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1

The Influence of Physiotherapy
and Climate on Functioning in
Multiple Sclerosis
Aspects of physical performance, fatigue and health-related
quality of life
Tori Smedal

Dissertation for the degree of philosophiae doctor (PhD)
University of Bergen, Norway
2010

2

Scientific environment
This thesis was carried out under supervision at Department of Public Health andPrimary Health Care, Physiotherapy research group and Department of Clinical
Medicine, University of Bergen.
The first study was carried out in cooperation between Department of Public Healthand Primary Health Care, University of Bergen; The Norwegian Multiple Sclerosis
Competence Centre, Department of Neurology, Haukeland University Hospital (HUS);
and Department of Physiotherapy, HUS.
The main study called Climate Influence on Physiotherapy in Multiple Sclerosis(CIOPIMS) was initiated by Section for Climate Therapy, Oslo University Hospital,
who got the assignment to initiate the study from the Ministry of Health and Care
Services of the Norwegian Government. The Norwegian Multiple Sclerosis
Competence Centre, HUS carried out the study in cooperation with: Department of
Public Health and Primary Health Care, University of Bergen; Department of Clinical
Medicine, University of Bergen; Section for Climate Therapy, Oslo University
Hospital; Department of Physiotherapy, HUS; Department of Neurology, Akershus
University Hospital (AHUS); and Department of Neurology, HUS. The patients weretreated at Clinica Vintersol Tenerife, Spain and at MS-Senteret Hakadal, Norway.

To Olav

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If the brain were so simple we could understand it, we would be so simple we couldn't.
Lyall Watson

4

Contents
SCIENTIFIC ENVIRONMENT......................................................................................................... 2
ACKNOWLEDGEMENTS................................................................................................................. 7
ABBREVIATIONS ............................................................................................................................ 11
ABSTRACT........................................................................................................................................ 13
LIST OF PUBLICATIONS............................................................................................................... 16
1.

INTRODUCTION ................................................................................................................... 17
1.1

MULTIPLE SCLEROSIS ............................................................................................................ 18
1.1.1

Patophysiology........................................................................................................... 19

1.1.2

Epidemiology.............................................................................................................. 20

1.1.3

Aetiology .................................................................................................................... 21

1.1.3.1.Genetic factors ......................................................................................................................... 22
1.1.3.2 Environmental factors .............................................................................................................. 22

1.1.4

Diagnosis ................................................................................................................... 24

1.1.5

Course of the disease and prognosis .......................................................................... 25

1.1.6

Clinical symptoms ...................................................................................................... 27

1.1.6.1 The International Classification of Functioning, Disability and Health ................................... 27
1.1.6.2 Motor symptoms ...................................................................................................................... 29
1.1.6.3 Other symptoms ....................................................................................................................... 30

1.2

1.1.7

Health-related quality of life ...................................................................................... 32

1.1.8

The effect of heat and climate in MS .......................................................................... 33

1.1.9

Medical treatment ...................................................................................................... 34

REHABILITATION IN MS ........................................................................................................ 35
1.2.1 Neuroplasticity and possible implications for rehabilitation............................................ 37

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1.2.2 Physiotherapy and physical training in MS...................................................................... 38
1.2.2.1 The Bobath Concept................................................................................................................. 40

2.

AIMS OF THE STUDY .......................................................................................................... 42

3.

MATERIALS AND METHODS ............................................................................................ 43
3.1

PATIENTS .............................................................................................................................. 44

3.2

MEASUREMENT TOOLS .......................................................................................................... 44

3.3

INTERVENTION ...................................................................................................................... 45

3.4

PAPER  ................................................................................................................................. 47

3.5

PAPER  ................................................................................................................................ 48

3.6

PAPER III............................................................................................................................... 50

3.7

PAPER V............................................................................................................................... 55

4.

SUMMARY OF RESULTS .................................................................................................... 56
4.1

PAPER  ................................................................................................................................. 56

4.2

PAPER  ................................................................................................................................ 56

4.3

PAPER ............................................................................................................................... 57

4.4

PAPER V............................................................................................................................... 60

5.

GENERAL DISCUSSION ...................................................................................................... 61
5.1

INTERVENTION STUDIES, PAPER I & III ................................................................................. 61
5.1.1

The climate influence on the effect of physiotherapy ................................................. 61

5.1.2

Physiotherapy based on the Bobath concept.............................................................. 63

5.1.3

Outcome measures, designs and methodological considerations .............................. 68

5.1.3.1 Outcome measures ................................................................................................................... 68
5.1.3.2 Study design ............................................................................................................................. 72
5.1.3.3 Other methodological considerations ....................................................................................... 74

5.2

NORWEGIAN VERSION OF MSIS-29, PAPER II ....................................................................... 75

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5.3

6.

5.2.1

The translation process of the MSIS-29 ..................................................................... 77

5.2.2

Psychometric properties of the Norwegian version of MSIS-29................................ 78

FATIGUE STUDY, PAPER IV ................................................................................................... 81
5.3.1

Associations between fatigue versus HRQoL and physical performance................... 81

5.3.2

Suggestions for a broader startegy in treating fatigue............................................... 83

CONCLUSIONS AND FURTHER RESEARCH ................................................................. 85

REFERENCES................................................................................................................................... 87
PAPERS -V.................................................................................................................................... 103
APPENDICES

7

Acknowledgements
The present thesis is based upon research carried out from 2002 to 2004 while I was amaster student and from 2006 to 2010 a PhD student at Department of Public Healthand Primary Health Care and Department of Clinical Medicine, University of Bergen.
The work was carried out at The Norwegian Multiple Sclerosis Competence Centre,
Department of Neurology, HUS. The studies were financed by: Section for Climate
Therapy, Oslo University Hospital; The Norwegian Multiple Sclerosis CompetenceCentre and the Western Norway Regional Health Authority.
It has been a privilege to work together with enthusiastic people aiming to improve theknowledge of factors that might improve functioning in multiple sclerosis (MS), and I
would like to thank all who have been important to me while carrying out this work.
My respect for, and gratitude to the patients with MS who have contributed withvaluable information during an extensive study period, is great.
My principal supervisor in both study periods, associate professor dr. philos. Liv Inger
Strand at Department of Public Health and Primary Health Care, University of Bergen,
has indeed guided me safely, patiently and wisely through “ups” and “downs” bycontinuously giving me valuable advices and encouragement. This has been offundamental importance for the execution of this work, and I am deeply indebted.
My co-supervisor professor dr. med. Kjell-Morten Myhr, the leader of The NorwegianMultiple Sclerosis Centre, gave me the opportunity to carry out the master project at
his department. He thereby introduced med to his research group, which has really
impressed and inspired me. I am indeed indebted to him for organizing the opportunity
to continue research in MS by engaging me as a research fellow at the centre. The way
he has supervised me and continuously supported me by constructive criticism andenthusiasm has been extremely valuable.

8
Statistician, PhD, Jan Harald Aarseth has contributed invaluable with his extensivecompetence in statistics in a brilliant combination with patience and humour, helping
me to keep optimistic, also when things looked a bit overwhelming.
I also express my special appreciation to my dear colleagues and friends Bente
Gjelsvik and Olav Gjelsvik. Olav died during the second study period. From the very
start of my physiotherapy career, they have both impressed me with their skilled andprofessional way of treating patients with neurological diseases. They contributed
continuously with decisive work in planning the projects, collecting data anddiscussing important topics for validating the projects.
In my early research career, as a master student, my co-supervisor Hildegunn Lygren,MSc, gave me important advices and support, which has inspired me to continue withfurther research activity.
I am also grateful to:- Antonie Giæver Beiske, who had the main responsibility for collecting the medical
data at the treatment centres and at AHUS, and also participated in important
discussions, in addition to sharing the first authorship of Paper IV.
- Solveig B Glad for valuable contribution in collecting medical data at HUS anddiscussing results.
- The rest of the CIOPIMS project co-operators for enthusiastic and skilledcontribution in collecting data and discussing important questions during the study
period: Anne Britt Rundhovde Skår, Kari-Anne Huser, Bente Frisk, Toril Mørkve
Knudsen, Torunn Grenstad, Kari Øen Jones and Randi Cesilie Haugstad.
- The staff at Section for Climate Therapy, Oslo University Hospital, especially the
project coordinator Tone Bråthen. Åse Lindrupsen, Yndis Staalesen Strumse, KarinØien Forseth, Anne-Cathrine Clarke-Jenssen and Anne Kristine Nitter have also
contributed in important discussions, as well as Petra Ahlvin Nordby at Sunnaas
Hospital.

9- Hilde Haukelid Johansen who in a thorough way contributed with the valuable workof translating and testing psychometric properties of a questionnaire (Multiple
Sclerosis Impact Scale) used in the CIOPIMS study, and sharing first authorship ofPaper II.
- Co-author Elisabeth Svensson for valuable cooperation in Paper IV.
- My office roommate Julie Dahl for inspiring discussions and inviting attitude.
- Geert Veerheyden and Håkon K Gjessing for valuable statistical advices.
- The staff at MS-Senteret Hakadal and Clinica Vintersol Tenerife, especially Agnete
Steensgaard Gade and Britta Sallnäs, respectively, for important co-operation inorganizing the treatment in the CIOPIMS study.
- Grete Marlen Forland for help in organizing the economics of the CIOPIMS study aswell as always being patient and helpful when I had data challenges.
- All my other colleagues and friends at The Norwegian Multiple Sclerosis
Competence Centre for valuable discussions and support; Nina Grytten Torkildsen,Øivind Fredvik Grytten Torkildsen, Stig Wergeland, Lars Bø, Tove Marøy, Nina
Aarskog, Liesbeth Kroondijk, Sveinung Fjær, Trond Riise, Sonia Gavasso and Tarja
Rajalahti.
- My colleagues at Department of Public Health and Primary Health Care,
Physiotherapy research group, University of Bergen, especially professor Rolf MoeNilssen, associate professor Alice Kvåle and research fellow Mona Kristin Aaslund,for valuable contributions.
- Professor Harald Nyland for having inspired me with his enthusiasm for people with
MS from the beginning of my career as a neurological physiotherapist.
- Professor Nils Erik Gilhus for valuable advices and support.
- The staff at Department of Clinical Neurophysiology and the Outpatient clinic at the
Neurological Department HUS, and the Outpatient clinic at the Neurological10Department AHUS, for always being forthcoming and helpful when we needed spaceand rooms for testing.
- Regina Kufner Lein at the Medical Library at the University of Bergen Library forcontinuously being positive when helping me search for relevant literature.
- The leader of Department of Physiotherapy, HUS, Else Sterndorff for her positiveand supporting attitude, having given me the opportunity to start and continue myresearch career.
- Julie Drevdal at Department of Physiotherapy, HUS for an important advice when
designing the study.
Finally, but not least, I want to express my warm and deeply felt thanks to my family
and friends: my dear husband Per Kristian for patiently giving me safety and love.
This work could not have been done without his support; my children: Ane, Bodil andSigurd who have shown empathy and helped me to remember that life is full of otherimportant aspects than work and science; my parents Grete and Harald for support andtender sympathy when I have needed it; the rest of my dear family and all my nearfriends for their important and valuable friendship.

11

Abbreviations
ADL

Activities of daily living

AHUS

Akershus University Hospital

AUC

Area under the receiver operating characteristics (ROC) curve

BBS

Berg Balance Scale

Borg RPE Scale

Borg Rating of Perceived Exertion Scale

CGIC

Clinical Global Impression of Change

CIOPIMS

Climate Influence on Physiotherapy in Multiple Sclerosis

CIS

Clinically isolated syndrome

CNS

Central nervous system

CSD

Clinically significant difference

EBV

Epstein-Barr virus

EDSS

Expanded Disability Status Scale

ES

Effect size

FSS

Fatigue Severity Scale

GA

Glatiramer acetate

GLM

General linear models

HRQoL

Health-related quality of life

HUS

Haukeland University Hospital

ICC

Intraclass correlation coefficient

ICF

International Classification of Functioning, Disability and Health

IFN-ßInterferon-beta

MCID

Minimal clinical important differenceMID

Minimal important difference

MRI

Magnetic resonance imaging

12MS

Multiple sclerosis

MSIS-29

The Multiple Sclerosis Impact Scale

MSIS-29 NV

The Multiple Sclerosis Impact Scale, Norwegian Version

NRS

Numerical Rating Scale

PGIC

Patient Global Impression of Change

PPMS

Primary-progressive multiple sclerosis

PRMS

Progressive-relapsing multiple sclerosis

QoL

Quality of life

RMI

Rivermead Mobility Index

ROC

Receiver operating characteristics

RRMS

Relapsing-remitting multiple sclerosis

RVGA

Rivermead Visual Gait Assessment

SDC

Smallest detectable change

SEMStandard error of measurement

SPMS

Secondary-progressive multiple sclerosis

SSED

Single-subject experimental design

TIS

Trunk Impairment Scale

TUG

Timed Up & Go

UVR

Ultraviolet radiation

VAS

Visual analogue scale

10MTW

10-metre timed walk

2MWT

2-minute walk test

6MWT

6-minute walk test

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Abstract
Multiple sclerosis (MS) is a chronic, immune-mediated disease affecting the central
nervous system (CNS), caused by interplay between predisposing genes andenvironment. The disease may result in a wide spectre of functional problems, besttreated by a multidisciplinary team of professionals. Physiotherapy has shown to
improve physical functioning related to mobility and has been advocated as a major
component in rehabilitation in MS. The CNS has the ability to change its function andstructure depending on demands, and this neuroplasticity also occurs after damage.
The Bobath concept is one of the most used treatment approaches in neurologicalphysiotherapy and is based on knowledge of neuroplasticity, aiming to relearn
appropriate movement strategies after damage.
The thesis includes two intervention studies in MS. The first study is presented inPaper I. The second study (the climate study) is presented in Paper III. Data from theclimate study are also used to investigate psychometric properties of a translated
version of the self-reported health-related quality of life (HRQoL) questionnaire, theMultiple Sclerosis Impact Scale (MSIS-29) (Paper II), and to analyse associations
between fatigue versus other variables (Paper IV).
A single-subject experimental design was used in the first intervention study (Paper I),
investigating the effect of three weeks of individualized daily outpatient physiotherapy
based on the Bobath concept, for two patients being their own controls. Twelve
repeated measures were performed over a time period of 17 weeks, using a wide
spectre of measurement-tools. We concluded that balance and gait were improved after
physiotherapy for the two patients, and that effect of treatment should be further
evaluated in a larger study.
In Paper II, the objective was to translate the MSIS-29 into Norwegian and to examine
psychometric properties of the Norwegian version for use in the climate study. The
questionnaire was answered by 64 patients prior to and at a screening session, and reanswered by 59 patients before and after four weeks of physiotherapy. Internal

14
consistency (Cronbach’s ) was 0.92 for the physical- and 0.85 for the psychologicalsubscale. Reliability by intraclass correlation coefficients were 0.86 for the physicaland 0.81 for the psychological subscale, smallest detectable change being 18.4 and21.1, respectively. The physical- but not the psychological subscale demonstrated
mostly satisfactory associations with other physical measures. Responsiveness by area
under the receiver operating characteristics (ROC) curve was satisfactory, 0.83 and
0.76, respectively. As hypothesized, effect size was larger for the physical (1.01) thanfor the psychological (0.76) subscale after treatment. We concluded that MSIS-29,
Norwegian Version demonstrated satisfactory psychometric properties.
In the main intervention study (Paper III) the objective was to examine climate
influence on the effect of physiotherapy in MS by comparing the effect of inpatientphysiotherapy in a warm (Spain) versus a cold (Norway) climate in a short- and longterm perspective. Sixty patients with gait problems and without heat intolerance were
included in a randomized cross-over study of 4-week inpatient physiotherapy. Twogroups of 30 patients were treated the first year in either Spain or Norway, andswitching treatment centre the year after. The 6-minute walk test (6MWT) as theprimary outcome measure, and other physical performance and self-reported measures,
were used at screening, baseline, after treatment and at three- and six months followup. Treatment effects were analysed by mixed models. All assessment tools
demonstrated improvement after treatment in both warm and cold climate, but todifferent degrees. After treatment, the mean walking-distance had increased by 70m in
Spain and 49m in Norway (p=0.060), and improvement in favour of a warm climate
was demonstrated at six months follow-up, 43m (Spain) compared to 20m (Norway)(p=0.048). The patients reported less exertion after walking (6MWT) in favour oftreatment in Spain at all time points (p<0.05). No significant differences in change
were detected for the other physical performance measures. Most self-reported
measures showed more improvement after treatment in Spain, but these improvements
were not sustained at follow-up. The results indicate that MS patients without heat
intolerance have additional benefits from physiotherapy in a warm climate.

15
In Paper IV, we also used data from the first part of the climate study. The aim was toinvestigate whether fatigue was associated with demographic-, clinical-, HRQoL- andphysical performance variables, and whether change in fatigue after treatment was
associated with changes in HRQoL and physical performance. Sixty patients were
included for inpatient physiotherapy, and fifty-six completed the study. Fatigue(Fatigue Severity Scale; FSS), HRQoL (MSIS-29) and physical performance (walking
ability and balance) were assessed at screening, baseline, after treatment and at followup after three and six months. We analysed possible associations between FSS andother variables at baseline by regression models, and between change in fatigue versus
changes in HRQoL and physical performance variables after physiotherapy, bycorrelation analysis. We found that fatigue at baseline was associated with HRQoL(explained 21.9 % of variance), but not with physical performance tests. Change infatigue was correlated with change in HRQoL, but not with changes in physicalperformance. All measures were improved after treatment (p0.001). While
improvements in fatigue and HRQoL were lost at follow-up, improvements in physicalperformance were sustained for at least six months (p0.05). The findings suggest thatfatigue in MS is not associated with physical performance as assessed in our study, butseemed to be associated with the patients’ experience of HRQoL.
The results from both intervention studies indicate that physiotherapy based on the
Bobath concept may cause improvement in physical performance in MS, in short- andlong term perspectives. For patients without heat intolerance, there seems to be afavourable effect of treatment in a warm climate. The translated version of MSIS-29
demonstrated satisfactory measurement properties in line with the original English
version and may therefore be recommended used as a measurement tool of HRQoL inpatients with MS. If the aim of treatment is improvement of fatigue, a broader
intervention, accounting for both physical and psychological aspects, seems necessary.

16

List of publications
The thesis is based on four papers, referred to by their roman numerals:
Paper Smedal T, Lygren H, Myhr KM, Moe-Nilssen R, Gjelsvik B, Gjelsvik O, Strand LI.
Balance and gait improved in patients with MS after physiotherapy based on the
Bobath concept. Physiother Res Int 2006;11(2):104-16.
Paper Smedal T, Johansen HH, Myhr KM, Strand LI. Psychometric properties of a
Norwegian version of Multiple Sclerosis Impact Scale (MSIS-29). Acta Neurol Scand
2009; Epub ahead of print. DOI: 10.1111/j.1600-0404.2009.01298.x.
Paper Smedal T, Myhr KM, Aarseth JH, Gjelsvik B, Beiske AG, Glad SB, Strand LI. The
influence of warm versus cold climate on the effect of physiotherapy in multiple
sclerosis. Acta Neurol Scand, resubmitted after minor revisions.
Paper V
Smedal T, Beiske AG, Glad SB, Myhr KM, Aarseth JH, Svensson E, Gjelsvik B,
Strand LI. Fatigue in multiple sclerosis: Associations with health-related quality of lifeand physical performance. Eur J Neurol 2010; Epub ahead of print. DOI:
10.1111/j.1468-1331.2010.03090.x.

17

1. Introduction
Patients with gait and balance problems caused by disease or damage of the central
nervous system (CNS) may profit from individualized physiotherapy. Intervention
based on the Bobath concept (Gjelsvik, 2008; Graham et al., 2009) aiming to improvephysical functioning through motor learning is frequently used. Knowledge of how the
CNS responds to injury and how patients reacquire lost behaviours by training havebrought promising new therapies for neurorehabilitation (Taub et al., 2002). The
theoretical basis for treatment according to the Bobath concept is neuroplasticity
referring to the ability of the CNS to change both its structure and function, as a
response to changing demands (Nudo, 2003).
Evaluation of the effect of treatment has changed during the last ten years; from
qualitative descriptions of the ability to move, to the use of more quantitative
measurements related to limitations in physical functioning. Evidence-based medicine
aiming to integrate individual clinical expertise and the best available clinical external
evidence from systematic research (Sackett et al., 1996), is strongly advocated inclinical practise today. There may, however, be a conflict between the philosophy
behind rehabilitation (in which physiotherapy is one part) and evidence based
medicine, as the reductionism commonly employed in clinical trials may be insensitive
to the individually tailored aims of rehabilitation medicine. To understand how tointegrate new scientific evidence into clinical practice, we should find the correctbalance between these two, which may be a challenge (Kesselring, 2004).
This challenge led us to design our first intervention study of this thesis (Paper I),
aiming to investigate whether physiotherapy based on the Bobath concept would
improve gait and balance in two patients with multiple sclerosis (MS). By using asingle-subject experimental design, in which the patients are their own controls, and byusing a wide spectre of outcome measures, we also aimed for finding appropriate
measurement tools, applicable for a possible future study.

18
When planning for the second intervention study which was designed as a randomized
cross-over study, the choice of measurement tools was partly based on experiencesfrom the initial study. The climate influence on the effect of physiotherapy in MS wasinvestigated, and as a part of this, we also discussed the change observed after
physiotherapy, independent of the climate influence. This climate study, which should
be considered the main work of this thesis, was carried out during approximately two
years, including pre-screening and nine repeated test points over the time period(Paper III).
We choose the Multiple Sclerosis Impact Scale (MSIS-29) for evaluation of healthrelated quality of life (HRQoL) in the climate study (Hobart et al., 2001). This
questionnaire was translated into Norwegian, and important psychometric properties of
the Norwegian version were investigated, aiming to assess whether it was applicablefor use in the climate study (Paper II).
Fatigue is one of the most frequent, but least understood symptoms in MS (Lapierre &Hum, 2007). The associations between fatigue and physical performance measures
have previously scarcely been investigated. Data from the first part of the climate
study were analysed for possible associations between fatigue and clinical- anddemographical baseline characteristics as well as HRQoL and physical performance
tests variables (Paper IV).
In our studies we have aimed to explore some important aspects of MS and treatmentthat may improve functioning.

1.1 Multiple sclerosis
MS is a chronic immune-mediated inflammatory demyelinating disease of the CNS
and is the most common non-traumatic disabling neurological condition in young
adults (Alonso & Hernan, 2008; Murray, 2006). The disease was first described in
1838, but the first extensive study and description of the disease was done by Jean-19
Martin Charcot in 1868, and Joseph Babinski wrote his medical thesis about MS in
1885 (Compston et al., 2005b). The aetiology is still enigmatic, and there is no
curative treatment. However, recent studies indicate that MS is triggered byenvironmental factors in individuals with complex genetic-risk profiles, and several
disease modifying preparations have become available (Compston & Coles, 2008).
The patients may experience a variety of symptoms, with recurring themes and an
unpredictable course (Compston & Coles, 2002). In most patients, the clinicalmanifestations indicate involvement of motor, sensory, visual and autonomic systems,
in addition to many other symptoms and signs (Compston & Coles, 2008; Noseworthy
et al., 2000). In addition to treatment of relapses and immunomodulatory treatments,
symptomatic treatments are also important for MS patients. Effective management
should require comprehensive and coordinated input from a multi-disciplinary team ofprofessionals, and different settings may be required to best meet the individual’s
needs (Freeman, 2001). MS is a challenging disease to study, as the course isunknown, the pathophysiologic mechanisms are diverse, and the unpredictable course
makes it difficult to determine whether an effect of treatment will sustain (Noseworthy
et al., 2000).

1.1.1 Patophysiology
The myelin consists of a condensed membrane spiralled around nerve cells (axons)and forms the insulating segmental sheath needed for saltatory axonal conduction.
Voltage-gated sodium channels cluster at the unmyelinated nodes of Ranvier, between
the myelin segments. The action potential is propagated and spread passively down the
myelinated nerve segment, triggering another action potential at the next node. Thus,
the myelin contributes to ensure the high velocity of conducting nerve impulses,
resulting in an effective system in bringing messages to and from the brain. In MS,
inflammatory demyelination occurs and leads to reduced velocity of impulses. The
symptoms of MS reflect the functional anatomy of the impaired conduction at theaffected sites (Compston & Coles, 2002). The severity and duration of symptoms and20recovery after an exacerbation are dependant of the intensity and resolution of theprocess and possibly remyelination. In addition primary or secondary axonal
degeneration have been demonstrated, leading to irreversible neurologic impairment(Trapp et al., 1998).
The sequence of events that initiates the disease remains unknown, but given apathological heterogeneity, it may be that more than one pathological mechanism
contributes to tissue injury (Noseworthy et al., 2000). It is presumed that genetic andenvironmental factors contribute to facilitate the movement of autoreactive T-cells anddemyelinating antibodies from the systemic circulation and into the CNS throughdisruption of the blood-brain barrier. The injury to the myelin membrane results indenuded axons that are no longer able to transmit action potentials effectively within
the CNS (Noseworthy et al., 2000). From considering MS as an intermittent disease
with inflammatory breakdown of myelin in the white matter, it is now evident that thedisease is more continues, with diffuse changes in the white and grey matter,breakdown of myelin and damage to axons (Murray, 2006). As a result of thesepathological processes, all parts of the CNS may be affected, leading to the productionof various neurological clinical symptoms (Noseworthy et al., 2000).

1.1.2 Epidemiology
About 2.5 million people are affected of MS worldwide (Compston & Coles, 2002). A
systematic review of incidence studies of MS published in Medline between 1966 and2007 indicate an overall incidence rate of 3.6 cases per 100.000 person-years inwomen and 2.0 in men (Alonso & Hernan, 2008). The prevalence varies considerablyaround the world (Compston & Confavreux, 2005), and MS is considered a placerelated acquired disease with a predilection for whites (Kurtzke, 1995). Earlier studies
have demonstrated that the incidence of the disease increased with the distance fromthe equator (Acheson et al., 1960; Miller et al., 1990), but the latitude gradient
presented in older incidence studies seems to be decreasing (Alonso & Hernan, 2008).
The highest prevalence of MS is seen in the Northern Europe, southern Australia and21in the northwest of the United States and southern parts of Canada (Compston &Confavreux, 2005; Kurtzke, 1995). African Americans develop MS less frequently
than Caucasian Americans (Kurtzke et al., 1979), but African Americans seem to havea more aggressive disease course (Cree et al., 2004). Caucasians from Scandinavian
and Scottish origin seem to be especially susceptible to the disease (Hogancamp et al.,
1997; Page et al., 1993; Rothwell & Charlton, 1998), and it has even been suggested
that the distribution of MS may be a result of Viking raids in the Middle Ages (Poser,
1995). The prevalence in Norway is around 150/100.000, but somewhat lower in thenorthern parts of the country (Gronlie et al., 2000; Grytten et al., 2006; Torkildsen etal., 2007). The Norwegian MS population is estimated to around 7000 (prevalence)(Torkildsen et al., 2007), with an incidence of about 5-6/100.000 (Celius & Vandvik,
2001; Dahl et al., 2004; Grytten et al., 2006) in recent years. The incidence has been
estimated increased from 1.8 per 100.000 in 1953 to 1957, to 6.0 per 100.000 in 1993
to 1997 (Grytten et al., 2006).
Both incidence and prevalence are approximately twice as high among woman as inmen (Hirtz et al., 2007; Noseworthy et al., 2000). An increase in the female/male
incidence ratio has been reported in recent decades for both Canada (Orton et al.,2006), northern Sardinia (Pugliatti et al., 2009) and northern France (Debouverie et al.,2007), and a recent systematic review conclude that the female-to-male ratio incidence
has increased over time from an estimated 1.4 in 1955 to 2.3 in 2000 (Alonso &Hernan, 2008).
The mean age of MS onset is approximately 30 years, and few cases are diagnosed
before the age of 15 or after the age of 50 (Hirtz et al., 2007).

1.1.3 Aetiology
Although MS has been described for more than a century, the cause of the disease isstill unknown. Epidemiologic studies support both genetic and environmental
components, and the most accepted theory is that MS is an immune-mediated disease22
with genetic susceptibility requiring an additional environmental factor (Ascherio &Munger, 2007b; Ascherio & Munger, 2007a; Compston & Coles, 2008; Kahana, 2000;
Pugliatti et al., 2008).

1.1.3.1.Genetic factors
Most MS cases occur sporadically, but about 20 % of patients have at least one
affected relative, indicating that there is evidence for genetic factors in MS (Kahana,
2000; Nielsen et al., 2005). As early as 1972, human leukocyte antigen genes were
found to be associated with MS (Jersild et al., 1972). Recently, several other immune
related genes have been identified, amongst them IL2RA and IL7RA (Hafler et al.,2007), and numbers are increasing (MSGene, 2010).

1.1.3.2 Environmental factors
An observed change in the attenuation of the latitude gradient also suggest that inaddition to genetic determinants, one or more environmental factors may play a role in
the aetiology of MS (Alonso & Hernan, 2008). Migrants, who move from an area
where MS is common into an area where it is rarer, show a decrease in rate of disease,
while people who migrate in the opposite direction tend to retain the low risk of theircountry of origin (Gale & Martyn, 1995). Age of migration within the first two
decades of life has been considered important in determining MS (Alter et al., 1978;
Dean & Kurtzke, 1971). However, similar prevalence of MS in individuals who
migrated before the age of 15 and those who migrated at older age has been
demonstrated (Hammond et al., 2000), which may indicate that the environmental
exposures may operate over a wide range of ages within the latent period (Pugliatti etal., 2008). A recent study was performed trying to identify the cause of increased
incidence of MS in French West Indies. The following environmental modifications
were suggested: return-migration from the mainland France and changes in lifestyleincluding less sun exposure and improved hygiene (Cabre, 2009).

23
Today, the most plausible environmental risk factors in MS seem to be: Epstein-Barrvirus (EBV) infection (Ascherio & Munger, 2007a), vitamin D/sun exposure
deficiency (Kampman et al., 2007; Kampman & Brustad, 2008) and smoking(Ascherio & Munger, 2007b; Riise et al., 2003).
The role of EBV in the aetiology of MS has been indicated in several studies (Myhr etal., 1998; Nielsen et al., 2007; Sumaya et al., 1985), and the EBV is the only infection
agent which has been found to be a risk factor. Risk of MS is about 10 times grater
among individuals who experienced an undiagnosed EBV infection in childhood, andat least 20 times greater among individuals who developed mononucleosis, which isoften the expression of EBV infection during adolescence or adulthood (Ascherio &Munger, 2007a). The risk of MS may be increased soon after infectious mononucleosis
and persists for at least 30 years after the infection (Nielsen et al., 2007).
Vitamin D has been shown to suppress the immune response mediated by T-cells,
which are known to be important in the MS disease process (Gorman et al., 2007).
There is indication that a functional variant of the vitamin D receptor gene interacts
with the sun exposure in childhood to influence the risk of MS (Dickinson et al.,2009), and the role of vitamin D/sun exposure has been demonstrated in several
studies. Higher sun exposure during childhood and early adolescence seems to be
associated with a reduced risk of MS, and insufficient ultraviolet radiation (UVR) may
influence the development of MS (van der Mei et al., 2003; Dalmay et al., 2010). Evennorth of the Arctic Circle, summer outdoor activities in childhood and adolescencemay be associated with a reduced risk of MS, and supplemental cod-liver oil may beprotective when sun exposure is less. This suggests that both climate and diet may
interact to influence MS risk at a population level (Kampman et al., 2007; Kampman& Brustad, 2008). Interestingly, the MS prevalence in Norway does not increase withlatitude (Kampman et al., 2007) and may be explained by the tradition of extensive
fish diet in a location with low solar UVR (Kampman & Brustad, 2008). A tendency
of more indoor activities and a diet containing less vitamin D, may account for theincreasing incidence of MS in Norway, and also in the indigenous Sami (Pugliatti etal., 2008). In general, changes in lifestyle may be associated to decreased sun

24
exposure, resulting in lower synthesis of vitamin D, and this may partly explain theattenuation of the latitude gradient (Alonso & Hernan, 2008). The relationshipbetween MS, geographic distribution, sunlight exposure and vitamin D is also
discussed in a review article of Ascherio and Munger (2007b), concluding that sun
exposure/vitamin D may reduce the risk of MS. Considering that vitamin D is
associated with MS, protection could possibly be achieved with doses of vitamin D
supplements (Ascherio & Munger, 2007b; Myhr, 2009; Niino et al., 2008; Smolders etal., 2008). An association between risk of MS and the season of birth, has been
described (Bayes et al., 2010; Salzer et al., 2010; Willer et al., 2005), and a deficiencyof active vitamin D due to reduced sun exposure during the pregnancy, may play arole, but should be further investigated (Salzer et al., 2010). For people who havedeveloped MS, season variations of relapse rate and active MRI lesions have beenreported in some studies, (Auer et al., 2000; Bamford et al., 1983; Ogawa et al., 2004),
but not confirmed in others (Killestein et al., 2002; Rovaris et al., 2001). In summary,the complex interrelationship between ultraviolet radiation, vitamin D, infections andrelapse rates require further investigation (Tremlett et al., 2008).
Cigarette smoking seems to be a risk factor for MS (Ascherio & Munger, 2007b), anda Norwegian study demonstrated that the risk of developing MS among individuals
who smoked, was nearly twice as high as in never-smokers (Riise et al., 2003).
Furthermore, an acceleration in transition from relapsing-remitting MS (RRMS) tosecondary progressive MS (SPMS) has been demonstrated in smokers (Hernan et al.,2005). The relation between smoking and risk of MS, may, in part explain the recently
reported increase in the female/male ratio in MS incidence (Ascherio & Munger,
2007b).

1.1.4 Diagnosis
MS is a clinical diagnosis, based on a careful neurological examination, and the patient
history is essential in the diagnostic process. There is no pathognomonic test for MS,
and the diagnostic criteria have changed according to new knowledge and technology.

25
Since the early 1980s, the Poser criteria were used. MS was indicated if the patient had
at least two relapses and there were evidence of involvement in white matter in morethan one cite in the CNS (Murray, 2006; Poser et al., 1983). When clinical criteria
were not met, paraclinical abnormalities within the CNS made it possible tosupplement the clinical evidence of the disease. Imaging, electrophysiology andcerebrospinal fluid examinations for oligoclonal bands were used as supplements. The
McDonald criteria is a newer system of classification which also incorporate magnetic
resonance imaging (MRI), aiming to demonstrate dissemination of disease both in timeand space (McDonald et al., 2001). These criteria allow an accurate diagnosis of MS
before the appearance of a second attack, enabling earlier decision about starting
disease modifying therapies, and a further revision of the McDonald criteria waspublished in 2005 (Polman et al., 2005).

1.1.5 Course of the disease and prognosis
The clinical course of MS in an individual patient is largely unpredictable and may
follow a variable pattern over time (Noseworthy et al., 2000). The most common
courses are either episodes of acute periods of worsening (relapses, exacerbations,attacks), or a more gradual progressive deterioration, or combinations of both (Lublin& Reingold, 1996). Relapsing-remitting MS (RRMS) is defined as “clearly defineddisease relapses with partial or full recovery; periods between relapses characterized
by a lack of disease progression (Lublin & Reingold, 1996). About 80-85 % of patients
present with a RRMS form, and a first attack is categorised as a clinically isolated
syndrome (CIS) (Murray, 2006; Noseworthy et al., 2000). About 15 % of patients withMS show a slowly progressive pattern without relapses, and this course is classified asa primary-progressive MS (PPMS). The definition of PPMS is ”a disease progression
form onset with occasional plateaus and temporary minor improvements allowed”(Lublin & Reingold, 1996). PPMS may be suggested clinically by a progressive coursethat lasts longer than six months, but laboratory studies are advised to obtainsupportive evidence (Noseworthy et al., 2000). A few of the patients with PPMS may

26later relapse, called progressive-relapsing MS (PRMS) (Lublin & Reingold, 1996;
Murray, 2006). Classification of MS is important, as the disease modifying drugs haveshown benefit only in the RRMS and not on PPMS (Murray, 2006). It has beensuggested that within 25 years duration of disease, the majority (90 %) of patients with
RRMS will develop a secondary-progressive MS (SPMS) (Weinshenker et al., 1989)
defined as “initial relapsing-remitting disease course followed by progression with orwithout occasional relapses, minor remissions, and plateaus” (Lublin & Reingold,
1996). Clinical subtypes of MS are presented in Figure 1.

Figure 1. Clinical subtypes of MS. The figures show the four main courses of MS.
(Adapted from Figure 4.7, page 195 in: Compston et al., 2005a) .

The clinical severity can be divided into “benign “ and “malign” MS. Benign MS has
been defined as a “disease in which the patient remains fully functional in all27
neurologic systems 15 years after disease onset”, while malign MS is characterized by“a rapid progressive course, leading to significant disability in multiple neurologicalsystems or death in a relatively short time after disease onset” (Lublin & Reingold,
1996).
The median survival time from onset has been estimated approximately 10 years
shorter for patients with MS than for the age-matched general population (BronnumHansen et al., 2004). Female patients and patients with young onset seem to have
longer median time to death, but higher relative risk of dying compared with thecorresponding population. Patients with PPMS have demonstrated both shorter mediantime to death from onset and a higher relative risk of dying (Grytten et al., 2008).

1.1.6 Clinical symptoms
MS is characterised by symptoms which are mainly determined by the location of theplaques in the brain and the spinal cord (CNS), the burden of the lesion and theeffectiveness of repair and compensatory mechanisms. The disease may result inmovement difficulties including gait- and balance problems due to muscular weakness,
spasticity, ataxia and tremor. Other common manifestations are: visual and sensory
disturbances, pain, fatigue, speech and swallowing difficulties, bladder-, bowel- andsexual dysfunctions, cognitive and mood changes and hypersensitivity to external andinternal temperature increases (Alusi et al., 2001; Boissy & Cohen, 2007; Noseworthy
et al., 2000; Ponichtera-Mulcare, 1993; Vazirinejad et al., 2008).

1.1.6.1 The International Classification of Functioning, Disability and
HealthThe clinical symptoms of MS influence on functioning in different ways, and whenassessing the effectiveness of drugs and rehabilitation programmes, the overall
functioning should be taken into account (Asano et al., 2009). The World HealthOrganization’s International Classification of Functioning, Disability and Health (ICF)28(World Health Organization, 2001) defines a common language for describing theimpact of disease at different components of functioning (Khan & Pallant, 2007). The
ICF is a comprehensive and integrated system for describing functioning and disability
for a person and is considered a bio-psychosocial model of functioning (Mills et al.,2010). The model (Figure 2) includes Body Functions and Structures and Activities aswell as Participation. In addition, Personal and Environmental factors are included ascontextual factors. Functioning is a term including all body functions, activities andparticipation, while disability serves as a term for impairments, activity limitations orparticipation restrictions (Stevenson & Playford, 2007). Dimensions of functioning are
affected by interactions between health conditions and contextual factors(environmental and personal). These components (except for personal factors) containmore than 1400 ICF categories (Kesselring et al., 2008). The ability of the ICF
categories to describe the spectrum of functioning and disability as well as
environmental factors in MS has been demonstrated (Holper et al., 2010). “Core Sets”
are lists of ICF categories considered to be most relevant for patients having aparticular health condition, and development of Core Sets for MS is now in process(Kesselring et al., 2008).

Figure 2. Interactions between the components of ICF (From Figure 1, page 18 in:
World Health Organization, 2001).

29
The wide spectrum of clinical symptoms in patients with MS, may affect the different
functional components in the ICF model. A multidisciplinary rehabilitation should
therefore focus on all components in the ICF model in the context of both
environmental and personal factors (Stevenson & Playford, 2007). The main focus in
our intervention studies was motor problems, mainly investigated at the Body
Functions and Structures and the Activities components. Consequently, these aspects
will be highlighted through the thesis. However, the importance of other symptoms
should be emphasized, also having in mind how a patient copes with different
problems, also influenced by socio-cultural-, psychological,- economic,- andenvironmental factors (Freeman, 2001).

1.1.6.2 Motor symptoms
Lesions in the pyramidal tracts (motor system) as well as brainstem, cerebellum andvestibular nuclei, may lead to disorders related to motor control. Symptoms likespasticity, ataxia, tremor, muscular weakness, fatigue and sensory disturbances maylead to reduced movement control (McDonald & Compston, 2005). When treating
movement disturbance in patients with MS, it is important to explore which CNS
systems that are affected by the disease and the functional consequences for thepatient. Treatment should be adjusted accordingly.
Gait- and balance disturbances due to weakness, spasticity and ataxia are commonly
seen in patients with MS (Olgiati et al., 1988; Rodgers et al., 1999; Soyuer et al., 2006;
Thompson, 2001). Patients report gait as one of the most valuable functions (Heesen etal., 2008). Factors reported to cause increased risk of accidental falls in MS arechanged gait pattern, limited walking ability, impaired proprioception and vision,
spasticity, divided attention, reduced muscular endurance, fatigue and heat sensitivity(Nilsagard et al., 2009). The ability to maintain balance in standing seems to be amarked problem (Frzovic et al., 2000), and low scores on balance and gait tests havebeen reported as significant predictors of perceived difficulties or dependence in
activities of daily living (ADL) (Paltamaa et al., 2007). After 15 years, the probability

30
of managing without walking assistance is estimated to about 60 % and managing
without a wheelchair, about 76 % (Myhr et al., 2001).

1.1.6.3 Other symptoms
Severe reduction in visual activity may follow serial episodes of optic neuritis or may
be a result from progressive visual loss. Visual disturbances may also relate to diplopia
due to brain stem lesions. Vertigo, dysarthria and dysphagia may be other disabling
brainstem symptoms (Thompson, 2001).
Involvement of the autonomic nervous system is frequently observed in MS(McDonald & Compston, 2005), and in particular bladder disturbances are known tohave an important impact on quality of life (QoL). In addition, sweating,gastrointestinal and cardiovascular disturbances may cause serious complaints, and it
is hypothesised that the autonomic dysfunction may not only be a consequence of thedisease, but may in itself affect the course of MS (Flachenecker, 2007). Cardiovascularand sudomotor autonomic abnormalities may not be explained by a lesion at any one
site within the CNS, but be due to wide spread abnormalities of the CNS (McDougall& McLeod, 2003). Respiratory insufficiency is another symptom, resulting from
respiratory muscle weakness or aspiration (Thompson, 2001).
A high number of persons with MS suffer from “invisible” symptoms, such as fatigue,
depression and cognitive dysfunction during both early and late stages of the disease(Stuke et al., 2009).
Fatigue is one of the most frequent, but least understood symptoms in MS (Lapierre &Hum, 2007; Putzki et al., 2008; Stuke et al., 2009) and has been reported as thesymptom that interferes most with daily life activities (Kesselring, 2004; Paltamaa etal., 2006). The syndrome of fatigue is characterised by uncontrollable apathy,
exhaustion, fatigability and lack of energy which has not been experienced to the same
extent before onset of the disease (Zifko, 2004). There is no universally accepted
definition of fatigue, but it may be defined as an overwhelming sense of tiredness, lackof energy or feeling of exhaustion (Comi et al., 2001). More recently fatigue has been

31
defined as “reversible motor and cognitive impairment with reduced motivation anddesire to rest. It could appear spontaneously or may be brought on by mental or
physical activity, humidity, acute infection and food ingestion” (Mills & Young,2008). As fatigue seems to be a multidimensional, complex and highly subjective
symptom, it is likely that several factors play a role in the origin. Primary fatigue may
result from centrally mediated processes like: brain lesions, axonal damage, functional
cortical reorganization, immunological and neoroendocrine factors and peripheral
mechanisms at muscle level (Kos et al., 2008). In general, patients with MS appear to
recruit a more extensive neural network, often bilateral, to maintain proper motor
output. This may explain some aspects of the phenomenon of fatigue (Morgen et al.,2004). It has also been suggested that impaired central motor activation is due tointerruption of the cortico-subcortical motor circuits involving the motor cortex(Andreasen et al., 2010) and that fatigue could be due to a higher brain working loadrequired to perform a mental or physical activity, or to an internal overestimation ofsuch load (Leocani et al., 2008). Secondary factors, which may lead to fatigue, aresleep disorders, reduced activity, psychological factors and depression. Due to theheterogeneity of the fatigue symptom, both primary and secondary fatigue can bepresent in one individual, and they may also have an impact on each other (Kos et al.,2008). Fatigue and depression in MS have been found to be unrelated to diseaseprogression and seem to persist at about the same level over time (Koch et al., 2008).
However, fatigue in MS has shown inverse correlation with self-esteem, suggestingthat fatigue may interfere with the way in which patients value themselves (Fragoso etal., 2009). It has also been suggested that physical activity is indirectly associated with
QoL through pathways that include fatigue, pain, social support, and self-efficacy inindividuals with MS (Motl & McAuley, 2009), but the effects of exercise on fatigue
are inconsistent (Heesen et al., 2006). The first step in managing MS-related fatigue
may be to identify and try to eliminate any secondary causes (Zifko, 2004), and it has
been suggested that treatment of fatigue requires a multidisciplinary approach(Kesselring, 2004).

32
Anxiety and depression is a more frequent problem for patients with MS as comparedto the general population, which has recently been confirmed in two Norwegianstudies (Dahl et al., 2009; Beiske et al., 2008). There seems to be a need of greater
focus also on these aspects to establish appropriate treatment.
Cognitive impairments like deficits of attention, memory and executive function arecommonly seen in patients with MS and have great effects both on the patients andtheir families and friends (McDonald & Compston, 2005). Cognitive rehabilitation
strategies have demonstrated some positive effects, but there is a need of larger studies
with more standardized treatment and outcome measures (Messinis et al., 2010).
Also pain and sensory complaints are frequent problems in patients with MS andfound to be independent of age, gender, and course and duration of the disease. Thereis a need of determining how these symptoms affect functioning in order to choose theappropriate treatment (Beiske et al., 2004). Pain symptoms have been divided into
three categories; tendinoskeletal-, psychogenic- and neurogenic, and pain has beensuggested to be more often of neurogenic origin than caused by secondary
tendinoskeletal disorders (Vermote et al., 1986). Presence of pain has a negative
impact on both QoL and ADL and seems to be an issue that warrants more attention(Grasso et al., 2008).

1.1.7 Health-related quality of life
Quality of life (QoL) embraces all aspects of well being and includes social,emotional, economic and cultural facets of our lives. The term “health-related qualityof life” (HRQoL) captures those aspects of life quality or function which are
influenced by health status (Benito-Leon et al., 2003). Clinicians focus on HRQoL,
although all aspects of life can be health-related in an ill or diseased patient, and twopatients with the same clinical criteria may often have completely different responses
on HRQoL (Guyatt et al., 1993). HRQoL studies represent a rather new field in MS
research, with the first study published in 1992 (Rudick et al., 1992), finding that33
patients with MS had the lowest HRQoL as compared to patients with rheumatoid
arthritis and inflammatory bowel disease. Impaired mobility and symptoms likefatigue, pain, depression and spasticity seem to be important factors related to reduced
QoL (Zwibel, 2009). QoL and HRQoL are multidimensional concepts, based on
subjective experiences, and may vary over time and in different situations. The validityof using quantitative instruments to measure a qualitative phenomenon, could bequestioned (Torkildsen, 2008). However, there is an increasing understanding that
global wellbeing of patients with MS is a valuable outcome in therapeutic trials as itemphasizes neuropsychiatric and social complications as well as impairment anddisability components, and therefore may give important information (Benito-Leon etal., 2003).

1.1.8 The effect of heat and climate in MS
A generally accepted opinion is that persons with MS may be sensitive to heat andexperience increased MS related symptoms due to increased temperatures. Decreased
tolerance for high temperatures has been frequently reported (Simmons et al., 2004).
However, the magnitude of increase in temperature that is necessary to precipitate
symptoms, appears to be unique to each person, and the relationship between
endogenous and exogenous sources of heat versus MS symptoms remains unclear(Ponichtera-Mulcare, 1993). Animal studies have indicated reversible conduction
block with increased temperature in partly demyelinated nerve fibres (Rasminsky,1973), while Uhthoff (1890) described a temporary worsening of vision withincreasing core body temperature in patients with optic neuritis. With increasing coretemperature, all activities in the body go quicker, and re-myeliniated nerve fibers may
have reduced function, leading to temporary increase in symptoms with increased
body temperature, such as after exercise or hot bath (Compston & Coles, 2008;
Ponichtera-Mulcare, 1993). Scholl et al. (1991) concluded that Uhthoff's symptom wasa prognostic indicator for the early development of MS, and for many years, the "hotbath test” (Davis, 1966) was used to diagnose MS. A person suspected of having MS

34
was immersed in a hot tub of water, and watched to see if neurological symptoms
appeared or got worse, which would earn them a diagnosis of MS. The aetiology of theheating reactions may be multifactorial, including heat itself, effects of serum calcium,
blockade of ion channels, circulatory changes, heat shock proteins and unidentified
humoral substances (Guthrie & Nelson, 1995). On the other hand, cooling therapy has
been associated with measurable, but modest improvement in motor and visualfunction (Schwid et al., 2003).
A study has indicated seasonal variation in MS exacerbations with significantly more
attacks in the warmest and coldest months in Japan (Ogawa et al., 2004). However,limited impact on relapses was demonstrated in connection with a summer heat wave
in France in 2003 (Tataru et al., 2006). The authors hypothesize that the adverse
symptoms associated with high temperature, may require rapid rise in ambient orinternal body temperature.
Norwegian patients with MS, who do not experience heat intolerance, have anecdotic
reported less stiffness and that it is easier to move in a warm climate.

1.1.9 Medical treatment
There is no curative treatment for MS. However, medical treatment strategies are
given in three main areas of intervention: 1) relapses (attack or exacerbation), 2)
disease-modifying treatment (first-, second- and third line treatment) and 3)
symptomatic treatment of common complaints in MS. The first two aim to influence
the inflammation to reduce secondary tissue damage (Myhr, 2008). Relapses usually
have a subacute onset and may appear as either new nervous system deficits or as
worsening of previous ones, and last for at least 24 hours (McDonald et al., 2001).
Relapses are treated with intravenous or oral methylprednisolone, aiming to speed up
the recovery, but there is no evidence for long term effects on the degree of recovery
or risk of new relapses (Myhr, 2008; Sellebjerg et al., 2005). A combination of steroids

35
with planned comprehensive multidisciplinary team care has been suggested to besuperior to standard therapy (Craig et al., 2003).
Disease-modifying therapies aim to minimize disease activity to prevent the
progression of disability, and four different modifying compounds are available:interferon-beta (IFN-ß), glatiramer acetate (GA), natalisumab and mitoxantrone.
Patients with CIS, who have substantial changes in MRI and/or serious functional loss,
are treated with first-line treatment; IFN-ß or GA. Patients with RRMS who recently
had an attack, should also be treated. Patients with SPMS, but still having some
attacks, should be considered for treatment with IFN-ß. Both IFN-ß and GA seem toreduce the relapse rate by about 30 % and MRI disease activity by 50-75 % and seemto slow down the development of permanent loss of function. With high diseaseactivity despite adequate first-line therapy with IFN-ß or GA, patients should beconsidered for second-line treatment; natalizumab. With still a high activity, third-line
treatment with mitoxantrone should be considered. SPMS patients with clinical or
MRI evidence of inflammatory disease activity, may be treated with mitoxantrone,
independent of previous treatment (Myhr, 2008).
In addition to medical treatment of relapses and disease-modifying treatment, it is also
important to evaluate patients with MS for treatment of symptoms like spasticity, pain,
depression and bladder dysfunction (Myhr, 2008).

1.2 Rehabilitation in MS
While disease-modifying therapies aim to influence the degree of disability, therelapse rate and clinical progression (Noseworthy et al., 2000), the aim of
rehabilitation is to ease the burden of symptoms by improving self-performance andindependence (Kesselring, 2004).
Rehabilitation has been defined as a reiterative, active, educational problem solving
process focusing on a patient’s behaviour (disability), and the following components

36
are involved: assessment, goal setting, intervention and evaluation. The rehabilitation
process aims to maximise the patient’s participation in his or her social setting, tominimize the pain and distress experienced by the patient, and to minimize the distresson the patient’s family and carers A rehabilitation service comprises amultidisciplinary team of people working together towards common goals for eachpatient, involving and educating the patient and family (Wade & de Jong, 2000). A
multidisciplinary team may include the following professionals; a neurologist or
rehabilitation physician, a rehabilitation or MS nurse specialist, physiotherapist,
occupational therapist, speech and language therapist, psychologist, psychiatrist,
family doctor, neuropsychologist, social worker, urologist and internist. In addition,other specialists may be involved when needed (Cabrera-Gómez, 2007; Stevenson &Playford, 2007). Neurological rehabilitation should be a continuous process
throughout the development of the disease and should take place both at specialized
centres and in the community (Cabrera-Gómez, 2007). When managing MS, the aim
should be to enable each patient to do as well as possible with regard to the disability
and symptoms, by treating the disease, the symptoms and the person who has thedisease (Schapiro, 2009).
In rehabilitation settings, the ICF model can be used to identify a patient’s impairment
in body functions and structures, limitations in activity, and participation restriction.
Management of these problems may be linked in with the psychosocial andenvironmental factors (Khan & Pallant, 2007). Using the ICF model in rehabilitationof patients with MS, therefore seems to be a suitable and practical way of organizing
the rehabilitation (Khan & Pallant, 2007).
While setting the agenda for rehabilitation in MS, it has been advocated thatrehabilitation needs to focus beyond ambulation and also address the “hidden”
disabilities, like the interaction between fatigue, depression and cognitive impairments
and how these problems may impact on participation in daily life (Mayo, 2008).
Nevertheless, various forms of physical training may be one important part ofrehabilitation (Wiles, 2008). In a population based survey of people with MS, ADL
and social/lifestyle activities were found to be affected in two-thirds, and the most37
affected items were items that could be classified as mobility-related and physicallydemanding. These results highlight the importance of adequate exercise treatment andrehabilitation aiming to improve independence (Einarsson et al., 2006).
Several studies have investigated the effect of inpatient and outpatient rehabilitation,
also including various forms of physical training. However, many lack a clear
description of the intervention, and in general, the long term effect is scarcely
investigated (Wiles, 2008). It may be a challenge to demonstrate the effect of anintervention that is “all-inclusive” and often poorly defined, for a patient group inwhich mechanisms of disability are poorly understood. Nevertheless, such studies areimportant and feasible, but demand that trial methodology and choice of outcome
measures have been carefully considered (Thompson, 2000).

1.2.1 Neuroplasticity and possible implications for rehabilitation
Although considerable changes in the brain may be detected at MRI, the lesions areoften associated with limited clinical symptoms; the so-called “clinico-radiologicalparadox” (Pelletier et al., 2009). One suggested explanation for this is the neuroplastic
mechanisms mediated by various processes, among them; a cortical reorganization
process. Functional and structural changes take place in the cerebral cortex after injury
and are shaped by the sensorimotor experiences. Undamaged parts of the brain are
remodelled during the recovery (Nudo, 2003). This neuroplastic processes may reducethe clinical expression of motor disorders during the early stage of MS, andrehabilitation strategies should be based on specific training to enhance thesemechanisms (Pelletier et al., 2009).

38

1.2.2 Physiotherapy and physical training in MS
The knowledge of brain plasticity gives optimism and supports the use of rehabilitative
training as a tool to improve brain reorganization and functional outcome (Kleim &Jones, 2008).
Physical training can be addressed in different ways, using different methods.
Previously, patients with MS were recommended not to exercise, because symptoms
might worsen with an elevated body temperature. Inactivity may, however, result inincreased fatigue, weakness and health risks (Heesen et al., 2006), and muscular
weakness may be a consequence not only of altered central motor drive, but also of
disuse (Gallien et al., 2007). Recent studies suggest that patients with a stable disease
and moderate disability (Expanded Disability Status Scale; EDSS score d 6.0)
(Kurtzke, 1983) can improve their physical fitness from exercise with supervision,
without adverse effects (Heesen et al., 2006; Rietberg et al., 2004). In a review study,no evidence was found in favour of specific exercise programmes compared to others
in improving activities and participation. Also, no evidence was provided for the effectof exercise therapy on fatigue (Rietberg et al., 2004). Resistance training has recently
been demonstrated to improve muscle strength and functional capacity in moderately
impaired patients (Dalgas et al., 2009). More research is needed to define the nature ofphysical training that provides health benefits without exacerbating underlying
inflammatory stress associated with disease pathology (Ploeger et al., 2009). There isalso a need to establish a stronger evidence base to support the use of physical activity
and exercises for various subgroups of adults with physical disabilities (Rimmer et al.,2010).
When the patients experience motor and sensory disorders, physiotherapy may be
implemented as an important part of the rehabilitation process. Depending on the stageof the disease, different aspects of functioning are emphasized, and over time, theimportance of improving or maintaining physical performance seem to be central(Stevenson & Playford, 2007). Physiotherapy has been suggested implemented early to
influence gait (Boissy & Cohen, 2007). In addition to being important for daily

39functioning, a walking patient is less likely to develop problems like contractures,decubitus ulcers, venous thrombosis, osteoporosis, as well as bowel and bladdercomplications (Kelleher et al., 2009). Physiotherapy is commonly given to patientswith MS, but limited scientific evidence of effect or non effect exists. However, it has
been demonstrated that specialized neurological physiotherapy helps to improve
mobility, balance, walking, wellbeing and mood (Wiles et al., 2001), indicating thatphysiotherapy may be one appropriate way of influencing neuroplasticity in order toenhance motor control. In this study, the physiotherapists used a facilitation approach,which seems to be similar to the Bobath concept.
Also other studies have demonstrated positive effects of physiotherapy in MS. A pilot
study indicated improved gait ability, gait quality and balance after treatment,
comparing a facilitation approach with a more task oriented approach. There was no
significant difference in improvement between the two approaches (Lord et al.,1998b).
Another study has compared the effect of neurophysiologically based physiotherapy
including individual facilitation techniques, with the effect of only aerobic training anda third group with a combination of these two modalities, as well as a comparisongroup of patients who did not change their training habits (Rasova et al., 2006). The
patients who participated in one of the training programmes, showed a significant
improvement in the examined parameters as compared to those who did not change
their training habits. The neurophysiologically based physiotherapy had the greatest
impact on the EDSS, while the aerobic training had the greatest impact on spirometricand spiroergometric parameters. The authors conclude that it is important for patientsto undergo a physiotherapeutic programme that should be specifically tailored to eachpatient (Rasova et al., 2006).
A recent review reports benefit from both physiotherapy, rehabilitation and otherspecific and non-specific techniques (Wiles, 2008). Interestingly, there is now an
ongoing two strand multi-centre trial evaluating which form of physical activity
optimises outcome for people with MS, in which the patients are stratified according to40
mobility. In this study different interventions like; yoga, physiotherapy led exerciseclass, fitness instructor led class, one on one physiotherapy and control groups will becompared (Coote et al., 2009).
Taken together, limited evidence makes it difficult to conclude regarding prescriptionof exercises and modalities of physiotherapy. Irrespective of such evidence for groupsof patients, treatment should be tailored to the individual’s need, as also suggested by
Asano et al. (2009); “the aim of gathering evidence would be to match intervention toindividuals’ needs and lifestyles”.

1.2.2.1 The Bobath Concept
The Bobath concept is presently described as a problem-solving approach to theassessment and treatment of individuals with disturbances of function and movement
due to a lesion of the CNS (Gjelsvik, 2008; Graham et al., 2009). It was developed by
the physician Karel and physiotherapist Bertha Bobath in the 1950s and has beencalled a neurofacilitation approach along with other treatment approaches developed in
the same time period (Rood, Brunnstrøm and Proprioceptive Neuromuscular
Facilitation; PNF) (Shumway-Cook & Woollacott, 2007). The current theories ofmotor behavior have been developed from systems theory (Shumway-Cook &Woollacott, 2007), and the organization of motor behavior is seen as a nonhierarchical,
self-organizing system driven by multisensory input. An important issue is also that
motivation is necessary for motor learning. The motor processes interact withcognitive and perceptual processes, and movement should be understood in a taskoriented context, as goal-directed actions which are based on past experiences and theenvironment. The Bobath concept is based on knowledge about plasticity and how the
CNS responds to injury. Function of the CNS may be altered on a synaptic level byexternal influences, and use and repetition is necessary for establishing new skills. The
use of facilitation during intervention has been a key feature of the Bobath concept
since its inception, and facilitation techniques are used when considered necessary to41
initiate movement and/or improve quality of performance (Gjelsvik, 2008; Graham etal., 2009).
The aim of treatment is to facilitate the recovery process, to regain and (re)learn motor
control, aiming to help the patients move as efficiently as possible. The CNS learns
how we move, and due to plasticity, the CNS may change its function depending on
experiences. In other words; learning by doing. The facilitation of postural control,
specifically core stability through trunk, pelvis and hip control, is considered a main
focus in treatment. Optimizing body alignment and maintaining range of movement isseen as a prerequisite for more efficient movement control. Analysis of movement infunctional activities determines which component of dysfunction (impairment) that
seems likely to cause activity limitation. When possible, the aim is to guide the patient
towards efficient movement strategies for task performance. In intervention, the focus
is on all three components in the ICF model; Body Functions and Structures, Activity
and Participation, and there is no single recipe for treatment. However, in the treatment
sessions the therapist and patient work mostly on the components of Body Functions
and Structures, and Activity. Assessment, goal setting, treatment planning andimplementation of treatment are individualized and tailored to each patient (Gjelsvik,
2008; Graham et al., 2009).

42

2. Aims of the study
The aims of the study were to explore the effect of physiotherapy, based on the Bobath
concept, on individuals with MS, and to examine whether the climate had an impact on
the effect of physiotherapy. In order to assess change in quality of life, the MSIS-29
was applied in the climate study after being translated into Norwegian and examined
for measurement properties. In addition we also aimed to examine the impact of
HRQoL and physical performance on fatigue.

The work consists of four studies with specific aims:
1. To evaluate the effect of physiotherapy based on the Bobath concept for patientswith balance and gait problems due to MS, and to evaluate the ability of different
functional tests to demonstrate change (Paper I).
2. To translate the Multiple Sclerosis Impact Scale (MSIS-29) into Norwegian, and to
examine psychometric properties of the Norwegian version (MSIS-29 NV) (Paper II).
3. To compare the effect of inpatient physiotherapy in a warm (Spain) versus cold
(Norway) climate in a short- and long term perspective, for patients with gait
disturbances due to MS (Paper III).
4. To investigate whether fatigue was associated with demographic-, clinical-, healthrelated quality of life (HRQoL)- and physical performance variables, and whether
change in fatigue after treatment was associated with changes in HRQoL and measuresof physical performance (Paper IV).

43

3. Materials and methods
The four papers were based on studies of patients with gait disturbances due to MS.
Information about the number of patients, gender, study design and statistics applied ineach of the four papers, are shown in Table 1.

Table 1. Overview of participants, gender, designs and applied statistics in the four
papers
Paper

Patients

DesignStatistics

1/1

Single-subject experimental design

Descriptive Statistics
2 SD band
Effect size

64

39/25

Repeated measurements;- test-retest- longitudinal

Descriptive Statistics
Cronbach’s alpha ()ICC (1,1)
SEM
SDC (2.77 x SEM)
Pearson correlation
Spearman rank correlation
Area under the ROC curve
Effect size

III

60

36/24

Randomized cross-over design

Descriptive Statistics
Independent t-test
Paired samples t-test
Mann-Whitney test
Chi-square test
Mixed model
SDC (2.77 x SEM)

IV

56

33/23

Cross-sectional andlongitudinal designn

Women/men

I

2

II

Descriptive Statistics
Univariate regression
Stepwise regression
GLM
Paired samples t-test
Pearson correlation
2 SD band = ±2 standard deviations of baseline scores, carried forward, evaluating data points outside this band;
ICC = Intraclass correlation coefficients; SEM = Standard error of measurement; SDC = Smallest detectablechange; Area under the ROC curve = area under the receiver operating characteristics curve; GLM = Generallinear models

44

3.1 Patients
Two patients were included in the first, and sixty in the second intervention study (theclimate study). For inclusion and execution criteria in the first study, see Paper I.
Paper II, III and IV are based on data from the climate study, including mostly thesame patient group.
In the test-retest analysis at screening (Paper II), we included data collected from 64
who underwent screening, although some dropped out at baseline.
In paper III, the analyses are based on data from the 60 included patients who started
treatment. Inclusion criteria for participation in the study were gait problems withmoderate disability equivalent to an EDSS score of 4.0-6.5. For further information
about inclusion and exclusion criteria, see Paper III.
In study IV, one patient dropped out during the treatment period, and three patients
dropped out after treatment. One patient was not tested physically at six months
follow-up due to a bone fracture, and mean change of the total group was added to theprevious test values for this test point. However, results were similar also whenexcluding data from this patient. Thus 56 patients were therefore available for analysis
in Paper IV.
Participation was based on written informed consent, and the studies were approved by
the Regional Committee for Medical and Health Research Ethics and the NorwegianSocial Science Data Services.

3.2 Measurement tools
Outcome measures used in each of the papers and suggested components offunctioning according to the ICF model are presented in Table 2. The data wereanalysed using the SPSS version 14 and 15, Stata version 10 and Excel.

45
Table 2. Outcome measures used in each of the four papers, and suggested captured
components of the ICF model
Paper
Test

ICF component

I

BFS, Activity

X

Rivermead Visual Gait Assessment

BFS, Activity

X

Berg Balance Scale

Activity

X

Timed Up & Go

Activity

X

Visual Analogue Scale; gait

Activity

X

Rivermead Mobility Index

Activity

X

Borg Rating of Perceived Exertion Scale

BFS

X

X
X

GAITRite

®

II

III

IV

X

X

X

X

X

Patient Global Impression of Change

Functioning overall

X

Clinical Global Impression of Change

Functioning overallX

Semi-structured interview

BFS, Activity, ParticipationX

6-minute walk test

Activity

10-metre timed walkActivity

X

X

Trunk Impairment Scale

BFS

X

X

Expanded Disability Status Scale

BFS, Activity

X

Multiple Sclerosis Impact Scale (MSIS-29)

BFS, Activity, Participation

X

X

X

Fatigue Severity Scale

BFS, Activity, Participation

X

X

Modified Health Assessment
Questionnaire

Activity, Participation

X

Numerical Rating Scale; gait and balance

Activity

X

Numerical Rating Scale; pain
BFS
ICF = International Classification of Functioning, Disability and Health
BFS = Body Functions and Structures

X

X

X

X
X
X

3.3 Intervention
The intervention studies were based on physiotherapy treatment according to the
Bobath concept, described in chapter 1.2.2.1. The treatment in the first study (Paper I)
was performed by two specialized physiotherapists. The treating physiotherapists inthe second study (Paper III) received a 4-day course on treatment based on the Bobath
concept.

46
To clarify the contents of treatment according to the Bobath concept, a description of ahypothetical treatment session is included:
A 40 years old woman with gait and balance problems due to MS, uses a unilateralwalking aid. Observation demonstrated a wide-stepping gait, stiff and flexed legs,
flexed posture, reduced weight transfer during stance, ataxia with mild distal
hypertonia and hyperreflexia of lower legs and feet, immobile head and staring eyes.
Through clinical reasoning it was hypothesized that her balance and walking problems
were due to: reduced postural stability, mobility and endurance of the trunk, pelvis andhips combined with reduced mobility and adaptability of the feet during weightbearing, with hyperreflexia of the calf muscles. It was hypothesized that her CNS
received disturbed somatosensory information due to impairments of tonus, mobility,
stability, coordination and alignment. In addition she compensated for reduced balance
by using visual feed-forward and cognitive strategies. The treatment aimed at
improving gait and balance. Through handling by the therapist, the mobility of legs
and feet was treated (in sitting and supine). The coordination of hips and pelvis was
facilitated through specific bridging exercises (in supine) in relation to the improved
adaptability of the feet. In sitting, her thoracic spine was mobilised into more
extension, and postural stability was facilitated. In standing, weight transference
through the feet in both anterioposterior and lateral directions, was facilitated by thetherapist, to improve the coordination through her body. In standing, guided by thetherapist, she further worked with going up and down on her toes, to increase posturalcontrol, strength and endurance. She also worked with coordination of the pelvis, feetand trunk in the activity of sitting to standing and to one-legged standing in
preparation for stepping and walking. In addition she practised standing with her eyes
closed, aiming to improve the perception of her body in space over more adaptable
feet. This was done to reduce overuse of visual and cognitive strategies. The patient
experienced walking with improved alignment and coordination, first throughfacilitation by the therapist and then independently.

47This treatment session demonstrates the combination of interventions on the Body
Functions and Structures, and Activity components of the ICF, and how the therapist
uses handling to improve motor control when necessary.

3.4 Paper 
One 32 years old man and one 48 years old woman with gait- and balance problems
and relapsing-remitting MS in a stable phase were included in this study. We used asingle-subject experimental design (SSED) with ABAA phases; A: at baseline, B:
during treatment, A: immediately after treatment and A: after two months. In thisdesign the patients are considered their own controls. The tests were performed 12
times, three at each phase, with one week between the tests. The treatment was given
for three weeks and was based on the Bobath concept. The outcome measures arelisted in Table 2. Due to the aim of evaluating the usefulness of different functional
tests, we did not consider one special test as the primary outcome measure prior to thestudy start. We also used semi-structured interviews three times; immediately after
treatment and three as well as eleven weeks after treatment. By the interviews weaimed to capture the patients’ experiences regarding bodily functioning, ADL andcomments from family and friends.
The effect of the intervention was examined using the 2 SD band method based on thebaseline data. A statistically significant change is indicated if at least two consecutive
data points after the baseline phase fall outside the 2 SD range (Nourbakhsh &Ottenbacher, 1994). To compare the amount of change and thus sensitivity to change
in the different measures, we calculated the effect size (ES). To obtain a more
representative value of variability of data expressed by the SD, we included all data
points at baseline and at follow-up to compute a common SD. The following
procedure was used: >mean change (follow-up ÷ baseline)@ / >(SD follow-up + SD
baseline)/2@. The ES is a unit-less term allowing direct comparison of change between

48
the measures. We also presented mean scores and SD for all time points and made asummary of the semi-structured interviews.

3.5 Paper 
We chose the Multiple Sclerosis Impact Scale (MSIS-29) to evaluate self-reported
HRQoL in the climate study. The questionnaire was originally generated frominterviews with patients with MS, opinions from multidisciplinary experts on MS andfrom literature reviews, and resulted in a 29-item questionnaire with two subscales.
Twenty items address the physical domain with questions regarding ambulation,
mobility, physical symptoms and functioning, while 9 items address the psychologicaldomain with questions about mood, role limitations and autonomy (Hobart et al.,2001). For each item there are 5 alternative levels for estimating the degree of the
problem, and the higher the score, the more is the impact of the disease on the patient's
daily life (MSIS-29: see Appendix 3).
MSIS-29 was translated into Norwegian (MSIS-29 NV; Norwegian Version) inagreement with Dr. J Hobart (Appendix S1 in Paper II). We made a forward andbackward translation procedure according to guidelines for translation and crosscultural adaptation (Beaton et al., 2000; Meadows et al., 1997; Sartorius N & Kuyken
W, 1994). The intention was to establish a Norwegian version which was conceptuallyequivalent to the original questionnaire and culturally relevant to the target populationin Norway. The original English version was translated by three physiotherapists,being independent and bilingual translators, whose first language was Norwegian. The
three translated drafts were used to develop a first joint Norwegian version. An expert
panel discussed the version, resulting in a slightly adjusted questionnaire. Three MS
patients, two males and one female were then asked to fill in the questionnaire. In agroup setting they were asked to consider the relevance of the different questions,
whether the questions were easy to understand, and whether the questionnaire was user
friendly. Finally, the backward translation was done by a bilingual Norwegian

49
physiotherapist and researcher. Particular problems encountered during the process oftranslation, and how they were solved, are outlined in chapter 5.2.1.
After the translation process, psychometric properties of the translated version were
examined. Repeated measurements, from 64 patients that underwent screening for theintervention study, were obtained, and test-retest reliability was calculated, estimating
both relative and absolute reliability. Relative reliability is based on the assumptionthat if a measurement is reliable, individual measurements within a group will
maintain their position within the group on repeated measurement. (Domholdt E,
2005). Relative reliability was calculated by intraclass correlation coefficient (ICC).
Absolute reliability indicates to what extent a score varies on repeated measurements
and is expressed by standard error of measurement (SEM). The smallest detectablechange (SDC) is an estimate of measurement error in two repeated measurements ofthe same individual, (2.77SEM) for 95 % of pairs of observations (Bland & Altman,
1996). Knowing the SDC of a measure helps the rehabilitation professionals or
researcher to evaluate whether a change is above measurement error in individual
patients.
Internal consistency by Cronbach’s alpha tells whether multiple items of aquestionnaire measure a single underlying concept. Internal consistency was calculated
for each subscale separately. The homogeneity of both subscales was evaluated bycorrelating the scores of each item and the respective total subscale score (item-total
correlations). The alpha value of each subscale was also examined when each of theitems were deleted (alpha if item deleted) (Streiner & Norman, 2008), but these results
were not included in Paper II. Construct validity was assessed by examining
predefined hypothesis as recommended by Terwee et al. (2007). Responsiveness is
considered the ability of a questionnaire to detect clinically important change overtime, even if these changes are small (Guyatt et al., 1989). The receiver operating
characteristics (ROC) curve is a graph depicting the true positive (sensitivity) versus
false positive (1- specificity) values for each cut-off points in score change. The area
under the curve (AUC) is a measure of responsiveness, being a measure of the abilityof an assessment tool to distinguish patients who have, and have not changed, using an

50external criterion of change (Deyo & Centor, 1986). In our study of responsiveness,
we used treatment versus no treatment as an external criterion and expected that aperiod with treatment would demonstrate a change, while a period without, would not.
We also evaluated responsiveness by testing a predefined hypothesis that ES of change
after intervention would be larger for the physical than for the psychological subscaleof the MSIS-29, since the focus of treatment was on physical functioning.

3.6 Paper III
In this study we compared the effect of inpatient physiotherapy in a warm versus cold
climate in a short- and long term perspective, for patients with gait disturbances due toMS.
Based on information from patient records at the Neurological Departments at
Haukeland and Akershus University Hospitals, possible participants were contacted by
telephone and asked if they would like to participate in the study. Some also contacted
the departments asking for participation after having heard about the study. Possible
participants were then pre-screened at the hospital by a neurologist, physiotherapist
and nurse. They underwent a neurological examination, were tested on the primary
outcome measure, the 6-minute walk test (6MWT) (Enright, 2003) and checked forinclusion and exclusion criteria. A randomized cross-over design was used, and thepatients were the first year randomized for individualized physiotherapy based on the
Bobath concept at a treatment centre in either a warm (Spain) or a cold (Norway)
climate, and switching treatment centre the year after. The patients went through acomprehensive test battery (Table 2). The 6MWT was prior to study start defined as
the primary outcome measure. The test has been found reliable for patients with MS(Paltamaa et al., 2005), and has been used as an outcome measure in MS studies(Goldman et al., 2008; Paltamaa et al., 2008). The 6MWT is discussed more in detailin chapter 5.1.3.1.

51
Data collection was performed at screening before randomization to the two treatment
cites, and also at baseline, after treatment and at three and six months follow-up forboth treatment periods, giving data at nine time points over a period of about 19
months. To account for possible effects of period and sequence of the treatment aswell as differences in carry-over effects, mixed model was used in the analysis ofdifferent effects of treatment (Brown & Prescott, 2006). Data from the screening were
not included in these analyses. For definition of the different variables included in themodel, see Table 3.

52
Table 3. Definition of the different variables included in the mixed model analysis,using an example for the 6-minute walk test
Variable

Description

ValuesType

6MWT
Patient numberTime

6-minute walk test (primary outcome)The number for each patient
Defines the time point of themeasured value of 6MWT. Thisvariable is not included in the model
but is used to define the rest of the
included fixed variables.

Dependent
RandomFixed

Sequence

Where they got treatment first (sameas group)
Measures the period effect

The measured values
1-60
1=baseline-I
2=after first treatment period
3=3 months after first treatment
period4=6 months first treatment period
5=(12 months) baseline-II
6=after second treatment period
7=3 months after second
treatment period
8=6 months after second
treatment period
1 - Spain first (SN)
2 - Norway first (NS)
1 - time=6 to 8
0 - otherwise
1 - time=2 or 6
0 - otherwise
1 - time=2 and sequence=2, or
time=6 and sequence=1
0 - otherwise

PeriodEffect Spain after
treatment
Addition Norway
after treatment

Effect in Spain
Effect in Norway in addition to theeffect in Spain (if negative, Spain has
best effect for the physical tests, andopposite for the self-reported
measures).
Effect 3 months after treatment in
Spain

Fixed
Fixed
Fixed
Fixed

Effect Spain 3
1 - time=3 or 7
Fixedmonths after
0 - otherwise
treatment
Addition Norway The effect in Norway in addition to
1 - time=3 and sequence=2, orFixed
3 months after
Spain after 3 months
time=7 and sequence=1
treatment
0 - otherwise
Effect Spain 6
Effect 6 months after treatment in
1 - time=4 or 8
Fixedmonths afterSpain
0 - otherwise
treatment
Addition Norway The effect in Norway in addition to
1 - time=4 and sequence=2, orFixed
6 months after
Spain after 6 months
time=8 and sequence=1
treatment
0 - otherwise
Carry-over effect Effect 12 months after treatment in
1 - time5
Fixed
Spain 12 months
Spain (measures carry-over/wash0 - otherwise
after baseline-I
out)
Addition Norway The effect in Norway in addition to
1 - time5 and sequence=2
Fixed
12 months after
Spain after 12 months (measures
0 - otherwisebaseline-I
carry-over/wash-out)
Period x
Interaction between period and group 1 - time=6 to 8 and sequence=1
Fixed
Sequence(excluded if not significant)0 - otherwise
To estimate the gait distance at baseline-I for the two different groups, Constant + Sequence for Spain andConstant + 2x Sequence for Norway were calculated.

53
Reporting the proportion of patients achieving improvement that is beyond
measurement error, is said to be an informative method of describing effects ofintervention (Haley & Fragala-Pinkham, 2006). Standard error of measurements(SEM) on the 6MWT was calculated based on scores from screening and baseline-I,
and SDC (2.77SEM) was calculated. The number and per cent of patients who scoredabove this level in connection with treatment, was calculated and compared, without
taking into consideration the cross-over design.
In addition to focusing on the climate effect, we have also analysed the change in testscores over the whole study period (19 months) for all participants by paired samples
t-tests, and did also calculate the change in scores for the patients treated in Norway
the first year, using general linear model (GLM) and Bonferroni-adjusted t-tests.

Assessment procedure
A standardized test procedure was strictly followed, and the sequence of physical tests
was the same from time to time (Trunk Impairment Scale; TIS, Timed Up & Go;
TUG, Berg Balance Scale; BBS, 10-metre timed walk; 10MTW and 6MWT). Before
performance of the two last tests, the patients had a break of 10 minutes, and between
the two last tests, a break of two minutes. The patients were examined by theneurologist, then the physiotherapists and finally the nurse. One of three neurologists
registered the neurological status (EDSS), medications and physical conditions. Threeof six physiotherapists did the physical performance tests, and one of three nurses
collected the self-reported measures and responded to questions from the patients. We
aimed for assessment at about the same time of day, the patients using the samewalking aids and footwear from time to time. We also aimed for using the sameassessors, specifically trained for particular tests. However, due to illness during thestudy period, two testers were replaced by three trained physiotherapists to collect datafrom the 6MWT and TIS. An overview of test points and data collected in the climate
study is presented in Table 4.

54

55

3.7 Paper V
In this study we aimed to explore possible factors with impact on fatigue. Of special
interest was the association between fatigue and scores on physical performancemeasures, as there seems to be limited knowledge regarding this association. We useddata from the first period of the climate study, including data from screening,baseline-I, immediately after treatment and at three and six month follow-up. As there
were no differences in fatigue between the two groups neither at baseline nor atfollow-ups, we analysed the data as one cohort.
Fatigue as measured by the Fatigue Severity Scale (FSS) (Krupp et al., 1989) was
included as the dependant variable in a multivariate regression model. In the initial
univariate analysis, we investigated associations of fatigue with demographic-,
clinical-, HRQoL- and physical performance variables at baseline. Further, we usedstepwise regression to identify possible factors with independent effect on the FSS.
We used the squared coefficient of correlation (R2) to measure the explained variancein the regression models. Of demographic variables, gender, age, work status andrehabilitation centre were included. Course of disease and duration of MS were
included as clinical variables, and data from the MS specific self-reported
questionnaire MSIS-29 were included as a measure of HRQoL. All the physicalperformance measures which were used in the climate study (6MWT, TUG, 10MTW,BBS and TIS) were included as the physical performance variables. Correlation inchanges of scores between fatigue versus HRQoL,- and physical performancevariables were demonstrated by graphs and by Pearson correlation coefficients. In
addition, the same correlations were calculated for change from before to after
treatment and from after treatment to six months follow-up. To investigate changeover time in variables, GLM and Bonferroni-adjusted t-tests were used.

56

4. Summary of results
4.1 Paper 
Balance and gait improved after three weeks of physiotherapy based on the Bobath
concept. Improved balance was demonstrated by BBS in both patients, and improved
quality of gait was indicated by Rivermead Visual Gait Assessment (RVGA). Amongthe physical performance tests these two measures demonstrated the highest change,
both regarding the 2 SD band graphs and the ES. For the 2SD band graphs, variability
at baseline for some of the other variables resulted in a broad band, giving less data
points outside the 2 SD range. An overall positive trend was demonstrated whileinspecting the graphs, indicating improvement also in most of the other variables.
Improvement of balance and gait was also demonstrated by satisfactory ES on the
TUG for both patients. Improved maximum gait velocity as measured by theelectronic walkway GAITRite® was indicated by ES, but not at follow-up for Mr B.
Other gait parameters recorded by the GAITRite®, changed, but differently in the twopatients. The patients also reported improved balance and gait function in theinterviews and scored their general condition after treatment and at follow-ups as“much improved” on the Patient Global Impression of Change (PGIC), also
confirmed by the therapist’s evaluations using the Clinical Global Impression of
Change (CGIC). Treatment seemed to improve components of Activity andParticipation, as well as components of Body Functions and Structures (ICF).

4.2 Paper 
The forward and backward translation of the MSIS-29, according to guidelines fortranslation, resulted in a Norwegian version of the questionnaire (Appendix S1 inPaper II). During the different steps of translation, discrepancies between the various
versions were adjusted in a dialog with the measurement developer Dr Hobart, andspecial issues regarding this, are presented in chapter 5.2.1.

57
For the Norwegian version of MSIS-29, the sum scores on the 0–100 point physicalsubscale ranged from 6.3 to 78.8 (mean 41.4, SD 18.1), and on the psychologicalsubscale from 2.8 to 80.6 (mean 29.6, SD 18.4). Missing data from the separate items
were low. Internal consistency (Cronbach’s ) was 0.92 for the physical- and 0.85 forthe psychological subscale, and item-total correlation ranged between 0.26 and 0.78
for the physical items and between 0.30 and 0.77 for the psychological. Most items
contributed to increase the total alpha. Reliability by ICC was 0.86 for the physicaland 0.81 for the psychological subscale. SDC was estimated to 18.4 and 21.1,
respectively. The physical- but not the psychological subscale demonstrated mostly
satisfactory associations with other physical measures. Responsiveness by the area
under the ROC curve for the physical subscale was 0.83. The optimal cut-off point ofchange providing the highest sensitivity (0.78) as well as specificity (0.81) was an
improvement of 8.1 points on the 0-100 scale. The area under the curve for thepsychological subscale was 0.76. The optimal cut-off point of change providing thehighest sensitivity (0.73) as well as specificity (0.80) was an improvement of 5.6
points on the 0-100 scale. As hypothesized since treatment primarily addressed
physical performance, the ES was larger for the physical (1.01) than for thepsychological (0.76) subscale after treatment.

4.3 Paper 
After treatment, the mean walking distance as measured by the 6MWT, had increased
more in Spain than in Norway (p=0.060). The improvement was 70m in Spain and
49m in Norway. At 6 months follow-up, the improvement was significant larger(p=0.048) after treatment in Spain (43m) as compared to Norway (20m). Afterwalking (6MWT), the patients reported larger decrease of exertion on the Borg
Rating of Perceived Exertion Scale (Borg RPE scale) after treatment in Spain ascompared to Norway at all time points (p<0.05). No significant differences between
treatment in a warm and cold climate were detected for the other physicalperformance measures. The proportion of patients that had an improvement above

58
SDC on the 6MWT was larger after treatment in Spain as compared to Norway (34 %and 17 %, respectively). After three months, 19 % versus 12 % scored above SDC,
and after six months, 18 % versus 12 %, respectively. Most self-reported measures
showed more improvement after treatment in the warm climate, but the
improvements were not sustained at follow-up. The PGIC scored immediately after
treatment, demonstrated significant more improvement in Spain than in Norway (p=0.006). Fifteen patients (27 %) scored “Very much improved” after treatment in
Spain, compared to five (9 %) after treatment in Norway.
In addition to focusing on the climate effect, we have also analysed the change in testscores over the whole study period (19 months) for all participants (Table 5).

59
Table 5. Mean scores and differences from baseline-I to 6 months after the second
treatment (19 months) for those who completed the whole study (n=50)

Test

Baseline-I

19 months

314

345

Difference (95%CI)

High scores are best
6MWT; m

31

(8,

55)*

BBS; scale 0-56

45.2

45.8

0.6

(-1.0,

2.3)

TIS; scale 0-23

13.7

15.7

2.0

(1.3,

2.7)*

TUG; m/s

0.56

0.59

0.03

(-0.01,

0.07)

10MTW; m/s

1.12

1.18

0.06

(-0.02,0.15)

Borg RPE Scale; 6-20

13.4

14.5

1.1

(0.2,

2,0)*

MSIS-29, Physical scale; 0-100

39.9

45.3

5.4

(1.0,

9.9)*

MSIS-29, Psychological scale; 0-100

25.6

31.2

5.6

(1.6,

9.6)*

FSS; scale 1-7

4.89

5.22

0.33

(-0.05,0.70)

MHAQ; scale 0-3

0.45

0.58

0.13

(0.01,

0.25)*

NRS; gait; scale 0-10

5.6

5.9

0.3

(-0.3,

1.0)

NRS; balance; scale 0-10

5.2

5.3

0.01

(-0.6,

0.7)

NRS; pain; scale 0-10

3.2

3.8

0.6

(0.01,

1.3)*

Low scores are best

6MWT = 6-minute walk test; BBS = Berg Balance Scale; TIS = Trunk Impairment Scale; TUG = Timed Up & Go;
10MTW = 10-metre timed walk; Borg RPE Scale = Borg Rating of Perceived Exertion Scale; MSIS-29 = Multiple
Sclerosis Impact Scale; FSS = Fatigue Severity Scale; MHAQ = Modified Health Assessment Questionnaire; NRS= Numerical Rating Scale.
* = significant difference (p0.05) from baseline to six months after the second treatment.

60

4.4 Paper V
Fatigue at baseline was associated with HRQoL (explained 21.9 % of variance), but
not with physical performance tests. Change in fatigue correlated with change in
HRQoL, but not with changes in physical performance. All measures were improved
after treatment (p0.001). While improvements in fatigue and HRQoL were lost at
follow-up, improvements in physical performance were sustained for at least six
months (p0.05).

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5. General discussion
5.1 Intervention studies, Paper I & III
The climate study is considered the main study of the thesis, and Paper III will
therefore be discussed first. Nevertheless, physiotherapy based on the Bobath concept
was less addressed in this paper, and is therefore discussed in chapter 5.1.2 alongwith the discussion of results from Paper I.

5.1.1 The climate influence on the effect of physiotherapy
From the climate study, we concluded that physiotherapy in a warm climate had
additional benefit. After 6 months, the improvement on the primary outcome after
treatment in Spain was statistically significant better than after treatment in Norway.
Also immediately after treatment the difference was close to being significant.
However, not only statistical, but also clinical significance should be addressed. The
methods of calculating clinical significance differ, and several terms are used, like:minimal important difference (MID), minimal clinical important difference (MCID)
and clinically significant difference (CSD) (Haley & Fragala-Pinkham, 2006).
However the amount of change needed to be clinically relevant, should be considered
in relation to the study population accounting for diagnosis, age and disability level,
and in addition the duration of the intervention. In fact, in patients with progressive
diseases, stabilization (no decline) over time could be considered a clinicallysignificant result. We have not found reference values of clinically significant
improvement estimated on a similar population as ours, for the tests used in ourstudy.
The difference after treatment between the two centres was especially demonstrated
by the primary outcome measure (6MWT). Taking into account the limited walking
distance at baseline, we consider a difference of 23 m after 6 months to be clinicallyimportant. In addition, we find it interesting that the patients also perceived less

62
exertion at all time points after having walked for a longer distance, after treatment ina warm as compared to a cold climate. This may imply that the patients will
experience reduced restrictions in physical activities during the day, but this aspect
was not specifically investigated in our study. Also the results from the PGIC,
demonstrated significant better improvement immediately after treatment in a warmas compared to a cold climate. For instance, 15 patients reported to be “Very much
improved” after treatment in Spain, while five patients reported that much
improvement after treatment in Norway, also indicating a clinically importantdifference.
The proportion of patients, who scored better than SDC, was largest after treatment in
Spain. The estimated SDC value in our study may seem large (77 m for individual
patients) and could have been influenced by the long time interval between test andretest (screening and baseline-I), and also by the fact that the test situation hadchanged after travelling to the rehabilitation centres. However, another study on
patients with MS, demonstrated a SEM value of about 31 m (Paltamaa et al., 2005),
giving a SDC of 86 m.
Treatment at the rehabilitation centre at Tenerife was compared to treatment at MSSenteret Hakadal, which is a specialized MS rehabilitation centre in Norway. We
therefore suppose that the patients received the best available treatment in Norway.
However, the results indicate that the warm climate in Spain provided additional
benefits. The reason for this is not straight forward to explain. Many of the patients
reported that the warm climate “did them well”. The warm temperature might have
had a relaxing effect, giving a feeling of less stiffness in muscles and joints. In
addition, when lightly dressed, it is easier to move and to be physically active. Thismight have made the patients more receptive for treatment and reduced their feelingof exertion after walking. In addition, the patients reported less exertion after the
6MWT, after treatment in Spain as compared to Norway at all test points, also after
returning to Norway. This might contribute to the sustained improvement of gait.

63
The difference in effect of physiotherapy in warm and cold climate might have been
affected by other factors than the warm climate alone. However, no differences weredetected between the centres regarding satisfaction with the rehabilitation centres, thephysiotherapy intervention, and social life during the study, assessed by the
Numerical Rating Scale (NRS). Overall their satisfaction was very high at both
places. The amount of physiotherapy and other organized physical activities during
the whole study period, as well as change in physical condition (like relapses andother illness) were registered for each patient during the whole study period.
Compatible data regarding these aspects were demonstrated between the two centres.
The climate was considered to be the main difference between the two rehabilitation
centres, but we can not establish that the subtropical climate was the only difference.
Change in lifestyle and being far away from home and daily duties, might as wellhave had an impact. Also, the sun-exposure might have given additional serum
vitamin D, which might have influenced disease activity. Based on a recent study(Tremlett et al., 2008), it was suggested that vitamin D could modify the infection
rate in patients with MS, as low ambient sunlight and low serum vitamin D areassociated with clinical disease activity (Kesselring, 2008). We did not systematicallyregister whether the disease activity changed after the stay in the warm climate byusing MRI. Nevertheless, travelling to a warm and sunny area during the wintermonths in Norway may increase serum vitamin D levels and thereby influence theimmune system (Falkenbach & Sedlmeyer, 1997).

5.1.2 Physiotherapy based on the Bobath concept
During prolonged clinical practice we have experienced that gait and balance tend to
improve after physiotherapy based on the Bobath concept. To investigate thisassumption scientifically, we carried out the first study (Paper I).
We concluded that balance and gait in the two patients did improve after thetreatment. Improved functioning at the Body Functions and Structures component

64(ICF) was demonstrated by the RVGA. Also the GAITRite® measures functioning at
the Body Functions and Structures component, being a more objective measurement
tool. Results from the GAITRite® demonstrated that the two patients changed their
gait pattern, but in different ways. While interpreting these results we found it
necessary to take each patient’s problems into consideration. Mrs A, who had an
ataxic gait, increased her double stance phase, which might indicate a positive changewith a more stable and less ataxic gait, allowing her to use more time in double
stance. On the contrary, Mr B, who demonstrated more imbalance in walking atbaseline, increased his double stance phase slightly after treatment, but at early andlate follow-ups, it was somewhat decreased. Due to his gait problems a decreased
double stance might indicate less need of standing on two feet during walking, andfor him indicate an improved gait. However, these results should be interpreted withcaution as no reference values exist. There seems to be a need to examine how gait
patterns change in MS in a larger group of patients.
Treatment according to the Bobath concept, imply a focus on quality of movement.
Specifically impaired movement components, considered influential on performanceof activities, are treated and put together in functional activities. Improved movement
control within the component of Body Functions and Structures is hypothesized tomake functioning at the Activity component easier. Other physiotherapy treatment
concepts, like the Motor Relearning Programme, focus more directly on performanceof activities, and less on skill and quality of movement. Whether one of the treatment
approaches are superior to the others, has not been demonstrated (Lord et al., 1998b;
Paci, 2003; van Vliet et al., 2005).
In our first study, it may not be a surprise that functioning at the Body Functions andStructures component improved after treatment, taking the focus of treatment
according to the Bobath concept into consideration. Interestingly, however,improvement was also demonstrated at the Activity component of the ICF, by the
TUG, which is a measure of gait and balance ability and by the BBS, which is ameasure of balance in functional activities. Measurement error by SEM has been
estimated to be 0.83 for the BBS in patients with MS (Paltamaa et al., 2005), meaning

65
that SDC for an individual is 2.3 (2.77 x SEM) (Bland & Altman, 1996). A change
for a single patient should be larger than this to indicate a real change. Both patientsin the study scored above this level at all follow-ups after treatment. In addition, they
improved their low scores from below the limit of increased risk of falling (45) toscores higher than this limit (Bogle Thorbahn & Newton, 1996), also indicating aclinically important change. Improvement after treatment was also shown at theParticipation component of the ICF, as the patients reported better gait and balance in
ADL activities, and improvement in overall functioning (PGIC). These subjective
reports from the patients further validate the results from the physical performance
tests. Based on experiences from clinical practise and results from this first study, we
also chose treatment according to the Bobath concept in the climate study to improve
gait and balance in patients with MS.
The main focus in the climate study was to examine whether there was a difference in
effect of physiotherapy in a warm compared to a cold climate (discussed in chapter
5.1.1). Nevertheless, despite not having a control group who did not receive anytreatment, we also considered the change in test scores after treatment, independent oftreatment place, to be a topic for discussion. The study design made it possible tocompare change after a time period without physiotherapy (screening and Baseline-I)
and time periods after physiotherapy. The patients could then be their own controls.
GLM analysis demonstrated change in all measures across the time points (p<0.05).
There were no differences in scores between screening and baseline-I, except for a
decline in the TIS. Immediately after the first treatment period, the improvement forpatients treated in Norway, was significant (p<0.05) for all measures except for
fatigue, indicating an effect of the treatment itself, also without the climate effect.
The mean improvement was 45m for the 6MWT. After 3 months, the improvement
was significant for 6MWT (41m, p=0.002), and for 10MTW (p=0.025), and for TIS(p< 0.001), and after 6 months still for TIS (p< 0.001). The p-values were Bonferroni
adjusted for the five different time periods.
In a progressive disease like MS, no decline in physical functioning over time may beof clinically relevance. From start of the study to after 19 months, the patients as a

66
whole group, walked significantly longer (mean 31m) (Table 5). In a population
based study of 118 people with MS and median EDSS of 2, gait distance was shown
to be reduced with about 10m over a period of two years without treatment (Paltamaa
et al., 2008). The improved gait distance for the patients in our study over a period of
19 months therefore seems to be of clinically importance. Interestingly, the TIS,
which captures aspects of Body Functions and Structures, was also significantly
improved (Table 5) which might be explained by treatment focusing on impairments
aiming to improve Activity and Participation (ICF). When the change scores frombaseline-I to 6 months after the second treatment for TIS (Body Functions andStructures) and 6MWT (Activity) were correlated, we found in fact a correlation of
0.65, meaning that 42 % of the variance of change scores of 6MWT was explained bychange scores on the TIS.
Over this long period, none of the five physical performance tests demonstrated
decline. The climate study indicated, accordingly, a positive effect of treatment
according to the Bobath concept. However, we can not say that this approach is better
than other physiotherapy approaches in treating patients with MS.
Improvement of the self-reported measures did not sustain, and most of themdemonstrated a significant decline over the time period of 19 months (Table 5) (data
not included in paper III). In patients with acute low back pain, it has been suggested
that self-reported assessments are more influenced by the patients’ psychologicalstatus than performance based assessments are (Wand et al., 2009), and perhaps thismay be the case also for our patient group. A recent effect study of multidisciplinary
rehabilitation in MS (Khan et al., 2008) demonstrated improvement in the physicalperformance as measured by the Functioning Independence Measure, but noimprovement in HRQoL. The authors argue that a response shift could be a possible
explanation for this. A response shift refers to a change in the meaning of thepatient’s self-evaluation of their target construct (Schwartz & Sprangers, 1999;
Sprangers & Schwartz, 1999). The patients in our study might have changed theirinternal standard or values as a result of having received inpatient physiotherapy
together with other patients with MS. This might have resulted in making them

67
reassess how they perceived their limitations (Costelloe et al., 2007). A response-shift
may be an important internal mechanism of mind whereby changes in QoL may notalways parallel function. This phenomenon emphasizes the case for clearly separating
QoL from functional assessment and attempt to make the latter as objective as
possible (Wiles, 2008). In any case, self-reported and performance based measures
seem to capture different aspects of functioning, and it therefore seems important toinclude both when planning for intervention studies.
Rehabilitation typically includes multiple simultaneous therapies and treatments in a“treatment package”. It may therefore be difficult to document specific treatment
effects that are due to only one therapy (Figoni, 1990). However, the intervention in
the climate study was not a multidisciplinary rehabilitation programme, butphysiotherapy according to the Bobath concept, aiming to improve movement control
and ambulation. Recent recommendations for treatment of patients with MS, focus on
different aspects of training, including exercises in general, resistance training,
aerobic training, aquatic exercise, endurance training, as well as functional training.
The importance of fitness has also been underlined (Dalgas et al., 2008; Gallien et al.,2007; Heesen et al., 2006; Rietberg et al., 2004). Physiotherapy according to the
Bobath concept does not focus on fitness and endurance training specifically, butrather on improving motor control of impaired movements, with the overall aim to
improve functional activities. We hypothesize, however, that improved ability towalk, may lead to a better opportunity to stay active and thereby also improve fitness,but we did not investigate this aspect specifically. In the climate study, improved
walking distances (6MWT) was demonstrated over a period of 19 months, indicatingthat the patients had improved their ambulation ability independent of treatment
place. Interestingly, Rogers et al. (1999) did not find improvement of gait, althoughaerobic fitness improved. Rather a reduction in gait velocity and range of motion
during walking was demonstrated after a 6-month aerobic programme with cycling.
We therefore hypothesize that training focusing on motor control in relation to
performance of activities, may be valuable in the attainment of improved activities,
such as walking in the climate study.

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5.1.3 Outcome measures, designs and methodologicalconsiderations
5.1.3.1 Outcome measures
When planning for the intervention studies, the feasibility and applicability ofoutcome measures was an important consideration. When choosing outcome
measures for the first study, we aimed to capture the main components in the ICF
model. Functioning at the Body Functions and Structures component was examinedby the RVGA (Lord et al., 1998a), the Borg RPE Scale (Borg, 1970) and theelectronic walkway (GAITRite®) (Bilney et al., 2003). The GAITRite® captures
footfall data providing both spatial and temporal gait parameters. We did not find any
earlier studies on patients with MS in which this walkway had been used, and theresults were therefore analysed based on our clinical experience of gait problems inpatients with MS, and of how gait may change in connection with treatment.
However, the lack of reference values for patients with MS, resulted in a decision of
not using the GAITRite® as an outcome measure in the climate study. This study
would also imply much travelling between different centres, both in Norway andSpain, which would have been rather strenuous with the GAITRite® equipment. The
RVGA is a measure of gait quality, in which 20 different components in the gait
cycle as well as upper limb position are evaluated subjectively by the assessor. Scoresare graded as “normal” or “mild”, “moderate” or “severe” deviations and are basedon guidelines for each item. The RVGA had demonstrated satisfactory measurement
properties for patients with MS, and was said to be relatively easy to learn (Lord etal., 1998a). Prior to start of the first study, two physiotherapists scored seven patientswith different neurological disorders in addition to the two included in the study. The
scoring was done independently by the two therapists at the same time point, and theresults were discussed. We needed time to agree on how to interpret the different
items of the test and how to score abnormality. The test is based on a subjective
judgement, and since the assessor was not blinded, we decided not to use this test in
the climate study.

69
In the first study, the BBS (Berg et al., 1989) and TUG (Podsiadlo & Richardson,
1991) were used as outcome measures at the Activity component of the ICF. Prior to
the first study, two physiotherapists discussed and practised scoring patients on the
BBS, and we experienced that it was easier to achieve agreement. Satisfactory testretest and inter-rater reliability have been demonstrated for the BBS (Paltamaa et al.,2005) and test-retest reliability has been demonstrated for the TUG (Nilsagard et al.,2007). Both these tests were found sensitive to change in the first study and wereconsidered applicable for use in the climate study in which change was also
demonstrated. However, regarding the BBS, the mixed model analysis demonstrated
a ceiling effect, and the results were therefore of less value in the climate study.
The Rivermead Mobility Index (Collen et al., 1991) did not demonstrate any change
in the two patients in the first study, and a ceiling effect was indicated, resulting in
the decision of not including this test in the climate study.
In the first study, the patients were asked to score the Borg RPE Scale after having
walked on the GAITRite®. This activity did not seem to have been very strenuous toany of the patients, and the change on the Borg RPE Scale after treatment was only
trivial. The Borg RPE Scale was used as an outcome measure also in the climate
study, but the rating was done after a more strenuous activity (6MWT). Previously,
the Borg RPE Scale has mostly been used during exercises to guide the degree ofexertion. However, in our two studies, we were interested in the experience ofexertion after having walked on the GAITRite® and performed the 6MWT,
respectively. When the patients in the climate study as a group graded the 6MWT as
less exhausting and at the same time walked a longer distance, we interpreted theseresults to be positive for the patients.
In both studies we aimed to explore the patients’ overall impression of perceived
change in their physical condition after treatment, assessed by the PGIC (Farrar et al.,2001). As the result from this test was in line with results from the other self-reported
measures in the climate study, and due to limited space, information about this test

70
was omitted from Paper III. However, it demonstrated a significant larger
improvement after treatment in a warm as compared to a cold climate.
In the climate study, the outcome measures were selected aiming to capture common
physical problems seen in patients with MS, and we chose outcome measuresconsidered to be sensitive to the expected change according to the intervention. Alsoin this study, we aimed to cover the consequences of disease as defined by the World
Health Organization, regarding the components of Body Functions and Structures,
Activities and Participation (World Health Organization, 2001). However, the main
focus of attention was on physical performance, especially related to gait, and 6MWT
was chosen as the primary outcome measure (ATS Committee on Proficiency
Standards for Clinical Pulmonary Function Laboratories., 2002; Enright, 2003). For
elderly people the 6MWT seems to be more a measure of general mobility andphysical functioning than a specific measure of cardiovascular fitness (Lord & Menz,
2002). Persons with cerebral palsy, who also have a disturbance of the CNS, describe
problems with stiffness in their legs rather than cardiorespiratory problems as themain reason for reduced walking distance (Andersson et al., 2006). In addition,
habitual walking performance seems to be best reflected by longer walking capacity
tests, such as either the 6MWT or the 2-minute walk test (2MWT) in patients withMS (Gijbels et al., 2010), supporting our choice of primary outcome. A measure ofwalking distance could therefore give valuable additional information about motor
control and movement ability, than simply walking distance. The test demands ability
to balance during walking and turning every 30 m. We expected that a possible
improvement in motor control and gait functioning would be reflected in a longer
walking distance as captured by the 6MWT. In addition to the 6MWT, we used the
10MTW (Wade, 1992), and TUG to assess walking speed and balance. By using allthese tests, we considered important aspects of gait to be sufficiently covered.
However, including an ambulant accelerometer-based ambulatory monitoring over alonger time period, could have given additional information regarding habitual
walking. (Gijbels et al., 2010).

71
In the climate study, we still wanted to capture functioning at the Body Functions andStructures component, in spite of having decided not to use the RVGA or the
GAITRite®. The recently developed TIS measures aspects of trunk performance, andtest scores have been found to be associated with gait and functional ability scores instroke patients (Verheyden et al., 2006b). As patients with MS commonly have
reduced trunk control (Lanzetta et al., 2004) and treatment focused on this aspect, we
included the TIS, which has also been found reliable and valid in patients with MS(Verheyden et al., 2006a). Together with using the Borg RPE Scale, we considered
important aspects of the Body Functions and Structures to be captured.
The EDSS (Kurtzke, 1983) is composed of eight subscales, each measuring a specificfunction within the CNS. The total EDSS index of severity of MS is ranging from 0(normal) to 10 (death). Scores lower than 4 address impairments (Body Functions andStructures components of the ICF), and scores from 4 to 7 address limitations inambulation (Activity component of the ICF). The EDSS is one of the most common
neurological outcome measures for patients with MS (Hoogervorst et al., 2003).
However, based on recent critical comments regarding standardisation and marginal
sensitivity to change (Balcer, 2001; De Souza, 1999; Hoogervorst et al., 2003), we
decided to use the EDSS only as a classification variable, as also suggested by
Hoogervorst et al. (2003).
By using self-reported questionnaires in the climate study, we aimed to capture
different components of the ICF related to HRQoL, fatigue, ADL and experienced
problems of gait, balance and pain. We found the MSIS-29 (Hobart et al., 2001)
applicable for investigating important aspects of HRQoL. This test is discussed in
more detail in chapter 5.2. The ADL was examined by the Modified Health
Assessment Questionnaire (Uhlig et al., 2006). We have not found MS studies inwhich this questionnaire has been used, but considered the questions to be relevant inour study. The FSS was chosen in the climate study to capture perceived fatigue, andthis test is more thoroughly described in chapter 5.3. From the first study, we found it
appropriate to assess the patients’ self-reported experience of gait problem by using
the Visual Analogue Scale (VAS). However, the 11-point NRS has been

72
recommended more feasible to use than the VAS (Jensen MP & Karoly P, 2001), andwe therefore decided to use the NRS in the climate study to capture experienced
problems related to gait, balance and pain.
In summary, the use of a wide spectrum of outcome measures in the two intervention
studies has given valuable information about change in different functional
components of the ICF.

5.1.3.2 Study design
Both intervention studies imply repeated measurements over a time period, giving
valuable information about variation in the patients’ condition over time.
In the first study, a SSED was used. Several registrations before and during treatment
make it possible to evaluate whether treatment has an effect beyond normal
variability in the condition over time. The patients are, accordingly, their own
controls (Figoni, 1990). In group designs, results can be generalized to a defined
population, but may not necessarily be applicable to each individual in the group.
Contrary, when using a SSED the findings may not be generalized to a broad
population, but related to subjects with similar characteristics as those in the study. A
detailed description of the participant(s), the testing procedure and the treatment
should therefore be emphasized (Figoni, 1990). We found the SSED relevant for use
in the first study and experienced that it gave valuable information about the twopatients and about the use of different outcome measures.
In the climate study, a randomized cross-over design was used, aiming to investigate
differences in treatment effect due to climate influence for a larger population. Whenusing this design, the patients are also their own controls, resulting in a need of fewer
participants as compared to when using a parallel group design (Altman, 1991).
Another advantage may be that all participants received the same treatment in
Norway and Spain although in different years, which might have given a highmotivation for participation and for completing the study. A cross-over design is73
applicable when investigating patients with a chronic and rather stable disease, notexpecting a substantial decline during the study period (Jones & Kenward, 2003;
Wang et al., 2006). The patients in our study had a chronic, often progressive disease,
but included rather stable patients, and the decline during the relatively short study
period was expected to be only minor. Thus we therefore found the design applicable.
A possible disadvantage of such a design, is the risk of drop-outs due to the longer
study durability (Wang et al., 2006). We found the drop-out of 9 out of 60 (15 %) to
be acceptable. Using mixed models allows for missing data, and we could therefore
include measured data from all patients in the analysis. A possible carry-over effect,
meaning that the second treatment is influenced by the first, may be a problem incross-over trials. The best way of preventing this, is to ensure an adequate washout
period (Wang et al., 2006). We considered eleven months to be a sufficient washout
period; not too long in case of a possible decline, and not too short in case of a
possible carry-over effect. Only a short-term effect of outpatient physiotherapy given
two times a week over a period of eight weeks was demonstrated in a previous crossover trial on patients with MS (Wiles et al., 2001). In this study, a period of eightweeks between the treatment periods was applied, and no carry-over effect wasdemonstrated. The authors concluded that the use of a cross-over design seems
applicable for patients with MS. In our study, one year between the two treatment
periods was necessary, to ensure as similar conditions regarding climate as possible
the two subsequent years. Possible differences in carry-over effect were controlled forin the mixed model, implying that this was not considered a methodological problem.
By testing the patients with the complete test-battery two times before start of the firsttreatment, we aimed to reduce the learning effects. Anyway, we presume that apossible learning effect would not differ between the two groups and would therefore
not influence the results regarding differences between effects at the two places. By
testing at screening before randomization, we also had the possibility to compare
these scores with those at baseline-I after the patients had been randomized andtravelled to the different places. Overall, scores from screening to baseline-I, werecompatible.

74
The data in the climate study were analysed using mixed models. In an ordinary
regression analysis, the independent variable (on the x-axis) is of a constant value andnot associated with uncertainty, while the value on the Y-axis may vary, being thedependant variable. In a mixed model we also permit the variable on the x-axis to be
associated with uncertainty. In our model, this was the participant number. By using
the mixed model, we were able to take into account the sequence of treatment, thetwo different treatment periods and possible differences in carry-over effects (Table
3). As we prior to study start had chosen a primary outcome measure, and thedifferent tests seemed to capture different aspects of the same function, the p-values
were not Bonferroni adjusted (Bland & Altman, 1995). Such an adjustment would be
too strict. However, when interpreting the results, it should be taken into
consideration that the use of many tests increases the risk of false significant results.

5.1.3.3 Other methodological considerations
In the SSED study (Paper I), we included only two patients since this design focus on
in depth knowledge of few individuals. However, it is realized that inclusion of morepatients would have made the study results more robust. At least three data points are
required at baseline as well as at the other study phases (Figoni, 1990). It can bequestioned whether this is sufficient to demonstrate a stable level or trend in eachperiod, but we considered it to be too strenuous for the patients to be exposed for
additional testing. Another limitation is the lack of blinding. The assessor knew thatthe patients participated in an intervention study, and did also know in which phase of
the study period they were tested. This might have influenced the results. However,results from the more objective measures like the GAITRite® and the TUG also
indicated improvement, and the positive subjective expressions from the patients
supported the results.
In Paper I, Table 1, below the column “Test”, the “Double stance phase” and “Steplength” should have been specified more precisely. “Step-length (m) at 0.4 m/s” wasestimated for Mrs A and should be followed by “for Mrs A and at 1 m/s for Mr B”.

75
This information should also have been included in connection with “Double stancephase (%)” in the same table, as the step-length and double stance phase were
estimated at 0.4 m/s for Mrs A and at 1 m/s for Mr B. In Table 2, the heading“Change in Mr B”, should have been placed above “Treatment” and not above “Latefollow-up”.
The awareness of being under observation, may influence the way a person behaves(the Hawthorn effect) (De Amici et al., 2000). The Hawthorn effect might haveinfluenced the treatment effects in both intervention studies, but should not haveinfluenced the differences in effect between the two centres in the climate study.
We found it necessary to limit the study population to an EDSS between 4 and 6.5,
making it possible to select appropriate measurement-tools for the target group andalso to tailor treatment focusing on gait functioning. Since gait has a direct impact on
ambulation, it appears to be important for an independent lifestyle. As participation
would imply laborious travelling and demand a great amount of testing, we did notconsider patients with an EDSS larger than 6.5 to be relevant for participation in the
study. The results should therefore primarily be considered for patients with similarfunctional levels as those included in the study. However, we hypothesize that alsopatients without heat intolerance and lower EDSS than 4 might benefit fromphysiotherapy in a warm climate.

5.2 Norwegian version of MSIS-29, Paper II
Research regarding development of HRQoL outcome measures for use in clinical
trials is increasing (Meadows et al., 1997), and there is also an increase inmultinational and multicultural research (Beaton et al., 2000). Most of thequestionnaires are developed in English-speaking countries resulting in a need oftranslating the questionnaires into new languages, also including a cross-cultural
adaptation (Beaton et al., 2000; Meadows et al., 1997). A poor translation process
may result in an instrument not equivalent to the original, which may imply limited

76
comparability across populations from different cultures and countries (Beaton et al.,2000).
When choosing a health outcome measure, an important consideration is whether ageneric or a condition-specific questionnaire should be used. A generic HRQoL
measure allows us to contrast and compare the impact of a disease on HRQoL acrossdifferent conditions, while a condition-specific instrument should be preferred when
the aim is to measure the impact of one particular disease or to evaluate the effect of
an intervention in a particular group (McColl E et al., 1997). Using condition-specificinstruments in effect studies, enhances the chance for increased responsiveness,
resulting from including only important test items relevant for the target population(Guyatt et al., 1993).
An optimal MS specific outcome measure should be multidimensional, but nonredundant, widely applicable across the full range of disease severity without floor or
ceiling effects and be reliable, valid, responsive and practical in use (Fischer et al.,1999). In the climate study, condition-specific questionnaires like the Functional
Assessment of Multiple Sclerosis (FAMS), the Multiple Sclerosis Quality of Life 54(MSQOL-54) and the Multiple Sclerosis Quality of Life Inventory (MSQLI) wereconsidered for possible use. However, based on the overall evaluation of the different
measurement tools (Gruenewald et al., 2004), we chose the MSIS-29 for our study, as
it has been found clinically useful and scientifically robust. The MSIS-29 takes about
15 minutes to complete (Benito-Leon et al., 2003). Items included in the two
subscales contain questions regarding a broad range of HRQoL aspects like Physical,
Emotional, Social, Cognitive, Fatigue, Mobility and Bladder/Bowel functioning.
Questions regarding communication and sexual and sensory functions are, however,not included (Benito-Leon et al., 2003). A recent Rasch analysis of the MSIS-29
demonstrated satisfactory psychometric properties of the two subscales, anddimensionality testing indicated that it was not appropriate to combine the two
subscales to calculate a total MSIS-score (Ramp et al., 2009).

77
The developer of the MSIS-29 did not name it a HRQoL questionnaire, but rather an
instrument that measures the impact of MS (Hobart et al., 2001). However, in recent
literature, it has been classified and used as a condition-specific HRQoL
questionnaire (Benito-Leon et al., 2003; Gray et al., 2009; Gruenewald et al., 2004;
Khan et al., 2008; Ramp et al., 2009). Nevertheless, it could be discussed whether
using the term ”HRQoL” should be replaced with “self-reported health”, since it may
be difficult to establish each individual’s quality of life, based on a generalassumptions of the meaning of this phenomenon.

5.2.1 The translation process of the MSIS-29
The MSIS-29 was found to be an appropriate measurement tool of HRQoL in the
climate study. Due to lack of a Norwegian version, we first translated thequestionnaire into Norwegian and then examined reliability, validity andresponsiveness of the translated version. The procedure of the translation process is
described in chapter 3.5. Below follows an overview of particular problems
encountered during the process of translation, and how they were solved:
Translating the five scoring-alternatives
In particular; the translation of the scoring alternatives 4 and 5 was discussed.
Number 4: ”quite a bit” was translated into “mye” (much), and number 5:”extremely” to “svært mye” (very much). Those answering–alternatives weresuggested by the target group as being more appropriate to use in Norwegian, andthese alternatives also seem to imply more even intervals between the 5 scoringalternatives, although this is not specifically examined.
Item 13: Limitations in your social and leisure activities at home?
The last part of item 13, referring to limitations in social and leisure activities athome, was discussed. We chose to leave out “at home” as we found that it might limit
the scope of the question to the individual’s house.

78
Item 17: Problems using transport (e.g. car, bus, train, taxi, etc.)?
There is a substantial difference between Norway and Great Britain when it comes to”transport” for physically disabled persons. In Norway the political focus has mostly
been to customize cars or other means of transport to individuals, while in Britain thefocus has been more into developing the public transport. Both the expert panel andthe target group advised us to change “transport” into “offentlig transport” (public
transport) and then delete the examples.
Item 28: Lack of confidence”Confidence” was probably the word we found most difficult to translate, and wecontacted the developers of MSIS-29 (Dr. Hobart) to clarify the scope of thequestion. After many discussions and suggestions from the experts, the item wastranslated into ”mangel på selvtillit”. In Norwegian this is usually understood as “lackof self-esteem”.
The original version of MSIS-29 was considered to have validity in the Norwegian
culture. A pragmatic approach was used in the translation process, aiming forequivalence and taking cultural differences into consideration (Sartorius N & Kuyken
W, 1994). The translated Norwegian version was therefore not completely identicalword by word to the source instrument, but well adopted for use in Norwegianpatients and rather similar to the original version.
Our overall impression, after having used the Norwegian version of MSIS-29 in the
climate study, is that the patients found the questionnaire easy to understand, andmost of the patients completed the questionnaire without missing items.

5.2.2 Psychometric properties of the Norwegian version of
MSIS-29
Reliability and validity are important measurement properties. When an assessment
tool is used to assess outcome, responsiveness to change implying the extent to which

79
a change in status is reflected in a change of scores, should also be documented.
Responsiveness to change depends on both reliability and validity (Domholdt E,
2005; Finch E & Brooks D, 2002).
Important quality criteria for measurement properties of health status questionnaires
have been proposed by Terwee et al. (2007), and these were used as guidelines whenevaluating psychometric properties of the translated version of the MSIS-29. Our
intention was not to change the original MSIS-29 regarding contents and number of
items or dimensions, but rather to obtain a similar questionnaire in the Norwegianlanguage, with satisfactory psychometric properties. We examined internalconsistency, construct validity, test-retest, reliability, responsiveness as well as floor
and ceiling effects.
Overall, the psychometric properties were in accordance with the original version, as
presented and discussed in Paper II. Test-retest reliability was examined asrecommended by Terwee et al. (2007). We also calculated the SDC for an individual
based on the SEM values, taking into consideration the measurement error at repeatedmeasurement with 95 % CI. The proportion of patients in a group scoring above andbelow the SDC value can then be calculated and compared between groups. Whenalso taking the systematic shift into consideration, the limits of agreement can be
estimated. In the present study the upper limit was an improvement of 20.6 and thelower limit a decline of 16.2 on the physical subscale, and an improvement of 24.5
and a decline of 17.7 on the psychological subscale.
Internal consistency was examined for each subscale of MSIS-29. Terwee et al.
(2007) also suggest that a factor analysis should be performed. The rationale for a
two-dimensional model was not examined in the Norwegian version as the sample ofpatients was not large enough.
Construct validity was examined by testing predefined hypothesis, as also
recommended by Terwee et al. (2007). The physical subscale of the MSIS-29 was
expected to demonstrate a larger correlation with physical performance measures,
than the psychological subscale. Among the physical performance measures used in

80
the climate study, only scores of the 6MWT and the BBS were applied in the present
study as they were considered most related to the physical subscale of MSIS-29. In
addition, we also included the EDSS classification scores in the validation. From ourresults, we concluded that construct validity was satisfactory, in accordance with ourpredefined hypothesis.
The ES is often used as an indicator of responsiveness to change of a measure, but it
may rather be a measure of treatment effect. We therefore followed recommendations
from Terwee et al. (2007) by predefining hypotheses regarding expected differencesin change between “known groups”. Taking the nature of treatment into consideration
focusing on physical performance, the ES of the physical subscale of MSIS-29 was
expected to be higher than the ES of the psychological subscale, which was shown in
our study. Responsiveness of the Norwegian version of MSIS-29 was also indicatedby satisfactory area under the ROC curve, demonstrating ability to differentiate
between a period of expected stability (without treatment) and a period with expectedchange (treatment).
The sum scores on the physical subscale ranged from 6.3 to 78.8 and on thepsychological from 2.8 to 80.6. The mean of the physical subscale was 41.4 (SD18.1), and of the psychological 29.6 (SD 18.4). A good distribution of scores and nofloor or ceiling effects were demonstrated for our study population.
The included patients in our study were restricted to an EDSS between 4.0 and 6.5,
which may be a limit regarding the evaluation of psychometric properties. However,
the results regarding measurement properties were in line with results from studies ofthe original version, including a broader range of patients.
In summary, we found important psychometric properties of the Norwegian versionof the MSIS-29 satisfactory, and we therefore considered the questionnaire to be
applicable for clinical and research purposes.

81

5.3 Fatigue study, Paper IV
In this study, we aimed to explore the phenomenon of fatigue in MS by analysing
possible explanatory variables. Only HRQoL (MSIS-29) was found to be associatedwith fatigue at baseline, and only change in HRQoL was associated with change infatigue after physiotherapy. No association was found between fatigue and thephysical performance measures of gait and balance. Improvement of physicalperformance sustained over time, while improvement in fatigue and HRQoL did not.
We therefore concluded that fatigue in MS was not associated with physicalperformance.

5.3.1 Associations between fatigue versus HRQoL and physicalperformance
The FSS is the most widely used measure of fatigue in cross-sectional andlongitudinal studies of patients with MS (Bakshi, 2003). The scale was consideredappropriate for our study, as it has a physical focus (Flachenecker et al., 2002)
measuring the impact of fatigue on daily living (Comi et al., 2001). It may be argued
that the scale should have been supplemented by newer multidimensional fatigue
scales (Goldman et al., 2008). By including newer scales with validated subdimensions of fatigue, the impact of independent variables on the various aspects offatigue might have been better explored.
Weak correlations have been found between different fatigue scales, and can best be
explained by the fact that fatigue is a multidimensional symptom and available tests
measure and weight different aspects of fatigue differently. A more exact definitionof fatigue and more valid scales to quantify the various aspects of fatigue might haveprovided different results in the present study. It has been suggested that, due to themulti-dimensional nature of fatigue in MS, the role of fatigue should be explored in a
broad perspective according to the bio-psychosocial ICF model (Mills et al., 2010).

82
Using scales with items selected to represent conceptually distinct domains of forexample physical, cognitive and psychosocial functioning, may question whether it
could be concluded that a total score measures a unidimensional construct of fatigue.
The FSS has been defined as unidimensional (Comi et al., 2001). However, a recent
Rasch analysis of the FSS indicated a reduction to a 5-item scale to provide a strictly
unidimensional scale (Mills et al., 2008). A recently developed unidimensional
assessment of fatigue (U-FIS), which was modified from the Fatigue Impact Scale(Meads et al., 2009) seems to capture a broader aspect of fatigue and has
demonstrated satisfactory psychometric properties. Also a fatigue scale named The
Neurological Fatigue Index (NFI-MS) has recently been developed (Mills et al.,2010), including a 10-item summary scale together with scales measuring thephysical and cognitive components of fatigue. It remains to be seen whether thesemeasures of fatigue will be more preferred than the FSS in future studies.
We found that fatigue was not associated with physical performance of gait andbalance. Frzovic et al. (2000) found that despite an increase in self-rated fatigue fromthe morning to the afternoon in patients with MS, little change was found in balancefrom the morning to the afternoon, supporting our results. It may be questioned
whether other physical performance measures than used in our study, would show
similar results. We can only conclude that fatigue was not associated with the
6MWT, TUG, 10MTW, BBS and TIS.
Due to the multidimensional characteristics of fatigue, we also find it plausible thatphysiotherapy according to the Bobath concept, would not alone result in a reductionof fatigue. Other factors related to the treatment, like social well-being, support andstaying away from home and daily duties, might have given a short term effect on theexperience of fatigue. We suggest that the improvement of fatigue after
physiotherapy in our study was related to other factors than improvement in physicalperformance of gait and balance.
In this study, we included patients from the climate study. They did not suffer fromexcessive fatigue that would preclude participation in the study protocol. However,83
when analyzing the results, the patients in the study were comparable with other MS
samples regarding fatigue severity, and the scores of fatigue using the FSS
demonstrated a normal distribution and scores all over the scale. Fatigue did not
differ between patients randomized to the two treatment sites, and we therefore found
it appropriate to analyse the data as one cohort.

5.3.2 Suggestions for a broader startegy in treating fatigue
The results that fatigue was not associated to physical functioning, lead us tohypothesise that physiotherapy alone, focusing on physical performance, is probably
not an adequate or sufficient remedy for improving fatigue, and a broader strategy
seems to be needed.
However, regular physical activity has been found to improve fatigue, depression and
QoL in persons with MS (Stroud & Minahan, 2009). In addition, physical activity has
been found to be indirectly associated with improved QoL through pathways that
include fatigue, pain, social support, and self-efficacy (Motl & McAuley, 2009).
Results from a recent study indicate that coping mechanisms are associated withdepression, anxiety and fatigue in MS, and the authors suggest a cognitive
behavioural therapy (Brajkovic et al., 2009). The results from this study support ourtheory about a need of a broader strategy in treating fatigue. Anothermultidisciplinary fatigue management programme demonstrated efficacy in reducing
the impact of fatigue, but no differences were found as compared to a placebointervention programme (Kos et al., 2007). The authors of the paper discuss whether
the two programmes were too similar, suggesting that further research should also
include a control group with no intervention. In addition, the intervention consisted ofonly 4 sessions of two hours spread over 4 weeks. Interestingly, a group-based
intervention for the management of fatigue in MS has recently been developed,
focusing on energy effectiveness and cognitive behavioural approaches. Preliminary

84
results of the effect look promising, and results from a randomized controlled trial
will soon be published (Thomas et al., 2010).
Nevertheless, we argue that the effect of treatment on fatigue should be investigatedover the long term. If improvement in fatigue is due solely to positive experiences of
having attended a programme, we expect the improvement to decrease after theintervention, while a sustained effect may indicate that the treatment itself has given amore sustained and positive effect.

85

6. Conclusions and further research
Results from the climate study demonstrated improvement of physical performance,
HRQoL, fatigue and ADL after physiotherapy. The improvement was larger for mostself-reported measures and tended to be larger for the primary outcome (6MWT) after
treatment in a warm climate (Spain). Over the long term, a significant additional
effect was demonstrated on the primary outcome after treatment in Spain, indicatingthat patients with gait disturbances due to MS, not suffering from heat intolerance,
may profit from physiotherapy in a warm climate. From the first intervention study
we concluded that balance and gait were improved after physiotherapy based on the
Bobath concept for the two patients, and from the climate study, we also found it
plausible to suggest that physiotherapy improved physical performance.
The Norwegian translated version of the MSIS-29 demonstrated satisfactory
psychometric properties and is recommended for use as a measurement tool of
HRQoL in patients with MS.
Fatigue, which is a common problem for patients with MS, was found to be
associated with HRQoL, but not with physical performance measures of gait andbalance. Change in fatigue was associated with change in HRQoL, but not withchanges in gait and balance. Fatigue might therefore not be related to how patients
perform on physical tests, which should be taken into consideration in treatment ofpatients with MS and fatigue.

Suggestions for further research
Effect of physiotherapy based on the Bobath concept was indicated in theintervention studies, but we do not know whether treatment based on this concept has
greater effect than other treatment approaches. We therefore suggest that a
multicentre study should be conducted. The including centres should adhere to86different treatment approaches to ensure that the treatment is given by competenttherapists within the different approaches.
When interpreting the results from the intervention studies, we looked for estimatesof clinically important change in outcome measures for the target group. As suchinformation was scarce, we suggest that this topic should be further investigated.
Regarding the investigated climate effect, we do not know whether a warm climate
alone may have an effect on physical functioning. This aspect could be further
investigated, by also including a control group living in a warm climate for fourweeks, without receiving physiotherapy. A possible additional effect from vitamin D
should also be considered, including serum analysis as well as registration of MS
specific disease activity, including relapses and MRI lesions.
To improve fatigue, we have suggested including strategies that challenge cognitive
interpretation and behavioural responses to symptoms. Further studies are needed toevaluate the effect of such an intervention.
A challenge in rehabilitation research in MS is to identify the main target for theintervention. It may be difficult to find the right balance between a holistic view andspecific problems captured by each professional. In any case, the knowledge ofplasticity of the brain should lead us to considering the brain as an important target
for improving functioning (Mayo, 2008). This makes rehabilitation in general andphysiotherapy, as part of rehabilitation, a demanding and optimistic challenge.

87

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