays in a 1-yr period

(dependent on number of people working – not very informative): EDSS ≤ 2.5: 49

CrosrelatoutcoasseSamchanEmponseAuthempho

we

have diseaanalystatuQ

UA

StudbaseFolloWork wideWork fashiIf subidenta) 

wa

progb) 

wa

NA 
162 

Evidence Table 4. Association of clinical findings with work ability (continued) Study Selected

Inclusion/ Exclusion Criteria 

Study Design Patients Findings

Considered

Results Com

EDSS 3-6: 109 EDSS ≥ 6.5: 40 

Dyck andJongbloed, 2000 and Jongbloed, 1996 

Inclusion: Women with definitive diagnosis of MS; working age (age 19-60) Exclusion: None specified 

Cross-sectional studyLocation/recruitment: Questionnaire surveyof all women with MS, age 19-60, who had attended MS clinic British Columbia, Canada Data collection: All data collected bypostal questionnaire; three different questionnaires used: 1) Women currently in paid employment (n = 252) completed Questionnaire A;2) Those who had been employed at time of diagnosis, but were no longer employed (n = 163), completed Questionnaire B;3) Those who were not employed at time of diagnosis (n = 119) completed Questionnaire C.Questionnaires A and B included questions on age, education, marital status, income, housing, transportation, use of adaptive aids, visibilityof MS, employment 

N = 534 eligible respondents (66%response rate) Age (mean): Currently employed: 39.6 Now unemployed: 43.3 Unemployed at diagnosis: NR Baseline measures of physical and mental functioning: Use of scooter: Currently employed: 5.8% Currently unemployed: 30.5% Unemployed at diagnosis: NR Use of wheelchair: Currently employed: 8% Currently unemployed: 36.6% Unemployed at diagnosis: NR Baseline work status (self-reported): Currently employed: 47% Currently unemployed: 31% Unemployed at diagnosis: 22% 

1) Physical: Use of mobility aids Visibility of MS 2) Mental: None(except self-reported barriers/helps to employment) 3) Laboratory: None 4) Radiographic: None 5) Other: Age Age at diagnosis Level of education Household income Job title at time of diagnosis Marital status Household composition Size of city of residence Home ownership Type of employment (self-employed, permanent, temporary, etc.) Place of employment Questionnaires also asked subjects (in open-ended way?) to identify factors contributing to their maintaining or leaving 

No direct measure of work capacity or abilityWork status measured through selfreport Work status (self-report): 

47% currently employed 31% no longer employed 22% never employed “Statistically significant differences in highest level of education”: Attended university (yes/no): 25.3% - currently employed 14.8% - no longer employed(statistical test and level not provided) Comparing currently employed with no longer employed in a regression model: Mobility aids used and employment status controlling for education and age in model: R2 = 0.20 

Factors contributing to maintaining employment – 44% of currentlyemployed women were limited in the kind and amount of work they could do because of MS including: NR – fatigue “most common” 16% - difficulty with standing and stairs 15% - walking 12% - writing 11% - memory/concentration 17% no longer working indicated “inability to negotiate reduced work hours” with their manager as reason for quitting work 

Samwork Empwas CrosrelatoutcoasseQualguide DiscissueVagufunctAuthinclufunctQUAStudbaseFolloWork wideWork fashiIf subidenta) waprogb) waNA 
163 

Evidence Table 4. Association of clinical findings with work ability (continued) Study Selected

Inclusion/ Exclusion Criteria 

Study Design Patients Findings

Considered

Results Com

history since diagnosis, and difficulties experienced at work. Questionnaire A asked women (in open-ended way?) to identify workrelated and social/ family factors thatallowed them to continue working;Questionnaire B asked women (in open-ended way?) to identifyfactors that contributed to their leaving employment; content of Questionnaire C not described. Study questionnaires developed on basis of in-depth interviewswith 54 women with MS in first (qualitative)phase of study

employment 

Edgley, Sullivan, and Dehoux, 1991 

Inclusion: Respondent to survey in MSCanada;currently orpreviouslyemployed; age 18-55 Exclusion: None specified 

Cross-sectional studyLocation/recruitment: Survey printed insummer 1989 issue of MS Canada, a newsletter distributed to approximately25,000 individuals across Canada (of whom approximately 20,000 have MS)Data collection: All data collected by

N = 602 eligible respondents; 562 included in multivariate analysis of covariance Age: Mean, 43 Baseline measures of physical and mental functioning: 1) Mobility status: No problems withambulation: 13% Some unsteadiness: 35% 

1) Physical: Mobility status (1-5 = no problems, some unsteadiness, assistive device required, wheelchair required for long distances, unable to walk)2) Mental: Self-perceived cognitive problems (0-4 = never, rarely,sometimes, often, 

No direct measure of work capacity or abilityWork status measured through selfreport 1) Determinants of employment status: Mobility (mean [SD]): Unemployed: 3.1 (1.2) Employed: 2.2 (1.0) p < 0.001 Results on Perceived Deficit Questionnaire (mean [SD]): Unemployed: 1.6 (0.7) 

CrosrelatoutcoasseEvalperceAll paempstatuconsSamthrouOccuBlishOccu
164 

Evidence Table 4. Association of clinical findings with work ability (continued) Study Selected

Inclusion/ Exclusion Criteria 

Study Design Patients Findings

Considered

Results Com

questionnaire survey; items included were sex, age, occupation, level of education, duration of illness, mobility status, selfperceived cognitive problems (Perceived Deficits Questionnaire), and self-perceived primaryreason for unemployment (openended question)

Assistive device required: 15% Wheelchair required for long distances: 27% Unable to walk: 10% 2) Perceived cognitive problems: Never: 0 Rarely: 23% Sometimes: 48% Often: 27% Almost always: 2% Baseline work status: Employed: 200 or 201 Unemployed: 402 or 401(discrepancy between text and Table 1)Only subjects employed at diagnosis or employed at time of study were included 

almost always; composite score obtained by summing 4 subscales of the Perceived DeficitsQuestionnaire) 3) Laboratory: None 4) Radiographic: None 5) Other: SexAge Years of education Number of people living at home Type of occupation (coded according to Blishen Socioeconomic Index for Occupations) Duration of illness Self-perceived primaryreason for unemployment (openended question)

Employed: 1.4 (0.7) p < 0.001 2) Study participants who indicated that they had quit working because of MS symptoms were asked an openended question about types of symptoms (n = 313; 78%):  Ambulation difficulties (41%)  Fatigue (39%)  Memory problems (12%)  Emotional problems (10%)  Visual difficulties (12%)  Problems with coordination (6%)  Pain (2%)  Incontinence (1%) 22% left employment for reasons unrelated to MS. Women (26%) were significantly more likely than men(11%) to cite reasons unrelated to MS as the primary cause of unemployment (chi-square = 9.3, P < 0.01). 

not pQUAStudbaseFolloWork wideWork fashiIf subidenta) waprogb) waYes/

Freal, Kraft, and Coryell, 1984 

Inclusion: Physician diagnosis of MS Exclusion: None specified 

Cross-sectional studyLocation/recruitment: Subjects recruited bythird parties, including hospitals, National MS Society chapters, a local MS association, and an epidemiological MS research studygroup (all in western Washington state) 

N = 656 completed initial questionnaire; 309 completed follow-up questionnaire on fatigue (60% response rate on follow-up questionnaire) Age: NR Baseline measures of physical and mental functioning: In follow-up population (n = 309): 

1) Physical: Fatigue 2) Mental: None3) Laboratory: None 4) Radiographic: None 5) Other: None

No direct measure of work capacity or abilityWork status measured through selfreport Responses to open-ended question about how study participants (n = 309 responding to fatigue questionnaire) had changed work or lifestyle to cope with fatigue (only work-related factors reported here): 30 (10%) quit work 

The examwith compMisswork EmponseQUAStudbaseFollo
165 

Evidence Table 4. Association of clinical findings with work ability (continued) Study Selected

Inclusion/ Exclusion Criteria 

Study Design Patients Findings

Considered

Results Com

Data collection: All data collected bysurvey questionnaires; initial questionnaire gathered data on MS symptoms experienced and whether or not these symptoms interfered with activities of dailyliving; follow-upquestionnaire on fatigue sent to all subjects identifying fatigue as a symptom; this questionnaire asked about characteristics offatigue, its frequency, environmental variables affecting fatigue, relationship of other MS disease variables to fatigue, and affect of fatigue on subjects’ lives

35% could walk without aids 32% used canes,walkers, or furniture when walking 33% used wheelchairs or were bedridden Baseline work status: NR 

10 (3%) changes in work 9 (3%) rest and work changes 6 (2%) quit work and social activities 

Work wideWork fashiIf subidenta) waprogb) waNA 

Genevie, Kallos, and Struening, 1987 

Inclusion: Member of NewYork CityChapter of the National MS Society;employed at time of MS diagnosis and not yet retired Exclusion: Incomplete data 

Cross-sectional studyLocation/recruitment: Survey questionnaires mailed to all members of the New York CityChapter of the National MS SocietyData collection: All data collected bysurvey questionnaire; 10-page instrument captured data ondemographic 

N = 333 eligible respondents Age: Median, 44Baseline measures of physical and mental functioning: NR Baseline work status: Employed: 41% (21% atjob they held when diagnosed, 20% had changed jobs) Unemployed (but not 

The following variables were examined for their relationship to job retention in correlation and stepwise multiple regression analyses. Symptom severity (16 items) was graded on a scale of 0 (“not at all severe”) to 5 (“verysevere”). Functional impairment (8 items) was measured on a scale of 1 (“can dowithout difficulty”) to 5 

No direct measure of work capacity or abilityWork status measured through selfreport 1) 31% of the variance in job retention was accounted for by demographic characteristics, symptom severity, and functional impairment. 2) 32% of the variance in job retention was accounted for by demographic characteristics, symptom severity, functional impairment, and vocational 

SSD“no” from disinmay work be drelatincensectiAll sttime QUA
166 

Evidence Table 4. Association of clinical findings with work ability (continued) Study Selected

Inclusion/ Exclusion Criteria 

Study Design Patients Findings

Considered

Results Com

characteristics, symptom severity (at time of diagnosis and present), functional impairment, vocational improvement, jobchange, sources of income, and medical, psychological, and vocational needs of patient 

retired): 48% (36% voluntarily, 12% dismissed because of MS) Subjects required to have been employed at time of MS diagnosis and not yet retired 

(“cannot do at all”). 1) Physical: Numbness/tingling Speech Vision Pain Fatigue Functional impairment Incontinence Ambulation 2) Mental: Affective labilityCognition Motor disturbance 3) Laboratory: None 4) Radiographic: None 5) Other: SexAge Family income Education Time since diagnosis Vocational improvement Job change Sources of income (savings/investments, SSDI, SSI, spouse) 

activity. 3) 49% of the variance in job retention was accounted for by demographic characteristics, symptom severity, functional impairment, vocational activity, and various sources of income (12% of this [49% of] variance was explained by SSI or SSDI being anincome source).

StudbaseFolloWork wideWork fashiIf subidenta) waprogabovb) waNA 
167 

E

vidence Table 4. Association of clinical findings 

with 

w

ork abilit

y (continued) 

Stu

d

y

S

electe

d

Inclusion/ Exclusion Criteria 

Study Design Patients Findings

Considered

R

esults C

o

m

Grima, Torrance, Francis, et al., 2000 

Inclusion: History of relapsingremitting MS (including some patients who had entered a secondaryprogressive phase within past 2 yr); EDSS < 7 (ambulatory); not in a clinical trial; age ≥ 18 Exclusion: None specified 

Cross-sectional study(estimating costs of relapsing-remitting MS to Canadian health care system and society, measuring health utilities of patients, and examining influence of EDSS scores on these outcomes); some data collected retrospectively for previous 12 mo Location/recruitment: Patients recruited during regular visits to MS clinics at two sites in Ontario, Canada Data collection: Patient survey (patient information, resource use, and health utilities), chart review(resource use, medications, lab tests, procedures), andEDSS status assessment. Note: resource use data not collected on patients in relapse at time ofstudy visit. 

N = 195 (153 in remission at time of studyvisit [44 of whom could recall a relapse in the previous 6 mo] and 42 in relapse at time of visit) Age (mean ± S

D): 

Remission patients: 41 ±

15 Relapse patients: 36 ±14 Baseline measures of physical and mental functioning (EDSS): Remission patients: 1 – 24% 2 – 27% 3 – 22% 4 – 10% 5 – 5% 6 – 12% Relapse patients: NR Baseline work status: Remission patients: Full-time: 29% Part-time due to MS: 4%Part-time not due to MS: 7% Unemployed due to MS: 37% Unemployed not due to MS: 20% No response: 2

%

Relapse patients: NR 

1) Physical: EDSS scores (assessed byneurologist at time of study visit)2) Mental: None3) Laboratory: None 4) Radiographic: None 5) Other: None

No direct measure of 

work capacity or 

abilityWork status measured through selfreport 1) EDSS 1 (n = 37): 

51% - work full-time  3% - work part-time, unable to work  full-time due to MS  8% - work part-time for other reasons 16% - not working due to MS 22% - not working for other reasons EDSS 2 (n = 41):37% - work full-time  7% - work part-time, unable to 

work 

 full-time due to MS 10% - work part-time for other reasons 15% - not working due to MS 32% - not working for other reasons EDSS 3 (n = 33):15% - work full-time  0% - work part-time, unable to work  full-time due to MS  9% - work part-time for other reasons 52% - not working due to MS 18% - not working for other reasons  6% - NR EDSS 4 (n = 16):31% - work full-time  0% - work part-time, unable to work  full-time due to MS  6% - work part-time for other reasons 50% - not working due to MS 13% - not working for other reasons EDSS 5 (n = 7): 0% - work full-time 0% - work part-time, unable to 

work 

No instatuCrosrelatoutcoasseDetaproceDetaempMultiknowhigh was The to examoabouQ

UA

StudbaseFolloWork wideWork fashiIf subidenta) 

wa

progb) 

wa

NA 
168 

Evidence Table 4. Association of clinical findings with work ability (continued) Study Selected

Inclusion/ Exclusion Criteria 

Study Design Patients Findings

Considered

Results Com

 full-time due to MS 0% - work part-time for other reasons 86% - not working due to MS 14% - not working for other reasons EDSS 6 (n = 19): 5% - work full-time 11% - work part-time, unable to work  full-time due to MS 0% - work part-time for other reasons 75% - not working due to MS 5% - not working for other reasons 5% - NR

Grønning, Hannisdal, and Mellgren, 1990 

Inclusion: Diagnosed with clinicallydefinite, probable, orpossible MS; resident of one of two counties in NorwayExclusion: No occupational data on file 

Retrospective cohort studyUnivariate and multivariate survival (time-to-response) analyses used to studyvariables at onset of MS as possible predictors of time to unemploymentLocation/recruitment: Included MS patients seen in neurological departments andclinics in two counties in NorwayData collection: All data taken from patient files recorded from1974-82; observation time from onset of MS to last follow up varied from 1-33 yr, withmean of 10 yr 

N = 79 (49 remittent, 12 remittent-progressive, 18 progressive) Age at MS onset: Mean, 30; range, 13-55Measures of physical and mental functioning at MS onset: NR Work status at MS onset: Housewives: 20% Light work (secretaries, nurses, teachers,engineers, drivers, students): 43% Heavy work (sailors, industrial workers, fishermen, craftsmen): 37% 

Possible predictors all assessed at time of onset of MS (time of first symptoms) 1) Physical: Diagnostic category(definite MS vs. probable/possible MS);Clinical course (remittent vs. nonremittent) Brain stem symptoms (no vs. yes)Paresis (no vs. yes)Sensory disturbances (no vs. yes)2) Mental: None3) Laboratory: None 4) Radiographic: None 5) Other: Occupation (light work/ housewives vs. heavy

No direct measure of work capacity or abilityWork status measured through selfreport. Work status determined byreceipt of disability pension. 1) Employed at last follow up, bydisease subtype:18/49 (37%) - Remittent MS 28/30 (93%) - Non-remittent MS 2) Employed at last follow up, by job type: 25/29 (86%) – Heavy work 21/50 (42%) – Light work 3) Employed at last follow up, by age: 26/50 (52%) ≤ age 30 20/29 (69%) > age 30 4) Univariate analyses of time to unemployment: Non-remittent MS vs. remittent (p < 0.001) Heavy vs. light work (p < 0.01) Male vs. female (p < 0.05) Age > 30 vs. ≤ 30 at onset (p < 0.01) 

Possexert“light the hin the houswork

signiReseto indwitholimitiSamtrue multiQUAStudbaseFolloWork wideWork fashiIf subidenta) waprog
169 

E

vidence Table 4. Association of clinical findings 

with 

w

ork abilit

y (continued) 

Stu

d

y

S

electe

d

Inclusion/ Exclusion Criteria 

Study Design Patients Findings

Considered

R

esults C

o

m

work) Age (≤ 30 vs. > 30) 

Sex (female vs. male) County of residence (Troms vs. Finnmark) 

5) In multivariate analyses, onlydisease subtype was predictive of earlyunemployment (p < 0.01). 6) In multivariate analyses, 

when 

disease subtype was not considered, light work vs. heavy (p < 0.01) and age > 30 years (p < 0.05) 

were predictive of 

early unemployment. 

Yesb) 

wa

Yes

Gulick, Yam, and Tou

w, 1989 

Inclusion: Previous diagnosis of MS; not a resident of a nursing home or long-term care facility; age ≤ 65; selfreported employment status one of following: “employed outside the home,” “homemaker,” “unemployed,” or “retired” (of 8 possible responses) Exclusion: None specified 

Cross-sectional studyLocation/recruitment: Subjects selectedrandomly from t

wo 

local chapters of the National MS Society(n = 412) and recruited from a universityaffiliated MS comprehensive care clinic (all in NewJersey) Data collection: All data collected bysurvey questionnaires, which included a personal data inventory, the A

DL 

Self-Care MS Scale, and t

wo open-ended 

questions about what conditions/situations make work or chores more difficult or easier to perform 

N = 508 eligible respondents (response rate “approximately90%”)Age (mean ± S

D): 

Employed outside home: 41.9 ± 8.9 

Homemaker: 48.0 ± 9.2 

Unemployed: 48.8 ± 9.9 Retired: 56.3 ± 7.0Baseline measures of physical and mental functioning: Walking ability (subscale of ADL Self-Care MS Scale; mean ± SD): Employed outside home: 20.5 ± 6.9 

Homemaker: 12.7 ± 9.0 

Unemployed: 5.8 ± 7.5 Retired: 8.9 ± 8.4 Baseline work status: Employed outside home: 110 Homemaker: 209Unemployed: 110 Retired: 79 

1) Physical: Walking ability(subscale of ADL SelfCare MS Scale) 2) Mental: None3) Laboratory: None 4) Radiographic: 

None 5) Other: Age SexMarital status MS duration (since diagnosis) Education Investigators also reported responses to two open-ended questions about conditions/situations that make 

work or

chores more difficult or easier to perform(responses to “easier to perform” questions not included in this 

No direct measure of 

work capacity or 

abilityWork status measured through selfreport 1) 1-way A

NOVA comparing 

work

groups on selected characteristics (f Ratio): 39.5 (p < 0.001) - Present age 18.8 (p < 0.001) - MS duration 14.1 (p < 0.001) - Education  4.8 (p < 0.001) - Walking 2) Ranked comparison of conditions/ situations that impede 

work 

performance (selected physical functions among those employed outside the home [n = 104] and unemployed [n = 92]; data on homemakers and retired participants not described here): Fatigue: Employed: 50

%

Unemployed: 25% Walking: Employed: 12

%

Unemployed: 0 Standing: 

CrosrelatoutcoasseNo sacrosEmpwas ackncategdistinwho empNo in“uneto antheir empQ

UA

StudbaseFolloWork wideWork fashiIf subidenta) 

wa

prog
170 

Evidence Table 4. Association of clinical findings with work ability (continued) Study Selected

Inclusion/ Exclusion Criteria 

Study Design Patients Findings

Considered

Results Com

table) Employed: 8%

Unemployed: 12% Numbness: Employed: 8%Unemployed: 5%Tremors:Employed: o Unemployed: 10% Use of wheelchair: Employed: 0 Unemployed: 10% Restricted mobility:Employed: 0 Unemployed: 9%Stiffness: Employed: 5%Unemployed: 0 

b) waNA 

Hammond, McLeod, Macaskill, etal., 1996 

Inclusion: Clinicallydefinite, probable, orpossible MS Exclusion: None specified 

Cross-sectional studyLocation/recruitment: Patients identified as part of epidemiological study of MS in NewSouth Wales, Queensland, South Australia, Western Australia, and Tasmania Data collection: Survey/interviewconducted byneurologists; included questions on age, sex, date of birth, occupation, marital 

N = 2307, of which 2099 were of working age (15-64) and reported both DSS and employment data Age: NR Baseline measures of physical and mental functioning: NR Baseline work status: Men: 50% employed, 45% retired or receiving a pension Women: 27% employed, 30% retired or receiving a pension 

1) Physical: Level of disability:Low (DSS 0-3) Moderate (DSS 4-6) Severe (DSS 7-9)2) Mental: None3) Laboratory: None 4) Radiographic: None 5) Other: Type of work (trade/farm vs.professional/clerical) 

No direct measure of work capacity or abilityWork status measured through selfreport 1) Reported being “employed”: Men: 78% = DSS-low27% = DSS-moderate  4% = DSS-severeWomen: 40% = DSS-low 8% = DSS-moderate  1% = DSS-severe2) Adjusting for age and sex, the relationship between DSS level and 

EmponseCrosrelatoutcoasseSamcontrusing QUAStudbaseFolloWork wideWork fashiIf sub
171 

Evidence Table 4. Association of clinical findings with work ability (continued) Study Selected

Inclusion/ Exclusion Criteria 

Study Design Patients Findings

Considered

Results Com

status, and education; DSS score assessed for prevalence day (30 June 1981) 

employment status was noted separately for men and women: Men – prevalence ratio (95% CI): Moderate vs. low DSS = 2.7 (2.1-3.6) Severe vs. low DSS = 17.6 (7.5-41.4) Women – prevalence ratio (95% CI): Moderate vs. low DSS = 4.0 (2.7-5.8) Severe vs. low DSS = 24.6 (8.0-76.1) Job type: Authors noted that trade and farm workers were less likely to be in paid employment than professional or clerical workers as their level of disability increased; however, no data were provided to support this statement. 

identa) waprogb) waNA 

Jacobs, Wende, Brownscheidle, et al., 1999 

Inclusion: Definite MS in the judgment of clinical site neurologists; entered into New York State MS Consortium registryExclusion: None specified 

Cross-sectional studyLocation/recruitment: Patients attended one of 12 MS centerscomprising the NewYork State MS Consortium Data collection: Consortium registry/ study data collected using a 5-page form consisting of 2 sections: (a) 3 pages of demographic data and self-report assessments completed by patient (some mailed, some completed duringoffice visit), and (b) 2 pages of clinical data 

N = 3019 (55% relapsingremitting, 31% secondary progressive, 9% primaryprogressive, 5% progressive relapsing) Age: Mean ± SD, 45.2 ±

11.2; median, 45.0 Baseline measures of physical and mental functioning: NR Baseline work status: NR 

1) Physical: MS disease course (relapsing-remitting vs. progressive) 2) Mental: None3) Laboratory: None 4) Radiographic: None 5) Other: None

No direct measure of work capacity or abilityWork status measured through selfreport 1) Employment status by disease course: Relapse-remitting: 55% employedPrimary progressive: 21% employed 2) Disabled and under age 60: 44% with primary progressive 17% with relapsing-remitting 3) There were no group differences in patients who were homemakers, unemployed, or retired after 60 years of age (2-12%) in relapsing-remitting or progressive MS. 4) Interesting summary of type ofinsurance coverage by stage of 

EDSexamstatuEmponseCrosrelatoutcoasseMultiimpofactoand econdQUAStudbaseFolloWork wideWork fashi
172 

Evidence Table 4. Association of clinical findings with work ability (continued) Study Selected

Inclusion/ Exclusion Criteria 

Study Design Patients Findings

Considered

Results Com

completed byexamining neurologist and/or study nurse (included physical exam findings, exacerbation history,MS type, EDSS score, and lab findings) 

disease, which may be directly related to employment status. Participants with relapsing-remitting MS were more likely to be insured by HMOs andcommercial carriers, and those with progressive MS were more likely to be covered by Medicare and Medicaid. 

If subidenta) waprogb) waNo 

Kornblith,La Rocca, and Baum, 1986 

Inclusion: Interviewed as part of US National MS SurveyExclusion: Never worked; did not admit to having MS 

Cross-sectional study;path analysis used to construct a causal model explainingvariation in employment status Location/recruitment: Subjects were subset of patients interviewed for US National MS Survey; sampling and recruitment of thispopulation not described in the current paper Data collection: Patient interviews designed to obtain disease history,employment history,and data on functional disability, utilization of medical services,costs incurred, and disruptions in the lives of patients and their families due to MS 

N = 987 met inclusion/ exclusion criteria; 949 provided complete data for multivariate analysis Age: Mean, 48.3Baseline measures of physical and mental functioning: Mobility dysfunction: No assistance needed: 31% Assistance needed halftime: 28% Assistance needed all the time: 41% Baseline work status: Employed: 20%Unemployed: 80% 

1) Physical: Duration of illness Functional disability(Mobility Dysfunction Index) ADL and leisure disability (studyspecific measure)2) Mental: None3) Laboratory: None 4) Radiographic: None 5) Other: SexAge Marital status Education level Number of other adults in the home Number of children younger than 14

No direct measure of work capacity or abilityWork status measured through selfreport Proxy of physical function was assessed using the MobilityDysfunction Index: a. No assistance needed indoor and outdoors b. Any combination of cane, walker, crutches, leg brace, use of person, for any amount of chair and wheel chair once in awhile c. Use of wheel chair more than half of the time indoors or outdoors. Data analyzed separately for males vs. females since sociocultural differences between sexes might affect employment in response to MS 1) Author’s comment: Mobility was a major determinant of employmentstatus in both males and females, while age and duration were minor. 2) Men: Each 1-point increase in the Mobility Dysfunction Index decreased the probability of males working by24.3%. 

Meas3-poenouthat aworkStrat

Menand dWomof illnstatuAuthoccuwas are nconsEmponseQUAStudbaseFolloWork wideWork fashiIf subidenta) waprogb) waNo 
173 

Evidence Table 4. Association of clinical findings with work ability (continued) Study Selected

Inclusion/ Exclusion Criteria 

Study Design Patients Findings

Considered

Results Com

3) Women: Each 1-point increase in the Mobility Dysfunction Indexdecreased the likelihood of females working by 15.4%.

LaRocca, Kalb, Kendall, et al., 1982 

Inclusion: MS Exclusion: None specified 

Cross-sectional studyLocation/recruitment: Patients recruited from an MS clinic in the Bronx, NY, and 3(unspecified) voluntary agencies Data collection: Highly structuredclinical interview, plus standard neurological exam with DSS assessment 

N = 312 Age: Mean, 43; range, 18-72 Baseline measures of physical and mental functioning: Mean DSS, 4.6 Baseline work status: 77% unemployed; out of work for an average of 9 yr 96% employed at some time in the past 

1) Physical: Duration of illness Symptoms Disability (measured by DSS scores)2) Mental: None3) Laboratory: None 4) Radiographic: None 5) Other: Age SexEducation Marital status Occupation Parenthood 

No direct measure of work capacity or abilityWork status measured through selfreport 1) 76% of study sample were unemployed at assessment and out of work an average of 9 years; however, 96% had been employed at some time. 2) 1-point increase in DSS was associated with a 7% decrease in the likelihood of being employed 3) Being male increased the probability of being employed by 11%. 4) 86% of variability in employment status unexplained by: 

Age SexEducation Marital status Occupation Parenthood However, variability in employmentstatus was explained by factors such as premorbid personality, coping style, characteristics of the workplace, and social support systems. Authors suggest that these findings contribute to the probability of a patient with MS staying at work. 

CrosrelatoutcoasseReasNo dauthoand No teQUAStudbaseFolloWork wideWork fashiIf subidenta) waprogb) waNA 
174 

E

vidence Table 4. Association of clinical findings 

with 

w

ork abilit

y (continued) 

Stu

d

y

S

electe

d

Inclusion/ Exclusion Criteria 

Study Design Patients Findings

Considered

R

esults C

o

m

Miller, Rudick, Cutter, et al., 2000 

Inclusion: Clinicallydefinite MS Exclusion: None specified 

Cross-sectional study(validation of Multiple Sclerosis Functional Composite [MSFC], consisting of timed 25-ft walk, 9-Hole Peg Test [9-HP

T], and 

Paced Auditory Serial Addition Test 3-min version [PASAT-3]) Location/recruitment: Patients with clinicallydefinite MS recruited from 4 clinical sites in the US and Canada; stratified sampling plan by disease severityand sex; subjectsselected to provide an even representation of mild (EDSS 0-3.0), moderate (EDSS 3.5-6.5), and severe(EDSS 7.0-8.5) neurological impairment Data collection: Following data collected (during clinic visits?): 1) MSFC 2) EDSS 3) Sickness Impact Profile (SIP) 4) SF-36 5) Fatigue Impact Scale (FIS) 6) Self-reported employment status 7) Social Support 

N = 300 Age (mean ± S

D): 44.7 

± 9.3 Baseline measures of physical and mental functioning: EDSS severity: Lo

w (0-3.0): 38% 

Moderate (3.5-6.5): 44

%

High (7.0-8.5): 17% Baseline work status: Full-time: 24.2%Part-time: 13.1

%

Unemployed: 62.8% 

1) Physical: EDSS scores MSF

C scores 

2) Mental: None3) Laboratory: None 4) Radiographic: None 5) Other: None

No direct measure of 

work capacity or 

abilityWork status measured through selfreport 1) Employment status by EDSS score:EDSS (0-3.0): None – 37.5

%

Part-time – 20.5%Full-time – 42.0

%

EDSS (3.5-6.5): None – 74.6

%

Part-time – 10.0%Full-time – 15.4

%

EDSS (7.0-8.5): None – 85.7

%

Part-time – 5.4

%

Full-time – 8.9%2) Employment status (0 = none; 1= part-time; 2 = full-time) correlated significantly with MSFC (Spearman coefficient = 0.43 [p < 0.001]), andcorrelation remained significant when EDSS controlled for (Spearman coefficient = 0.13 [p < 0.05]). No MSFC score is provided 

with regard to 

employment status. 3) When stratified by disease severity, Spearman correlations between MSFC and 

work status for: 

EDSS 0-3.0: 0.21 (p = NS) EDSS 3.5-5.5: 0.32 (p < 0.001) EDSS 7.0-8.5: 0.18 (p = NS) 

The 

validthat eas a statuempcorreAuthnumbsubglack signistatuselec“provEDSQ

UA

StudbaseFolloWork wideWork fashiIf subidentWas progoverareflecb) 

wa

NA 
175 

Evidence Table 4. Association of clinical findings with work ability (continued) Study Selected

Inclusion/ Exclusion Criteria 

Study Design Patients Findings

Considered

Results Com

Survey-Tangible Support subscale 

Rao, Leo, Ellington, etal., 1991 

Inclusion: MS Exclusion: None specified 

Cross-sectional studyLocation/recruitment: Sample described as coming from a “large community-basedsample of MS patients”; sampling/ recruitment not described in detail in this publication Data collection: Cognitive status (intact vs. impaired) determined on basis of performance on 31 cognitive test scores; patients then assessed using Minimal Record of Disability (includes EDSS, Kurtzke Functional Systems, Incapacity Status Scale, and Environmental Status Scale), a 2-hr occupational therapyevaluation, various self-report measures (Zung DepressionScale, State-Trait Anxiety Inventory, SIP), and relative/ friend ratings (Katz Adjustment Scale) 

N = 100 MS patients (38 relapsing-remitting, 19 chronic-progressive, 43 chronic-stable); 100 nonMS controls used to determine cognitive impairment levels onlyAge: Mean, 45.9Baseline measures of physical and mental functioning: EDSS (mean): 4.1 Baseline work status: NR (“Actual Work Status” scores reported onlygraphically [Figure 1]) 

1) Physical: None 2) Mental: Cognitive status (intact vs. impaired) 3) Laboratory: None 4) Radiographic: None 5) Other: None

No direct measure of work capacity or abilityWork status measured through selfreport Mean score on the EnvironmentalStatus Scale (range 0-4) for the “actual work status” item (1 of 7 items) was lower (approximately 1.8) for cognitively impaired versus cognitivelyintact (approximately 2.8) subjects (p < 0.01 [Figure 1.0])

Non-in KadeteCrosrelatoutcoasseEmponseQUAStudbaseFolloWork wideWork fashiIf subidenta) waprogb) waNA 
176 

Evidence Table 4. Association of clinical findings with work ability (continued) Study Selected

Inclusion/ Exclusion Criteria 

Study Design Patients Findings

Considered

Results Com

Rozin, Schiff, Cooper, et al., 1982 

Inclusion: Possible or probable MS bymodified Allison and Miller criteria (diagnosis verified byresearch team); age 17-50; diagnosed during 1970-72 Exclusion: None specified 

Cross-sectional studyLocation/recruitment: Study described below(Rozin, Schiff, Kahana, et al., 1975) updated with new series ofpatients contacted during 1974-78 Data collection: Interviews conducted by social workers in patients’ homes; included questions on demographic data, family history, educational and occupational history,present economicstatus, usual daily schedule, and desire to work or be trained; neurological exam also performed and disability assessed using Hyllested scale. All patients classified according to functional groups as follows: A = completelyhandicapped, no rehabilitation potential; B = potential for vocational rehabilitation (including those who were working, but needed vocational rehabilitation services); and C = working, holding on to their 

N = 117 eligible; 101 interviewed and classified according to functional group Age: Mean, 36 Baseline measures of physical and mental functioning: Disability:Mild (0-2): 57% Moderate (3-4): 36% Severe (5-6): 6%Functional groups (see under “Study Design” at left): A: 16% B: 24% C: 60% Baseline work status: Working: 60% (functional group C) 

1) Physical: Neurological exam, content unspecified 2) Mental: None3) Laboratory: None 4) Radiographic: None 5) Other: Disability assessed using Hyllested scale, graded 0-6 Years of education 

Direct measure of work capacity orability was conducted Work status measured through selfreport Study participants initially grouped as follows (Series I and II combined; n = 299) n = 71 - Group A: Completelyhandicapped with no rehabilitation potential n = 53 - Group B: Potential for vocational rehabilitation, but unemployed or currently employed, but needs rehabilitation services for continuation of employment 

n = 175 - Group C: Currently working, holding previous jobs or changed jobs without intervention of rehabilitation services 1) Type of MS disability by Group (Series I and II combined): No disability:NR - Group A  3% - Group B 29% - Group C Physical MS: 59% - Group A 75% - Group B 61% - Group C Physical and mental MS: 30% - Group A 11% - Group B  6% - Group C Mental MS: 1% - Group A 2% - Group B 

Evalis unCrosrelatoutcoasseNot cclassHylleblindQUAStudbaseFolloWork wideabilitWork fashiIf subidenta) waprogb) waNA 
177 

Evidence Table 4. Association of clinical findings with work ability (continued) Study Selected

Inclusion/ Exclusion Criteria 

Study Design Patients Findings

Considered

Results Com

previous jobs, or changed jobs without the intervention ofrehabilitation services 

1% - Group C Other causes: 7% - Group A 2% - Group B 1% - Group C MS and other: 3% - Group A 7% - Group B 2% - Group C “Comparison of Group A with Group C with mental disability due to MS (with or without physical disability) is higher in Group A than C – 31% vs. 7%, respectively – p < 0.001.” “Group A and Group C had similar percentages of subjects with physical disability due to MS. “ 2) Hyllested Criteria of Disability(Series I and II combined): Group A (n = 71):15% - Mild (0-2) 38% - Moderate (3-4) 46% - Severe (5-6) Group B (n = 53):36% - Mild (0-2) 51% - Moderate (3-4) 13% - Severe (5-6) Group C (n = 175): 74% - Mild (0-2) 25% - Moderate (3-4) 0.6% - Severe (5-6) 
178 

Evidence Table 4. Association of clinical findings with work ability (continued) Study Selected

Inclusion/ Exclusion Criteria 

Study Design Patients Findings

Considered

Results Com

Rozin, Schiff, Kahana, et al., 1975 

Inclusion: MS; age 20-50in 1971 Exclusion: None specified 

Cross-sectional studyLocation/recruitment: Patient population derived from a surveyof MS patients in Israel, updated in 1968 and including all MS patient living in Israel at the time (n = 490); those age 20-50 in 1971 included in present studyData collection: Interviews conducted by social workers in patients’ homes; included questions on demographic data, family history, educational and occupational history,present economicstatus, usual daily schedule, and desire to work or be trained; neurological exam also performed and disability assessed using Hyllested scale; all patients classified according to functional groups as follows: A = completelyhandicapped, no rehabilitation potential; B = potential for vocational rehabilitation (including those who were working, but needed 

N = 222 eligible; 159 interviewed; 172 classified according to functional group Age: 53% older than 40 Baseline measures of physical and mental functioning: Disability:Mild (0-2): 38% Moderate (3-4): 29% Severe (5-6): 33% Functional groups (see under “Study Design” at left): A: 24% B: 21% C: 55% Baseline work status: Not working: 76% 

1) Physical: Neurological exam, content unspecified 2) Mental: None3) Laboratory: None 4) Radiographic: None 5) Other: Disabilityassessed using Hyllested scale, graded 0-6 

Direct measure of work capacity orability was conducted Work status measured through selfreport Study participants (n = 172) were initially grouped as follows: n = 41 - Group A: Completelyhandicapped with no rehabilitation potential n = 37 - Group B: Potential for vocational rehabilitation, but unemployed or currently employed, but needs rehabilitation services for continuation of employment n = 94 – Group C: Currently working, holding previous jobs or changed jobs without intervention of rehabilitation services 1) Type of MS disability by group:No disability:NR - Group A NR - Group B 50% - Group C Physical disability due to MS: 39% - Group A 81% - Group B 41% - Group C Physical and mental disability due to MS: 56% - Group A 19% - Group B 3% - Group C Mental disability due to MS: 

NR - Group A NR - Group B 1% - Group C 

Evalis unCrosrelatoutcoasseExamacrosQUAStudbaseFolloWork wideabilitWork fashiIf subidenta) wprogb) wNA 
179 

Evidence Table 4. Association of clinical findings with work ability (continued) Study Selected

Inclusion/ Exclusion Criteria 

Study Design Patients Findings

Considered

Results Com

vocational rehabilitation services); and C = working, holding on to their previous jobs, or changed jobs without the intervention ofrehabilitation services 

Other causes of disability not connected with MS: 5% - Group A NR - Group B 5% - Group C 3) Hyllested Criteria of Disability:Group A (n = 41):0% - Mild (0-2) 0% - Moderate (3-4) 100% - Severe (5-6) Group B (n = 37):0% - Mild (0-2) 57% - Moderate (3-4) 43% - Severe (5-6) Group C (n = 94): 70% - Mild (0-2) 30% - Moderate (3-4) 0% - Severe (5-6) 4) Changes in work status from onset of MS to time study in 1971. Work type by work groups: Group A (n = 41):Unskilled labor: 18% - onset of MS0% - at time of studySkilled, semiskilled, service: 27% - onset of MS0% - at time of studyClerical, profession, student: 37% - onset of MS0% - at time of studyHousewives: 2% - onset of MS0% - at time of studyNot working: 6% - onset of MS100% - at time of study
180 

Evidence Table 4. Association of clinical findings with work ability (continued) Study Selected

Inclusion/ Exclusion Criteria 

Study Design Patients Findings

Considered

Results Com

Group B (n = 37):Unskilled labor: 28% - onset of MS3% - at time of studySkilled, semiskilled, service: 31% - onset of MS 3% - at time of studyClerical, profession, student: 31% - onset of MS21% - at time of studyHousewives: 5% - onset of MS8% - at time of studyNot working: 5% - onset of MS65% - at time of studyGroup C (n = 94): Unskilled labor: 22% - onset of MS8% - at time of studySkilled, semiskilled, service: 18% - onset of MS17% - at time of studyClerical, profession, student: 40% - onset of MS37% - at time of studyHousewives: 12% - onset of MS38% - at time of studyNot working: 8% - onset of MS0% - at time of study4) Authors note that “of the 131 clients with working potential, only 18% stopped working because of MS” –supporting data not provided. 
181 

Evidence Table 4. Association of clinical findings with work ability (continued) Study Selected

Inclusion/ Exclusion Criteria 

Study Design Patients Findings

Considered

Results Com

Scheinberg, Holland, Larocca, et al., 1980 

Inclusion: MS; patient at studyclinicExclusion: None specified 

Cross-sectional studyLocation/recruitment: Sample of patients from a multidisciplinaryMS clinic assembled by selecting alternate names from an alphabetic file Data collection: Structured interviewcontaining 20 questions administered either byphone or in person; areas assessed included employment, education, household activities, and medical care

N = 401 selected; 257 (64%) completedinterviewsAge: 37% ≤ 39; 53% 40-59; 9% ≥ 60 

Baseline measures of physical and mental functioning: NR Baseline work status: Employed: 19.5%Independent homemaker: 21.4% Semi-independent homemaker: 12.8% Employed in sheltered workshop: 1.2%Retired: 3.9%Student: 2.3%Unemployed: 38.5% Other: 0.4% 

1) Physical: Selfreport of physical limitations 2) Mental: None3) Laboratory: None 4) Radiographic: None 5) Other: Job category

No direct measure of work capacity or abilityWork status measured through selfreport Among those having left employment, the most common reason for leaving among multiple reasons given by 182 subjects (categories not mutuallyexclusive): 52.7% - Physical difficulty15.9% - Visual difficulty12.1% - Transportation difficulty 9.3% - Fatigue  1.3% - Emotional difficulty37.4% - Other (mainly marriage and/or  pregnancy) Job category of currently employedsubjects (n = 51): 35.3% - Clerical 23.5% - Professional 13.7% - Semi-Professional 13.7% - Skilled Labor  7.8% - Managerial  2.0% - Unskilled Labor  3.9% - Other Among the unemployed, 18.3% were seeking employment, training, oreducation, and 21.4% were able tocare for their own home with little or no assistance. 

Self-withoEmponseCrosrelatoutcoasseSamdifferconsmultiDescAuthselec

selecrecrumore betteserviwith Authunemwith shortrehapubliserviconsQUAStudbaseFolloWork wideWork fashiIf subident
182 

E

vidence Table 4. Association of clinical findings 

with 

w

ork abilit

y (continued) 

Stu

d

y

S

electe

d

Inclusion/ Exclusion Criteria 

Study Design Patients Findings

Considered

R

esults C

o

m

a) 

wa

progb) 

wa

NA 

VerdierTaillefer, Sazdovitch, Borgel, etal., 1995 

Inclusion: Clinically orlaboratory definite MS byPoser criteria; EDSS 3-7; age 20-50 Exclusion: None specified 

Case-control studyLocation/recruitment: Subjects were consecutive patients at 4 neurology clinics in France between Jan and Dec 1991 Data collection: Studyneurologist examined patients to determine type of MS, age at onset, and EDSSscore. Neurologist then administered questionnaire asking about demographic characteristics and 14 specific items relating to the occupational environment of current (or past) job; subjects also asked (in openended way?) why theystopped working

N = 171 total = 77 cases (unemployed for < 5 yr at time of study) and 94 controls (still employed)Type of MS: Cases: 31% relapsingremitting, 53% relapsingprogressive, 16% primary progressive Controls: 48% relapsingremitting, 36% relapsingprogressive, 16% primary progressive Age (mean ± S

D): 

Cases (unemployed): 39.0 ± 0.9 

Controls (employed): 40.5 ± 0.7 

Baseline measures of physical and mental functioning: EDSS (mean ± SD):Cases: 5.4 ± 0.1 

Controls: 4.5 ± 0.1Baseline work status: Cases (45% of total study population)unemployed Controls (55

% of total 

study population)employed 

1) Physical: EDSS See further under “Specific job characteristics,” below2) Mental: See under “Specific job characteristics,” below3) Laboratory: None 4) Radiographic: None 5) Other: Age SexMarital status Job grade (high, medium, low) High school education (yes/no)Age at onset Type of MS Specific job characteristics: a) Public sector b) Desk job c) Sitting position

d) Possibility of obtaining specific arrangements e) Travel time > 30 min/ dayf) Daily working time > 8 hr 

No direct measure of 

work capacity or 

abilityWork status measured through selfreport Work status (

Yes/No) 

Cases = unemployed Controls = employed 1) Disease stage and 

work status 

(p = 0.01): Relapsing-remitting: Cases = 31%Controls = 48% Relapsing-progressive: Cases = 53%Controls = 36% Primary progressive: Cases = 16%Controls = 16% 2) EDSS (mean ± SD) and work status: Cases = 5.4 ± 0.1 Controls = 4.5 ± 0.1 

p = 0.01 3) Work require

ments and odds of 

unemployment (odds ratio [95% CI]): 0.9 (0.4-1.8) – close attention 0.7 (0.3 -1.5) – good memory7.6 (3.2-18.2) – physical strength 3.1 (1.6 - 6.3) – manual precision 

RetroknowempAuthunemtime they diagnindicit is atime Cogn(TabrepoQ

UA

StudbaseFolloWork wideWork fashiIf subidenta) 

wa

progb) 

wa

NA 
183 

Evidence Table 4. Association of clinical findings with work ability (continued) Study Selected

Inclusion/ Exclusion Criteria 

Study Design Patients Findings

Considered

Results Com

g) Accessibilityproblems h) Work requiring: - Close attention- Good memory- Physical strength - Manual precision - Rigid work schedule - Decision-making - Frequent moves 

2.2 (1.1 - 4.6) – rigid work schedule 1.7 (0.7 - 3.4) – decision making 2.5 (1.3 - 4.9) – frequent moves 4) Job characteristics and odds of unemployment (odds ratio [95% CI]): 0.3 (0.1 - 0.5) – desk job 0.3 (0.1 - 0.7) – sitting position 0.4 (0.2, 0.8) – possibility of obtaining  specific arrangements 1.7 (0.9-3.2) – travel time > 30 min 2.6 (1.2-5.7) – daily work hrs > 8 h1.9 (0.9-4.0) – accessibility problems 5) Logistic regression of job characteristics significantly related to unemployment (odds ratio [p-value]): 0.4 (p < 0.05) – work in public sector 4.5 (p < 0.01) – work needing physical strength 
E

vidence Table 5. En

vironmental factors and 

w

ork abilit

y

184 

Stu

d

y

S

electe

d

Inclusion/ Exclusion Criteria 

Study Design Patients En

vironmental 

Factors Considered

R

esults C

o

m

Gulick, Yam, and Tou

w, 1989 

Inclusion: Previous diagnosis of MS; not a resident of a nursing home or long-term care facility; age ≤ 65; selfreported employment status one of following: “employed outside the home,” “homemaker,” “unemployed,” or “retired” (8 work status categories possible, but results werereported only for respondents in the above four categories because “too few subjects fit into categories of homebound employment, sheltered workshop, student, and volunteer for meaningful analysis”) Exclusion: None specified 

Cross-sectional studyLocation/recruitment: Subjects selectedrandomly from t

wo 

local chapters of the National MS Society(n = 412) and recruited from a universityaffiliated MS comprehensive care clinic (n = 96; all sites in Ne

w Jersey) 

Data collection: All data collected bysurvey questionnaires, which included a personal data inventory, the A

DL 

Self-Care MS Scale, and t

wo open-ended 

questions about what conditions/situations make work or chores more difficult or easier to perform 

N = 508 eligible respondents (response rate “approximately90%”)Age (mean ± S

D): 

Employed outside home: 41.9 ± 8.9 

Homemaker: 48.0 ± 9.2 

Unemployed: 48.8 ± 9.9 Retired: 56.3 ± 7.0Sex:Respondents were comprised of 371females and 137 males. No sex differences were noted among the work groups regardingeducation, duration of MS since diagnosis, or walking ability. Males working outside the home 

were older than 

their female counterparts (mean age 45.14 vs. 39.48; p = 0.001), but among the unemployed, males were younger (45.85 vs. 50.23; p = 0.047); the same was true in the retired group (males 54.31 vs. females 59.22; p = 0.002) (too few males in the homemaker group [n = 6] for sex differenceanalysis). Baseline measures of physical and mental 

Rater-assigned responses to 

workimpeding categories of 

“heat/temperature intolerance” and 

workenhancing category of 

cool temperature(Subject responses 

were to open-ended questions about conditions/situations that make it difficult [impeders] or easier [enhancers] to perform work or chores)

Work ability

was not directly assessed. 

The only relevant work capacityvariable was self-reported 

work status. 

Responses to open-ended questions regarding impediments to and enhancers of 

work performance 

were 

grouped into condition/situation categories by two independent raters. Inter-rater agreement coefficients ranged from 0.84 to 0.98 for four 

workimpeding categories and from 0.82 to 

1.0 for five 

work-enhancing categories 

(particular categories tested for interrater agreement were not specified). 22 conditions that impede 

work 

performance 

were identified by 5

% or 

more of participants. Among those employed outside the home, 7%

included high temperature as a condition/situation that impeded work performance, along 

with 11 other workimpeding items such as fatigue (50%), 

walking (12

%), vision (12%), balance 

(10%), standing (8%), writing (8%), numbness (8%), insufficient time (7%), pain (6%), lifting (5%), and stiffness (5%). Ho

wever, none of those 

employed outside the home included cool temperature as a work-enhancer. High temperature was also cited as a work-impeding item by 6

% of 

homemakers (along 

with 8 other items 

including fatigue, balance, weakness, walking, vision, pain, fine motor skills, and bending); and 8% of homemakers cited cool temperature as a 

workenhancer. 

Authwoulhomeprevand tnevethemAuthdifferas accondappa“heawork grouSignwork repoand 

w

factoassotempWork was Only provintolewere workbet

w

statisbeen withiThe these nece
185 

Evidence Table 5. Environmental factors and work ability (continued) Study Selected

Inclusion/ Exclusion Criteria 

Study Design Patients Environmental 

Factors Considered

Results Com

functioning: 

Walking ability (subscale of ADL Self-Care MS Scale; mean ± SD): Employed outside home: 20.5 ± 6.9 

Homemaker: 12.7 ± 9.0 

Unemployed: 5.8 ± 7.5 Retired: 8.9 ± 8.4 Baseline work status (“work category/group”): Employed outside home: 110 Homemaker: 209Unemployed: 110 Retired: 79 

By contrast, high temperature was not 

among the 13 work-impeding items cited by the unemployed, nor among the 11 work-impeding items cited bythe retired group; although 6% of the retired listed cool temperature as a work-enhancer. 

interpconsdomawork consversuhomeStudrepoquesQUAStudbaseFollo“appWork wideWork fashiIf subidentWas proginter-since abilitb) waNo 
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Acronyms/Abbreviations Used in the Evidence Tables 

4-AP 4-aminopyridine 

9-HPT 9-Hole Peg Test 

ACTH adrenocorticotropic hormone 

ADL activities of daily living 

AE adverse event 

AI Ambulation Index 

ANOVA analysis of variance 

APOE apolipoprotein E 

ASQ Anxiety Scale Questionnaire 

AUC area under curve 

AZA azathioprine 

BAEP brainstem auditory evoked potential 

BBT Box-and-Block Test 

BDI Beck Depression Inventory 

B/l baseline 

BMS benign MS 

BTX botulinum toxin 

CBT cognitive-behavioral therapy 

CDQ Clinical Depression Questionnaire 

CHF congestive heart failure 

CI confidence interval 

CNA certified nursing assistant 

CNS central nervous system

Cop1 copolymer 1 = glatiramer acetate 

CPMS chronic progressive MS 

CSF cerebrospinal fluid 

CT computed tomography 

CYCLO cyclophosphamide 

DBP diastolic blood pressure 

DEX Dysexecutive Syndrome Questionnaire 

DSM-IV Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition

DSS Disability Status Scale 

DTR deep tendon reflex 

EADL Extended Activities of Daily Living Scale 

EDSS Expanded Disability Status Scale 

EEG electroencephalogram

EMG electromyogram

EMQ Everyday Memory Questionnaire 

ENS electrical neuromuscular stimulation

FIM Functional Independence Measure 

FIS Fatigue Impact Scale 

FLAIR fluid-attenuated inversion recovery 

FSS Fatigue Severity Scale 

GA glatiramer acetate = copolymer 1 

193
GEMS Global Evaluation-MS 

GHQ-28 General Health Questionnaire-28 

GI gastrointestinal 

GNDS Guy’s Neurological Disability Scale 

GP general practitioner 

HIV human immunodeficiency virus 

HPLP-II Health Promoting Lifestyle Profile II 

HMO health maintenance organization 

hr hour(s) 

HRSD Hamilton Rating Scale for Depression 

IECS Internal-External Control Scale 

IFNβ-1a interferon beta-1a 

IFNβ-1b interferon beta-1b 

IgG immunoglobulin-G 

IgM immunoglobulin-M 

IL-2 interleukin-2 

IM intramuscular 

IQR interquartile range 

ISS Incapacity Status Scale 

ITMS intrathecal IgM synthesis 

ITT intention-to-treat

IV intravenous 

LHS London Handicap Scale 

MAQ Memory Aids Questionnaire 

MEP motor evoked potential 

MFIS Modified Fatigue Impact Scale 

MIU million International Units 

MMPI Minnesota Multiphasic Personality Inventory 

MMSE Mini Mental State Examination 

mo month(s) 

MP methylprednisolone 

MRD Minimal Record of Disability 

MRI magnetic resonance imaging 

MS multiple sclerosis 

MSFC Multiple Sclerosis Functional Composite 

MS-FS MS-Specific Fatigue Scale 

MSIS MS-Impairment Scale 

MSQLI MS Quality of Life Inventory 

MTX mitoxantrone 

NA not applicable 

nIFNβ natural interferon beta 

NPV negative predictive value 

NR not reported 

NRS Neurologic Rating Scale 

NS not statistically significant 

NSAID non-steroidal anti-inflammatory drug 

194
PAIS-SR Psychological Adjustment to Illness Scale – Self-Report 

PASAT Paced Auditory Serial Addition Test 

PEX plasma exchange 

PFC Problem-Focused Coping score from Ways of Coping Checklist 

PO per os (by mouth) 

POMS Profile of Mood States 

PPMS primary progressive MS

PPV positive predictive value 

PRQ Personal Resources Questionnaire 

QOL quality of life 

RCT randomized controlled trial 

ROM range of motion 

RR risk ratio 

RRMS relapsing-remitting MS 

SBP systolic blood pressure 

SC subcutaneous 

SCI spinal cord injury 

SD standard deviation 

SDDR Standard Day Dependency Record 

SDDRE Standard Day Dependency Record-Essential Subscale 

SDDRO Standard Day Dependency Record-Occasions Subscale 

SDMT Symbol Digit Modalities Test 

SE standard error 

SEAB Self-Efficacy for Adjustment Behaviors Scale 

SEG supportive-expressive group therapy 

SEP somatosensory evoked potential 

SES Self-Esteem Scale 

SET Tempelaar Social Experience Checklist 

SF-36 Medical Outcomes Study 36-Item Short-Form Health Survey 

SIP Sickness Impact Profile 

SN sensitivity 

SNRS Scripps Neurological Rating Scale 

SP specificity 

SPMS secondary progressive MS 

SSDI Social Security Disability Insurance 

SSI Supplemental Security Income

STAI State-Trait Anxiety Inventory 

STAI-S State-Trait Anxiety Inventory-State 

STAI-T State-Trait Anxiety Inventory-Trait 

STAXI State-Trait Anger Expression Inventory 

THC tetrahydrocannabinol 

UTI urinary tract infection 

VAMC Veterans Affairs Medical Center 

VAS visual analog scale 

VEP visual evoked potential 

VFS Visual Faces Scale 

195
WBC white blood cell 

wk week(s) 

WMS VR Wechsler Memory Scale Visual Reproduction 

yr year(s) 

196