Quality of Life in Epilepsy,Multiple Sclerosis, andBeyond

In this issue of the Annals, Spencer and colleagues1 andRudick and colleagues2 report on improvements in“health-related quality of life” from two different inter-ventions, resective surgery in epilepsy and natalizumabin multiple sclerosis. The articles present a timely op-portunity to understand better how quality of life ismeasured, why it is valuable, and what role it may playin many current health care controversies, rangingfrom regulating rofecoxib (Vioxx) to controlling accessto acetylcholinesterase inhibitors.

Measuring health can be viewed as a three-step pro-cess that involves: (1) classifying health states often inresponse to an intervention, (2) valuing those healthstates, and (3) comparing the resulting health gainsagainst the risks or costs of an intervention (Fig). Spen-cer and colleagues1 and Rudick and colleagues2 takethe first and important step of classifying health statesin response by asking patients to complete health-related quality-of-life surveys. The Short Form 36Health Survey (SF-36) is one such survey that asksquestions such as, “Compared to one year ago, howwould you rate your general health now?” and “Duringthe past four weeks, how much did pain interfere withyour normal work?”3 The Quality of Life inEpilepsy-89 (QOLIE-89) asks, “Has your epilepsy lim-ited your social activities?” and “Have you worriedabout having another seizure?” followed by choicesranging from “all of the time” to “none of the time.”4

In many cases, disease-specific measures, such as theQuality of Life in Epilepsy-89, build off of genericmeasures, such as the Short Form 36 Health Survey.

Health-related quality-of-life metrics have limita-tions. By their nature, they are subjective and may notadequately reflect all considerations that are importantto health. However, these metrics are frequently sensi-tive to changes in clinical conditions. For example,Spencer and colleagues1 found quality of life in epi-lepsy to be sensitive to seizure freedom, and Rudickand colleageus2 found quality of life in multiple scle-rosis to be correlated with disability progression andnumber of relapses.

Increasingly, as also demonstrated in these studies,these quality-of-life metrics are responsive to novel andhigh-risk interventions.5 Demonstrating the beneficialeffects of interventions on patient-reported outcomes iscritical because many clinical trial end points do notreflect outcomes that are important to patients.6 To

address this shortcoming, the Food and Drug Admin-istration in February 2006 issued draft guidance on theuse of patient-reported outcome measures, which in-clude health-related quality-of-life metrics, in medicalproduct development.7

Measuring quality of life is increasingly important inother technology assessment methods, such as risk–ben-efit and cost-effectiveness analyses (see Fig, Step 3). Forexample, a risk–benefit analysis can weigh the principalbeneficial effects of natalizumab on reducing relapsesand slowing disease progression against the adverse effectof progressive multifocal leukoencephalopathy in relaps-ing multiple sclerosis. When performed over 2 years, theanalysis indicates that the benefits substantially outweighthe risks.8 Such information can be helpful in commu-nicating information to patients, selecting the appropri-ate treatment, developing formal treatment recommen-dations,9 and making regulatory decisions.10

The cases of natalizumab, and more generally rofe-coxib11 and rosiglitazone12 (Avandia), highlight theneed to make formal risk–benefit assessments in trialsand over time. In response to the withdrawal of rofe-coxib, the Institute of Medicine made many recommen-dations to improve drug safety and evaluation. Amongthem was that the Food and Drug Administration “de-velop and continually improve a systematic approach torisk-benefit analysis for use throughout the FDA [Foodand Drug Administration] in the pre-approval and post-approval settings.”10 Two studies1,2 in this issue of An-nals take a step in this direction by assessing quality oflife in a clinical trial and in a longitudinal study. Moreformal assessments could systematically quantify theprincipal risks (eg, surgical complications with epilepsysurgery, progressive multifocal leukoencephalopathy withnatalizumab) that then could be measured against thetherapeutic benefits observed in the study. Together, theinformation would provide a quantitative assessment ofthe risk and benefits of an intervention that couldgreatly assist the regulatory process.10

Cost-effectiveness analysis can improve resource allo-cation. With health care costs continuing to rise atrates above inflation and with the population aging,payors face increasing pressure to contain costs. Tomaximize health benefits and minimize costs, payorsuse cost-effectiveness analysis to compare the costs of ahealth intervention relative to its health benefits. Bymeasuring preferences for health states, one can calcu-late the value of the health either gained or lost due tothe intervention (see Fig, Step 2).13 These health out-comes are often measured in quality-adjusted life-yearsor similar metrics, which incorporate the value of ahealth state (eg, having frequent seizures) and the timespent at each health state. Traditional clinical trial endpoints, such as seizure frequency and disability progres-sion, are not as well suited for such analyses becausethey are not readily comparable across disease states.

EDITORIALS

© 2007 American Neurological Association 307Published by Wiley-Liss, Inc., through Wiley Subscription Services

The health effects of an intervention can then be com-pared with the costs associated with the intervention(eg, the cost of the intervention, required follow-up,caregiver time) to determine the cost necessary to gaina certain measure of health.14

Cost-effectiveness analysis is increasingly used tomake decisions about treatment coverage. For example,in the United Kingdom, the National Institute forHealth and Clinical Excellence routinely relies on suchanalyses to make treatment coverage decisions for theNational Health Service. Recently, National Institutefor Health and Clinical Excellence made a controversialdecision15 to restrict coverage of acetylcholinesteraseinhibitors to only individuals with moderate Alzhei-mer’s disease.16 Many commonly used neurologicaltherapeutics and interventions with demonstrated clin-ical benefit (eg, interferons for multiple sclerosis17 andscreening for carotid stenosis in asymptomatic individ-uals18) are not cost-effective. Although such results donot explicitly lead to restrictions on access in theUnited States, the analyses often guide coverage andaccess decisions informally (eg, through formulary de-cisions or price-sharing arrangements). With the con-tinued growth of new technologies and the increasedresponsibilities of public payors (eg, Medicare Part D),the use of cost-effectiveness analysis will likely expand.

Two studies1,2 in this issue increase our understand-ing of the impact on quality of life of two disparateneurological interventions and highlight the impor-tance of such measures in addressing current debates inhealth and medicine. Improving our methods for mea-suring health, understanding their limitations, and cre-

ating new applications can lead to meaningful publichealth improvements.

E. Ray Dorsey, MD, MBA1

and Robert G. Holloway, MD, MPH1,2

Departments of 1Neurology and 2Community andPreventive Medicine

University of Rochester Medical CenterRochester, NY

References1. Spencer S, Berg A, Vickrey B, et al. Health-related quality of life

over time since resective epilepsy surgery. Ann Neurol 2007;62:327–334.

2. Rudick R, Miller D, Hass S, et al. Health-related quality of life inmultiple sclerosis: effects of natalizumab. Ann Neurol 2007;62:335–346.

3. Swinburne University. SF36 Health Survey. Available at: http://www.swin.edu.au/victims/resources/assessment/health/SF36.pdf.Accessed July 6, 2007.

4. RAND Health. Quality of Life in Epilepsy Inventory. Availableat: http://www.rand.org/health/surveys_tools/qolie. AccessedJuly 6, 2007.

5. Deuschl G, Schade-Brittinger C, Krack P, et al. A randomizedtrial of deep-brain stimulation for Parkinson’s disease. N EnglJ Med 2006;355:896–908.

6. Holloway RG, Dick AW. Clinical trial end points: on the roadto nowhere? Neurology 2002;58:679–686.

7. U.S. Food and Drug Administration. Guidance for industry—patient-reported outcome measures: use in medical product de-velopment to support labeling claims. Food and Drug Admin-istration. Available at: http://www.fda.gov/cder/Guidance/5460dft.pdf. Accessed July 6, 2007.

8. Dorsey ER, Thompson JP, Noyes K, et al. Quantifying therisks and benefits of natalizumab in relapsing multiple sclerosis.Neurology 2007;68:1524–1528.

9. Kappos L, Bates D, Hartung HP, et al. Natalizumab treatmentfor multiple sclerosis: recommendations for patient selectionand monitoring. Lancet Neurol 2007;6:431–441.

10. Garrison L Jr, Towse A, Bresnahan B. Assessing a structured,quantitative health outcomes approach to drug risk-benefitanalysis. Health Affairs 2007;26:684–695.

11. Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular eventsassociated with rofecoxib in a colorectal adenoma chemopreven-tion trial. N Engl J Med 2005;352:1092–1102.

12. Nissen SE, Wolski K. Effect of rosiglitazone on the risk ofmyocardial infarction and death from cardiovascular causes.N Engl J Med 2007;356:2457–2471.

13. Noyes K, Dick AW, Holloway RG. Pramipexole v. levodopa asinitial treatment for Parkinson’s disease: a randomized clinical-economic trial. Med Decis Making 2004;24:472–485.

14. Gold MR, Siegel JE, Russell LB, Weinstein MC, editors. Cost-effectiveness in health and medicine. New York: Oxford Uni-versity Press, 1996.

15. NICE to see the bigger picture. Lancet Neurol 2006;5:103.16. National Institute for Health and Clinical Excellence. NICE

announces Alzheimer’s disease drug appeal outcome and NHSguideline to support patients and carers. Available at: http://www.nice.org.uk/page.aspx?o�373237. Accessed July 6, 2007.

17. Prosser LA, Kuntz KM, Bar-Or A, et al. Cost-effectiveness ofinterferon beta-1a, interferon beta-1b, and glatiramer acetate innewly diagnosed non-primary progressive multiple sclerosis.Value Health 2004;7:554–568.

18. Lee TT, Solomon NA, Heidenreich PA, et al. Cost-effectivenessof screening for carotid stenosis in asymptomatic persons. AnnIntern Med 1997;126:337–346.

Fig. Measuring health. Measuring health can be viewed as athree-step process. Step 1 classifies patients into health statesgenerally through responses to quality-of-life surveys (eg, ShortForm 36). Step 2 values these health states (often on a linearscale from zero to one) using preference-based measures (eg,Health Utilities Index). Step 3 compares the benefits of anintervention to its risk (risk–benefit analysis) or to its costs(cost-effectiveness analysis).

308 Annals of Neurology Vol 62 No 4 October 2007