• Cost-effectiveness;
  • Methods;
  • Results


  1. Top of page
  2. Abstract

Summary: This article provides an overview of methods used and findings from economic analyses in epilepsy. Cost-effectiveness studies have evaluated different drugs for monotherapy and add-on therapy, and compared alternative treatment modalities for refractory epilepsy. The methodological characteristics of these studies are examined, and their results are compared and interpreted. Health outcome measures are defined and data sources described. Methods for assessing the direct and indirect costs, and/or cost savings, with a treatment's use, are explored. Directions for future research are identified and discussed.

In health systems throughout the world, there is a growing interest in the economic aspects of health and health care. For many conditions, including epilepsy, surprisingly little information exists about important economic issues such as the cost of treatment programs, the possibility of achieving similar clinical outcomes at lower cost, and the cost-effectiveness of new treatments.

In several clinical and health service areas, the economic assessment of epilepsy treatments is warranted. In this overview, these areas are described, the general approach of economic assessment in epilepsy is outlined, and findings from recent studies are reviewed. Major methodologic challenges are considered, including identifying appropriate outcome measures by which to judge the effectiveness of treatments, and measuring the use and value of resource utilization associated with epilepsy treatment. Limitations and uncertainties with existing studies are summarized and discussed.


  1. Top of page
  2. Abstract

Over the last 20 years, there has been a dramatic increase in therapeutic options available to treat epilepsy. Epilepsy can be treated with 15 different antiepileptic drugs (AEDs) (1), and new surgical techniques and methods of case selection and diagnosis continue to be developed (2). Many of these developments, especially new drug treatments, are more expensive than their replacements. For example, a 12-month dose of lamotrigine (LTG) as initial treatment in adults may cost 20 times that of phenytoin (PHT) (3). However, to focus on the purchase price of a drug without reference to its other effects on patients may be shortsighted. If a person taking a new AED is able to return to work, or if the new drug has advantages in terms of causing fewer side effects or improving seizure control, then the benefits may justify the higher cost of the drug. These issues are addressed by economic analysis in which treatments are considered in terms of their effect on patient outcomes and their impact on direct and indirect costs.

Economic evaluations of AEDs have examined the choice of treatment for patients with new-onset epilepsy and epilepsy that does not respond well to medical treatment. Physicians choose not only between different classes of AEDs, but in some cases, between generic and branded forms of therapy. The choice of drug is important, as patients whose epilepsy responds to a particular AED are likely to continue to be treated with that drug for many years, as drug changes can be associated with deterioration in seizure control and side effects. The use of expensive treatments as “first-line” choices can therefore have significant economic effects as the ongoing cost of treatment accumulates.

Economic issues also are important when considering nonpharmacologic treatments for epilepsy, such as surgery and vagal nerve implantation. These interventions often involve high initial expenditure but may result in long-term cost savings as patients who are successfully treated require fewer medical services and AEDs.

Epilepsy services themselves can be scrutinized in terms of their cost-effectiveness. Epilepsy is a condition that is treated in a wide variety of settings by various types of providers. Patients may be evaluated by generalist physicians or by those who are specialists in general neurology, psychiatry, or learning disabilities. Diagnoses may be assisted by the use of computed tomography (CT) scans and magnetic resonance imaging (MRI), and these may be administered on an inpatient or outpatient basis. The cost of services for epilepsy provided by different providers in different settings and with and without the aid of diagnostic procedures varies, but it is not clear which produce the best outcome per dollar spent.


  1. Top of page
  2. Abstract

The evaluation of epilepsy treatment and services using the methods of health economics involves the comparative assessment of alternative courses of action in terms of their relative cost and effectiveness (4,5). A cost-effectiveness ratio is calculated for each treatment or service being assessed, where the denominator reflects the incremental gain in health, and the numerator reflects the additional cost of achieving that health gain. Economic assessment models differ in terms of the measures used to express the health benefits of treatment. All require that there is an accounting of appropriate costs of treatment and cost saving.

Cost-effectiveness (CE) analysis, the most widely used approach, requires that health benefit attributable to treatment be expressed in nonmonetary clinical terms such as reduction in seizure frequency or severity. The CE ratio, evaluated against the no-treatment option is the net cost of the treatment divided by the total number of cases with reduced frequency or severity of seizures.

An alternative form of economic evaluation is cost–benefit analysis, where both the health benefits and resource costs of treatment are expressed in monetary terms. Because of the ethical and methodologic concerns with monetarizing health gains, few true cost–benefit analyses have been performed in health care (6).

In some cases, it may be assumed that treatments produce identical health benefits. When this assumption is appropriate, cost-minimization analyses are conducted in which the aim of a study is to determine the relative cost of each treatment. This has been the most common type of analysis in evaluating new drug treatments for epilepsy. In the absence of head-to-head trials, the available evidence on the effectiveness of new epilepsy drugs has been inconclusive, that is, there is significant overlap in the efficacy ranges. Consequently, many economic analyses have assumed equal efficacy and conducted evaluations by applying the cost-minimization model.

When the gain in health is expressed in terms of health-related quality of life, such as Quality Adjusted Life Years (QALYs) or Healthy Year Equivalents (HYEs), the economic assessment study is described as cost–utility analysis (5). Cost–utility analysis has become the gold standard in economic assessment of health care because the outcome measure reflects both the morbidity and mortality effects of treatment from the viewpoint of the patient. To derive QALYs, for example, the change in life expectancy attributable to a treatment is adjusted for different health states experienced by the patient and weighted according to the patient's preferences. The values of cost per QALY gained have been reported for a number of interventions and illnesses, allowing comparisons of the economic profiles of epilepsy treatments with those of treatments for other diseases.

The equation that summarizes the calculation of cost per QALY is the following:

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The variables in this equation are defined as follows: Cost/QALY = the cost per quality-adjusted life year of the proposed intervention as compared with the status quo. CT, The present value of the cost of the proposed intervention. CSE, The present value of the cost of treating the side effects of the intervention. CMorb, The present value of the cost saved from not treating conditions that were prevented or ameliorated. CLE, The present value of the additional cost to the medical care system of caring for conditions that would not have occurred if the person had not lived longer. YT, The present value of the change in life years due to the intervention. YSE, The adjustment for changes in quality of life due to the side effects of treatment. YMorb, The adjustment for changes in quality of life due to the reduction or prevention of disease. The cost/QALY ratio, evaluated against the status quo, is the net cost of the treatment divided by the total number of quality-adjusted life years gained.


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  2. Abstract

Ideally, in cost-effectiveness analysis, the benefits of treatment should be defined as broadly as possible so that comparisons can be made among the variety of treatments and services in epilepsy, and among treatments in epilepsy and other diseases. The value of conducting cost-effectiveness analysis systematically is that it permits the analyst to assess efficiency of different treatments within and across diseases. In addition, precise information on medical resource utilization associated with each treatment also is needed. Unfortunately, because epilepsy is a diverse and complex condition, the relevant outcomes used to assess the benefits of treatment continue to be debated (see the Langfitt and Wiebe article in this issue). Furthermore, precise data on resource utilization and treatment effects have generally been lacking, so most studies are conducted for hypothetical cohorts of patients based on data derived from clinical trials and expert panels.

Outcome measures

Epilepsy treatment outcomes are typically described in terms of improvements in specific clinical indices, such as seizure frequency and/or severity. There is some dispute about which measure to use (7). The main argument for these clinical measures is their relative ease of measurement and interpretation. However, they fail to reflect “quality-of-life” outcomes that are associated with the treatment of epilepsy. Trials of monotherapy show that ≤90% of patients treated with AEDs will experience adverse symptoms related to their medication (8). These side effects can vary from mild feelings of fatigue to life-threatening hypersensitivity reactions. AEDs may also have adverse psychological and/or cognitive effects. Treatments sometimes fail to achieve adequate seizure control to offset these adverse effects, leading patients to discontinue the treatment.

The quality-of-life (QOL) outcomes of treatment are significant to patients and physicians, but are difficult to measure. A variety of generic and epilepsy-specific scales have been developed to describe different health states in epilepsy (9). However, there is no consensus on which is most appropriate for general use. Furthermore, to reflect the patient's preferences, the QOL scales must be weighted by the value people place on different health states. This requires deriving utilities for different health states, using a rating scale, standard gamble, or time trade-off method. For example, the time trade-off method involves patients stating how much of their life expectancy with their current state of health they would be willing to give up to live the remaining years in excellent health. The resulting responses are converted into a health utility index ranging from 0 (worst response) to 1 (best response, unwilling to give up any time). The index can then be used to adjust expected years of survival in a given health state by the utility of that health state to derive QALYs or HYEs.

Cost measures

Another requirement of an economic evaluation is an accurate and complete assessment of both the short-term and long-term net cost of a considered treatment. The net cost of a new therapy, for example, should include the acquisition cost of the treatment, the cost of resources used in the management of adverse side effects of treatment, the cost of therapeutic switching if the treatment fails, and the cost increases or saving from current and future outcome differences, if such differences occur (see above equation). Direct cost and saving arise in relation to the treatment of an illness. Health care resources generate direct cost, such as payments for outpatient visits to physicians, pharmaceuticals, hospital admissions, and laboratory investigations. Social service cost can also arise from treatment including such items as payments for transportation, childcare, and respite care for a family caregiver.

Cost analyses in cost-effectiveness studies should attempt to measure the long-term incremental differences in health care, social service, and patient and caregiver cost attributed to a given treatment versus its comparator (10). Relevant health care cost items for epilepsy include AEDs (drug cost and pharmacy fee), hospitalization, emergency room services, physician visits (inpatient and outpatient), diagnostic procedures, surgery, diagnostic tests, and laboratory tests. Relevant social service items may include social worker services, psychologist–psychiatrist visits, day care, remedial schooling, and residential care. Patient and caregiver cost measures may include time spent seeking care, time spent undergoing care, child care cost for parents during care, transportation expense to access care, time family members spend in home care, cost for respite care, cost of safety equipment, special furniture, etc. Some of the direct cost measures may be omitted if they are known to be relatively small or do not differ significantly across the treatment regimens being compared.

Direct cost and saving are measured in terms of the monetary value of resources used. Cost refers to the economic value of resources consumed as a consequence of treatment. Economists measure such resources in terms of “opportunity costs:” the value those resources would have generated in their next best alternative use. In most countries, health care and social services are exchanged for money; for example when pharmaceuticals are bought from pharmaceutical companies or when hospitals employ staff and purchase equipment to provide health care. Economic evaluations usually rely on the payments made for these goods and services when calculating the cost of treatment, assuming that, in the absence of information on the cost of production, payments reflect the social opportunity cost of the resources.

The effect of epilepsy and its treatment on patients' time and productivity are described as indirect cost, and this cost is usually valued in terms of lost productivity in the workplace. Epilepsy can reduce productivity if patients perform less well at their jobs, have to take time off because of their seizures, or become unemployed. Premature mortality can also be considered in terms of the time that would have been devoted to work or leisure that is lost. Epilepsy treatments may reduce the indirect cost that accrues both to the individual and society at large.

Productivity cost for individuals is estimated in terms of their age and sex-group average value of lost earnings. This process has its basis in the human capital method (11), which values a person's time in terms of expected earnings. This method has also been applied to value the effects of temporary illness on an individual's ability to do the job. For example, the cost of missing 5 days work through epilepsy would be valued as the equivalent of the loss of 5 days' average earnings for that individual worker.

Indirect cost is more difficult to value when the time lost is not paid by wages. For example, time devoted to housework and childcare are important to the individuals concerned and also to the general economy, but such work is rarely paid for in a financial transaction. In the developing world, large numbers of people in rural areas perform work that is unwaged. In these cases, “shadow” pay rates can be used, based on the prices charged for hiring workers to perform similar jobs. Although the human capital method has been shown to have theoretical flaws and raise ethical issues (5), it is relatively easy to apply and has been used to estimate the economic impact of epilepsy in the workplace in cost-of-illness studies in epilepsy (12) and in some economic evaluations of AEDs (13).

Intangible savings and costs arise because of the sense of well-being associated with improved health or vice versa. They are described as intangible because they are difficult to measure. In a chronic condition such as epilepsy, which is often socially stigmatized, this cost is likely to be significant. Unfortunately, no method of assessing the financial value of improved health and well-being in epilepsy has been developed. Contingent valuation methods such as willingness-to-pay for a treatment or outcome can be used to estimate such cost from patients' perspectives, but these techniques have not been used widely in health care.

In economic evaluations of epilepsy treatments using the cost–utility model (discussed in the prior section), indirect and intangible cost is theoretically reflected in the QALY outcome measure in the denominator. Consequently, an advantage of using this model is that net cost calculations in the numerator may be limited to the direct cost of an intervention, avoiding the problems with having to estimate productivity effects and intangibles (14).

The cost of resources used in treatment depend on the perspective that is considered. In most developed countries, patients rarely pay directly for treatments. Individuals most often receive health care that is paid for by national insurance schemes or private insurance companies. Consequently, from the perspective of the patient, health care cost, at the time of consumption, is minimal, other than any user charges or copayments that are required. In this case, it is most useful to perform economic analysis from a societal perspective considering all costs and benefits of a treatment regardless of the source of payment or who benefits. This may not be the case in poorer countries. People living in less wealthy countries are often expected to pay for most or all of any antiepileptic treatment they receive. Those performing economic evaluations must select a perspective that is most appropriate for the decision-makers targeted by the analysis. However, whenever possible, the societal perspective should also be adopted in the analysis so that results will be comparable across studies.

Estimation methods

A preferred method for economic assessment in epilepsy would be to collect cost data alongside prospective clinical trials. The benefits of this approach are that results would reflect actual data from real patients, and the internal validity of the data could be assessed through controlled clinical conditions. The disadvantages of this approach are that the treatment pathways and patient samples may not be generalizable to the larger population. Naturalistic studies (retrospective or prospective) provide a more realistic alternative by using patient survey to obtain outcome data and medical claims to assess cost. The strength of this approach lies in the representativeness of patients, treatments, and treatment settings. However, there may be internal validity problems due to selection bias and other confounders. The most common approach used in epilepsy research to date is to model the costs and outcomes of different treatments. This involves reviewing clinical data from drug trials to assess outcome differences and developing cost estimates using clinical data from drug trials, expert opinion, and/or data from existing literature (15).

Acceptable approaches to cost measurement vary by the degree of precision required. The most accurate is microcosting, and involves specific enumeration and summation of payment for inputs (i.e., personnel, facility, supplies) used in providing health care and social services that are consumed in treatment. Because input data are generally not available, gross costing methods are typically used in empiric cost studies in which payment for more global units of service (i.e., the average payment for a physician visit or a day in the hospital) are documented.


  1. Top of page
  2. Abstract

A number of studies have recently been published evaluating the cost-effectiveness of various treatments in epilepsy. These studies have evaluated different drugs for monotherapy and add-on therapy, and compared alternative treatment modalities (i.e., drug therapy versus surgery) for refractory epilepsy. The methods vary, making comparisons difficult, and there has been only one study that has evaluated an add-on drug treatment using the cost/QALY model.

Studies of economic evaluation in epilepsy diverge in terms of their basic aims (i.e., cost-minimization, cost-effectiveness, cost–utility). Those with similar aims also vary depending on the types of patients that are studied, the nature of the treatment being evaluated (i.e., monotherapy, adjuvant therapy, treatment modalities), the time period covered by the study, and the perspective adopted. No prospective studies have been performed that consider the economic impact of epilepsy treatments. Most economic evaluations have relied to a varying extent on assumptions, expert opinions, and modelling of underlying cost and effectiveness.

As clinical trials generally have concluded that alternative drugs for monotherapy do not differ in effectiveness, economic evaluations of these drugs have used the cost-minimization model (Table 1). Two studies in the U.K. (3,16) and one in the U.S. (17) have considered treatment cost and side effects, but disregarded social service and indirect cost. Utilization and cost of different treatments were modelled based on clinical trial data and expert panels. The results were recently compared by Levy (18), although they differed in the type of treated patients, treatment pathways, dosage regimens, study duration, and the direct cost items considered. Two of the studies include switching among alternative drugs. As such, the mean cost per patient is a weighted average of different treatments. There is a consistent pattern with respect to the cost of the drugs that have been evaluated; PHT and carbamazepine (CBZ) are of similar cost and about half as expensive as LTG, whereas valproate (VPA) is in the middle.

Table 1.  Cost-effectiveness of antiepileptic drugs as monotherapy
StudyHeaney, Shorvon, and Sander, 1998Shakespeare and Simeon, 1998Navarro and Ashraf, 1993
  1. CBZ, carbamazepine; LTG, lamotrigine; PHT, phenytoin; VPA, valproate.

PatientsNewly diagnosed epilepsyNewly diagnosed partial and/or tonic–clonic seizuresComplex partial seizures
Treatment pathwayFirst-line switched to second-line monotherapy or polytherapyIf withdrawal, CBZ switched to VPA and LTG switched to CBZContinuous treatment
Cost measuresDrugs, tmt of side effects, switching of trtDrugs, tmt of side effects, switching of trtDrugs, tmt of side effects, routine trt
Outcome measuresNoneNoneNone
Estimation methodModel using data from clinical trials, expert panels, and related literatureModel using data from clinical trials, expert panels, and related literatureModel using data from clinical trials, expert panels, and related literature
Time period2 yr1 yr5 yr
Estimated cost per patient per year U.S.$1104–1152 PHT 1193–1244 CBZ 1302–1326 VPA 2288–3114 LTG269 CBZ 783 LTG326 PHT 355–411 CBZ 861–1,181 VPA

Add-on therapy with some of the new products has been examined in studies using cost-minimization (19), cost-effectiveness (20–22), and cost/QALY models of economic evaluation (23)(Table 2). The studies vary in terms of the cost measures addressed, time periods covered, treatment pathways, and outcome measures. The most common outcome measures have been reductions in seizure occurrence. The general conclusion from these studies is that the new antiepileptic treatments appear to be similar in terms of economic value. However, the most recent study by Selai et al. (20), and the only study based on observational data, indicated a much larger difference between two of the drugs considered, raising questions about the validity of the models. Two studies comparing LTG with placebo differ (22,23), with one suggesting a cost/QALY that is relatively expensive for pharmacologic treatments, and the other indicating a cost/seizure-free day that seems relatively low. Both studies attempt to include the patient's point of view in their outcome measurement, but use different approaches that are not comparable.

Table 2.  Cost-effectiveness of antiepileptic drugs as add-on therapy
StudySelai, Smith, and Trimble, 1999Messori et al., 1998Markowitz et al., 1998Hughes and Cockerell, 1996O'Neill, Trimble, and Bloom, 1995
  1. LTG, lamotrigine; TPM, topiramate; VGB, vigabatrin; GBP, gabapentin; QALY, quality-adjusted life year.

TypeCost effectivenessCost utilityCost effectivenessCost-minimizationCost effectiveness
Drugs comparedLTG, TPMLTG, older AEDsLTG, older AEDsLTG, VGB, GBPLTG, VGB, clobazam
PatientsIntractable epilepsyIntractable epilepsyIntractable epilepsyIntractable partial epilepsy over age 12Intractable epilepsy
Treatment pathwaysContinuous treatmentContinuous treatmentContinuous treatmentContinuous treatmentSwitching among these three drugs if not controlled
Cost measuresDrug, tmt of side effects, routine trtDrug, routine trtDrug, tmt of side effects, routine trtDrug, tmt of side effects, routine trtDrug, extra visits from switching
Outcome measures50% seizure reduction, patient satisfaction (on drug, no side effects, no adverse events, 50% seizure reduction)QALYSeizure-free daysNoneSeizure control (at least 50% reduction in seizure frequency over 9 mo)
Time period6 moLifetime10 yr1 yr1 yr
Estimation methodProspective observational studyModel using data from clinical trials, related literature, expert panels, and patient surveysModel using data from clinical trials, related literature, and expert panelsModel using data from clinical trials, standard practice patterns, and related literatureModel using data from clinical trials, and standard practice patterns
ResultsLTG: $9,395 per satisfied patient, $2,819 per 50% seizure reduction TPM: $4,953 per satisfied, $2,312 per 50% seizure reduction$41,343 per QALY$6.90 per seizure-free day$1,643 GBP $1,671 LTG $1,715 VGB per patient per year$1,551 clobazam $2,171 VGB $2,219 LTG per person with >50% reduction in seizures

There have been three published studies of the cost-effectiveness of surgery (24–26)(Table 3). They estimate the incremental cost/QALY of surgery to range from $16,000 to $27,000 per QALY, and the cost per seizure-free patient to be about one sixth of medical therapy over a lifetime. The studies use modelling and expert opinion to develop estimates of both effects and costs, as there are no controlled trials assessing the effectiveness of epilepsy surgery. Adequately designed, controlled trials and/or observational studies are necessary to determine more accurately and comprehensively the effectiveness of each treatment alternative to verify the findings from these studies.

Table 3.  Cost-effectiveness of alternative treatments
StudyLangfitt, 1997King et al., 1997Wiebe, 1995
  1. QALY, quality-adjusted life year.

TypeCost utilityCost utilityCost effectiveness
Treatments comparedSurgery, medical therapySurgery, medical therapySurgery, medical therapy
PatientsIntractable complex partial epilepsyIntractable temporal lobe epilepsyIntractable epilepsy, adults
Treatment pathwaysSurgery evaluation followed by surgery or continued medical therapySurgery evaluation followed by surgery or continued medical therapySurgery evaluation followed by surgery or continued medical therapy
Cost measuresSurgery evaluation and trt, routine trtSurgery evaluation and trt, routine trtSurgery evaluation and treatment, routine trt
Outcome measuresQALYQALYNumber seizure free
Time periodLifetimeLifetime35 yr
Estimation methodModel based on data from records of clinic patients and related literatureModel based on records of clinic patients, expert panels, and related literatureMedical records of clinic patients, published literature, expert opinion, patient survey
Results$15,581 per QALY for surgery$27,200 per QALY for surgery$108,238, surgery $680,290, medical therapy per seizure free patient


  1. Top of page
  2. Abstract

Epilepsy is a diverse and heterogeneous condition, and those seeking to assess the economic impact of treatment face three main challenges: (a) the choice of outcome measures that express health gains in terms of quality of life and patient utility, (b) the inclusion of appropriate cost that adequately reflects the breadth of resources arising from treatment, and (c) the use of estimation methods whose validity can be accurately assessed.

The economic assessment of epilepsy treatment is in an early developmental stage relying largely on modelling to produce estimates of the cost and benefit of treatment. To date, the most common method for cost-effectiveness analysis in epilepsy studies is hypothetical modelling of outcomes from different treatments, services involved in treatment, treatment of side effects, and treatment switching. This involves combining data from different sources (i.e., other cost studies, clinical trials, and expert panels). The advantage of this approach is the feasibility of estimating a broad set of cost and outcome issues over a long period. The assumptions and qualitative and quantitative data that are combined in these studies need to be validated using observational methods that are more defensible.

Lacking in the literature are prospective evaluations of the cost and outcomes of treatments combining rigorously designed cost studies with the outcome assessments of the treatments in question. Such efforts have begun and more need to be completed. This approach offers to eliminate many of the problems of modelling. Alternatively, retrospective naturalistic studies need to be conducted using medical claims and administrative data to generate cost estimates. Such studies can also provide information on effectiveness, although efforts must be made to control for confounding factors and selection bias.

Clinical trials and observational studies are time-consuming and expensive to perform. Consequently, it is also necessary for economic modelling in treatment assessment to be improved, particularly with respect to the use of qualitative methods and sensitivity analysis. It is essential that when assumptions are made, the methods by which they are derived be stated explicitly. Where possible, formal methods of arriving at such estimates should be used. Qualitative research methods such as consensus techniques and Delphi panel techniques can be used to establish the opinions of physicians expert in treating epilepsy. These methods are designed to maximise the generalizability of results obtained from small panels (26).

Where assumptions are made in economic analysis, it is also necessary to test the impact of error in such assumptions using sensitivity analysis (10). The form of sensitivity analysis adopted should be stated clearly. Univariate sensitivity analysis involves sequentially testing the impact of changes in single variables on the study findings. Individual parameters are varied across a range that is either based on available evidence or according to a formally derived estimate. Multivariate sensitivity analysis involves testing more than one assumption at a time. Probabilistic sensitivity analysis involves determining probability distributions for each variable to be tested. Statistical software packages can then be used to generate pseudo-confidence intervals for cost-effectiveness ratios.

There is work to be done in the development of generic and specific measures of health states in epilepsy that are appropriate for general use in cost-effectiveness studies. Additional research is also needed to determine the preferences people have for different health states. The development and application of broad measures of outcome are particularly important so that we may go beyond the limited measures related to the clinical control of seizures to capture effectiveness in terms of quality of life. This will allow us to compare the cost/utility of epilepsy treatments with that for other neurologic and nonneurologic conditions.


  1. Top of page
  2. Abstract
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