### Evidence Report/Technology Assessment: Number 39

# Management of Newly Diagnosed Patients with Epilepsy: A Systematic Review of the Literature

## Summary

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Under its Evidence-based Practice Program, the Agency for Healthcare Research and Quality (AHRQ) isdeveloping scientific information for other agencies and organizations on which to base clinical guidelines,performance measures, and other quality improvement tools. Contractor institutions review all relevantscientific literature on assigned clinical care topics and produce evidence reports and technologyassessments, conduct research on methodologies and the effectiveness of their implementation, andparticipate in technical assistance activities.

Overview / Reporting the Evidence / Methodology / Findings / Future Research / Availability of Full Report

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## Overview

This project represents one phase of a multiphase task order nominated by the Centers for Disease Control and Prevention (CDC) to develop a framework for organizing the health care services necessary for providing optimal care to patients with low-prevalence, highly chronic conditions, in this case, epilepsy.

In this phase of the project, a clinical trial evidence base was developed through a systematic review of the literature pertinent to diagnostic, treatment, and monitoring interventions for patients with newly diagnosed epilepsy. Results have been qualitatively synthesized to provide an evidence-based evaluation of the health care services that contribute to optimal patient outcomes.

It is intended that this synthesis of the best available evidence will serve as an information resource for local decisionmakers and developers of practice guidelines and recommendations. It should also serve to highlight gaps in the literature and areas ripe for future research. Lastly, the approach to developing a matrix framework of patients and services, with a systematic review of the evidence addressing each patient-service intersect of the matrix, provides a useful model for assessing health care services for patients with other chronic conditions with relatively low prevalence.

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## Reporting the Evidence

The key questions that guided this review were the following:

- 	What elements (expertise, services, and tests) may be needed to make the first diagnosis and initiate and monitor optimal treatment? What is the cumulative contribution (in order of increasing invasiveness and cost) of each of the following tests:    - Electroencephalogram [EEG]—standard, ambulatory, video, invasive.
  - Computed tomography [CT].
  -  Magnetic resonance imaging [MRI].
  -  Lumbar puncture.
  -  Blood tests. What is the cumulative contribution (in order of increasing invasiveness and cost) to the accurate diagnosis of patients undergoing a first diagnosis? What is the positive and negative predictive value of each test alone? In what instances do additional tests add little useful information? Is there evidence to show that not applying particular tests will lead to incorrect diagnosis, negative health, or negative psychosocial outcomes? Are these tests useful for all patients undergoing first diagnosis or for only particular subpopulations? Which components of the patient's history are necessary to accurately diagnose the first seizure?
- 	What criteria should be used to guide decisions about the timing and selection of treatments for patients undergoing first diagnosis?
- 	Which interventions are necessary to adequately monitor patients on their first epileptic drug regimen or to ensure that the first diagnosis was correct? For what period of time should this monitoring occur? Should such monitoring be routine or prompted by particular symptoms/events?
- 	What aspects of clinical/pharmacologic expertise have been demonstrated to result in optimal patient outcomes (maximum reduction of seizure frequency with minimal side effects)? Clinical/pharmacologic expertise is defined as:    -  Selection of optimal antiepileptic drugs (AEDs) based on epilepsy diagnosis and patient characteristics.
  -  Adjusting drugs and dosages to reduce seizures.
  -  Monitoring and limiting adverse drug reactions and interactions.
  -  Monitoring patients' tolerance and compliance with particular drug regimens.
  -  Recognizing changes in seizure characteristics.
  - Ordering and interpreting appropriate laboratory tests based on knowledge of specific adverse events associated with different drugs.
- 	What is necessary for patients at the time of first diagnosis in terms of social services, counseling (regarding, for example, employment or driving), or assistance and information from the Epilepsy Foundation? Is there evidence demonstrating that counseling improves patient followup, compliance, or quality of life?

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## Methodology

This project was carried out in two phases. The first phase involved a stakeholder meeting at which a matrix framework of specific patient populations and health care interventions was developed. Literature citations were then broadly categorized according to the matrix of patients and interventions. 

In the second phase, all interventions (diagnostic, monitoring, and treatment) for a single population of interest (patients with newly diagnosed epilepsy) were chosen as the subject of a full systematic review. In general, MetaWorks investigators used systematic review methods derived from the evolving science of review research.

The review followed a prospective protocol that was developed a priori and shared with the nominating partner on the project (CDC), a panel of technical experts (with representation from consumer groups and health care providers in neurology, epileptology, primary care, and nursing), and the Task Order Officer at the Agency for Healthcare Research and Quality (AHRQ). The protocol outlined the methods to be used for the literature search, study eligibility criteria, data elements for extraction, and methodologic strategies to minimize bias and maximize precision during the process of data collection, extraction, and synthesis. 

The published literature was searched in two phases corresponding to the two distinct phases of this project, ultimately covering the period from 1980 through December 1, 1999. MEDLINE was first searched as follows:

-  Explode epilepsy and all treatment and human.
-  Explode epilepsy and diagnosis and human.

In the second phase of the project, another search was run in MEDLINE using the following sequence: 

-  Explode epilepsy.
-  Human.
-  1999.
-  Diagnostic use (Medical Subject Heading, MeSH).
-  Diagnosis.
-  Therapy (MeSH).
- Therapeutic use.
-  4 or 5 or 6 or 7.

Review articles for the manual search were also identified in MEDLINE by searching back to 1996 using the following sequence:

-  Explode epilepsy.
-  Human.
-  Diagnosis (MeSH).
-  Review (text word, TW).

 Bibliographies of these reviews were perused for other likely citations. In addition, the 1999 Current Contents' CD-ROM was searched for the following terms:

-  Epilepsy (key word, KW).
-  Diagnosis (KW).
-  1 and 2.
-  Epilepsy (KW).
- Treatment (KW).
-  4 and 5.
-  Epilepsy (KW).
- Monitoring (KW).
- 7 and 8.

The Cochrane Library of Systematic Reviews was searched by:

-  Checking the Database of Systematic Reviews for epilepsy (KW).
- Checking the Database of Abstracts of Reviews of Effectiveness for epilepsy (KW).

Lastly, Internet searches were performed on December 2, 1999, by checking the following Web sites for studies, guidelines, authors, and special interest groups: Dr. Koop.com, WebMD.com, ReutersHealth.com, Intellihealth.com, Medscape.com, and NewsPage.com and the Epilepsy Foundation (efa.org).

All citations and abstracts were printed and screened at MetaWorks for any mention of patients with a first seizure, a first presentation, or a new diagnosis of epilepsy, for which full papers were obtained. The electronic searches noted above were supplemented by a search of the reference lists of all eligible studies and relevant review articles. To be included in the review, studies had to report results of any diagnostic, treatment, or monitoring intervention pertinent to newly diagnosed epilepsy in adults or children, with at least 10 patients as total sample size. Studies reported in English were accepted.

Each accepted study was extracted by one investigator and agreed to by a second. Key data elements sought for extraction from each study included study, patient, and intervention characteristics. In addition, for all diagnostic tests, sensitivity, specificity, and positive and negative predictive value, with its gold standard, were sought. All eligible papers were scored on features pertinent to study design, execution, and reporting, with a range of possible scores from 0.3 to 5.0.

No quantitative analyses were performed beyond descriptive statistics to summarize findings. Data were synthesized qualitatively. A group of 19 peer reviewers drawn from consumer groups and professional organizations, along with our technical experts and partners, was assembled to review and provide suggestions to the draft final report describing this project. Their comments were incorporated wherever possible within the original scope of the project.

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## Findings

Of 13,128 citations, 120 studies—mostly European and published in English since 1990—met all eligibility criteria. The study designs comprised 70 interventional and 50 observational studies. These studies covered 21,213 patients; all ages were represented, with balanced gender distribution and all major seizure types (generalized and partial).

No quantitative syntheses were possible because of insufficient and/or inconsistent reporting of results.

The evidence supports the following conclusions:

- 	Diagnostic interventions supported by the literature to rule in a diagnosis of epilepsy, prevent delayed or missed diagnoses, and predict remission outcomes are: a complete history and physical examination, including neuropsychologic assessment and a standard EEG.
- 	Other diagnostic interventions (e.g., CT or MRI) are more important to rule out secondary causes of seizures or to resolve uncertain diagnoses (e.g., video EEG).
- 	Monitoring interventions supported by the literature that may have an impact on outcomes are:   -  Clinical/pharmacologic expertise.
  -  Periodic blood tests.
  - 	Possibly cognitive tests in children.
- 	Treatment interventions supported by the literature include:    - Clinical/pharmacologic expertise for choice of AEDs.
  - Monitoring AED dose, side effects, and compliance.
- 	Limitations of evidence include:    - Low methodologic rigor.
  -  No gold standard for diagnosis.
  -  Patient populations poorly defined and not consistent study to study.
  -  Inconsistent terminology.
  -  Lack of patient-centered outcomes, e.g., quality of life and health care utilization.
  -  Lack of economic assessments.
  -  Gaps in topic coverage (no nonpharmacologic treatments and little monitoring research).

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## Future Research

It is clear from this review of the literature addressing newly diagnosed patients that more research is needed to answer basic questions of diagnosis, monitoring, and treatment. This new research can be categorized as better studies and more studies.

In the better studies category, the following recommendations are made:

- 	All future diagnostic studies should measure and report sensitivity and specificity. This will require that a gold standard for diagnosis be agreed on. At this time, it seems this gold standard should be a clinical/EEG standard according to the latest International League Against Epilepsy (ILAE) classification scheme. 
- 	Treatment trials should use common terminology, e.g., distinguishing seizures from epilepsy and defining "newly diagnosed" in a common way, enrolling "pure" populations of patients with unprovoked seizures, and using common definitions of "optimum" outcomes inclusive of both seizures and side effects domains.
- 	Treatment trials should use a core set of efficacy outcomes that are comparable across trials, e.g., seizure remission rates, time to recurrence, mean number of seizures per patient per unit of time, and time to remission.
- 	Treatment trials need to report more often the efficacy, safety, and compliance associated with AEDs, in the long term.
- 	All new trials should include "patient-centered" outcomes whenever appropriate, e.g., quality of life, health care utilization measures, and economic impact of interventions. Different research methods/designs may be required to optimally study these outcomes.

In the more studies category, the following recommendations are made:

- 	Studies relating the volume of practice (as a hypothesized surrogate for clinical/pharmacologic expertise) to patient outcomes. These would include studies of the consequences of delayed diagnosis or misdiagnosis.
- 	Studies of the individual components of clinical/pharmacologic expertise to determine which of these components may or may not affect patient outcomes and which are related to volume of practice.
- 	Studies based outside of academic epilepsy centers (e.g., community-based studies) that would better capture populations with new onset epilepsy and would include other caregivers besides academic neurologists.
- 	Studies of the impact of patient counseling, education, and support interventions on patient outcomes.
- 	Studies of the impact of both old and newer (e.g., Internet based) patient monitoring methods on patient outcomes.Journal editors and reviewers should solicit and give preference to such studies, as well as raise the standard for the type of material acceptable for publication. More commentaries, opinions, narrative reviews, and anecdotes are not going to advance the field.

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## Availability of Full Report

The full evidence report from which this summary was derived was prepared for the Agency for Healthcare Research and Quality (AHRQ) and the Centers for Disease Control and Prevention (CDC) by MetaWorks, Inc. (an Evidence-based Practice Center) under contract  No. 290-97-0016. Requestors should ask for EvidenceReport/Technology Assessment  No. 39, *Management of Newly Diagnosed Patients with Epilepsy: A Systematic Review ofthe Literature* (AHRQ Publication  No. 01-E038). A booklet of appendixes is also available (order AHRQ Publication No.01-R035).

This Evidence Report is also online at www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat1.chapter.55359. The appendixes for this report can be downloaded as a zipped file online at www.ahrq.gov/clinic/evrptfiles.htm#epilepsy. 

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*AHRQ Publication Number 01-E037Current as of February 2001*

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**Internet Citation:**

*Management of Newly Diagnosed Patients with Epilepsy: A Systematic Review of the Literature*. Summary, Evidence Report/Technology Assessment:Number 39. AHRQ Publication Number 01-E037, February 2001. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/epcsums/epilepsum.htm

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