The epidemiology of epilepsy revisited Josemir W. Sander

The epidemiology of epilepsy revisited Josemir W Sander Purpose of review Epidemiology is the study of the dynamics of a medical condition in a population There are many shortcomings in the understanding of the epidemiology of epilepsy mostly caused by methodological problems These include diagnostic accuracy, case ascertainment, and selection bias In this article recent progress in this area is discussed and suggestions for future research are made Recent findings It is generally accepted that in developed countries the incidence is around 50/100 000/year In resource-poor countries, the incidence is likely to be higher Prevalence of active epilepsy is in the range of 5 10/1000 in most locations, although it might be higher in some isolates Age-specific incidence rates have changed, with a decrease in younger age groups and an increase in persons above 60 years The overall prognosis for seizure control is good and over 70% will enter remission Epilepsy carries an increased risk of premature death particularly in patients with chronic epilepsy Sudden unexpected death has been increasingly recognized as a major culprit for this increased mortality Summary There is geographic variation in the incidence of epileptic syndromes likely to be associated with genetic and environmental factors, although as yet causality has not been fully established The complete range of aetiologies in the general population is not known Few predictors of outcome are recognized and it is difficult to prognosticate in any individual case Knowledge is patchy about the epidemiology of sudden unexpected death in epilepsy Future epidemiological research needs to address these issues if we are to progress Keywords epidemiology, epilepsy, incidence, prevalence, prognosis Curr Opin Neurol 16:165 170 # 2003 Lippincott Williams & Wilkins Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London, UK Correspondence to Josemir W Sander, Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK Tel: +44 20 7837 3611 x3867; fax: +44 20 7837 3941; e-mail: lsander@ionuclacuk Current Opinion in Neurology 2003, 16:165 170 Abbreviations AED antiepileptic drug CVD cerebrovascular disease SUDEP sudden unexpected death in epilepsy # 2003 Lippincott Williams & Wilkins 1350-7540 Introduction Epidemiology is the study of the dynamics of a medical condition in terms of its distribution, determinants and natural history in a population It consists of three domains: descriptive, analytical and experimental epidemiology Descriptive epidemiology concerns the vital statistics of a condition and is usually observational, with no designed control group Analytical epidemiology attempts to establish associations and determinants of a condition, often by comparing individuals with the condition or risk factors for it with those without, for example in cohort and case control studies Studies under conditions that allow an investigator to control relevant factors constitute experimental epidemiology [1 ] The epidemiology of epilepsy is largely based on descriptive and analytical studies, as very little experimental work has been carried out for a number of reasons, including logistical and ethical Despite epilepsy being amongst the most common serious neurological conditions, there are many deficiencies with regards to our understanding of its epidemiology This is partly due to methodological problems and also due to the failure to take fully into account epilepsy s heterogeneous nature [2,3] Epilepsy is the tendency to the occurrence of unprovoked epileptic seizures Different conditions may express themselves solely by recurrent seizures and thus be labelled epilepsy Epileptic seizures may also occur as a result of a plethora of acute brain insults and metabolic derangements Those seizures triggered by clear precipitants are termed acute symptomatic seizures and do not constitute epilepsy even if repeated The distinction between provoked and unprovoked can be difficult, particularly in less sophisticated medical settings The range of aetiologies and risk factors for the development of epilepsy varies with age and geographic location [2,3] Congenital, developmental and genetic conditions are mostly associated with the development of epilepsy in childhood, adolescence and early adulthood Head trauma, central nervous system infections and tumours may occur at any age and may lead to the development of epilepsy, although tumours are more likely over age 40 Cerebrovascular disease (CVD) is the most common risk factor for epilepsy in people over the age of 60 years Endemic infections are associated with epilepsy in certain environments, particularly in resource-poor countries, DOI: 101097/01wco0000063766158778e 165

166 Seizure disorders and these include malaria, neurocysticercosis and paragonomiasis [4 9] Recently, toxocariasis has joined this list [10 ] The presence of a family history of epilepsy seems to enhance other risk factors and this may suggest that the aetiology of epilepsy is multifactorial [11,12,13,14 ] It is evident that the successful detection of an aetiological or risk factor depends upon the extent of investigation and unless this is standardized and specified in any study, evaluation of the results is problematic [2,3] The use of the terms idiopathic epilepsy and cryptogenic epilepsy is a particular source of confusion Idiopathic epilepsy should be reserved for epilepsies which have a genetic component with strictly defined clinical and EEG findings, but is often used to refer to any case in which aetiology has not been established This article is concerned with shortcomings in the current knowledge of the descriptive epidemiology of epilepsy and will highlight areas in which research is urgently warranted In epilepsy, these include incidence and prevalence rates, the natural history in terms of prognosis for seizure control and mortality Diagnostic accuracy and case ascertainment Major problems in epilepsy epidemiology are diagnostic accuracy and case ascertainment [2,3] It is often difficult to diagnose or to rule out epilepsy with confidence in all cases of seizures The differential diagnosis of epilepsy encompasses all causes of transient alterations of consciousness Epileptic seizures are pleomorphic, although usually stereotyped for a given individual Unlike most neurological disorders, the majority of patients with epilepsy do not have permanent physical signs and can be diagnosed only by taking a history or by the chance observation of a seizure Diagnosis is a discretionary judgment that may vary depending on the skill and experience of the diagnostician and the quality of witness information available EEG is useful in classifying epilepsy, but is of limited help in making the diagnosis Acute symptomatic seizures, despite having clear epileptiform phenomenology, are not classified as epilepsy In practice, both false positive and false negative diagnoses are common Even if the diagnosis of epilepsy is accurate, case ascertainment poses a variety of problems [2,3] Some patients with seizures may never seek medical attention because they ignore or misinterpret the symptoms, or indeed may be unaware of them It is likely, therefore, that epidemiological studies of epilepsy often miss patients unless sensitive screening techniques are included This has seldom been achieved The incidence of epilepsy Incidence here refers to the number of people who developed the condition of interest during a 1-year period divided by the total person-time at risk during that period, and is expressed as the number of cases per 100 000 people in the population The overall incidence of epilepsy is generally taken to be around 50 per 100 000/year (range 40 70 per 100 000/year) in industrialized countries [15,16,17 ] and people socioeconomically deprived are at higher risk [18,19,20 ] Only a few studies have come from resource-poor countries and in these a range of 100 190 cases per 100 000/year is generally quoted [4,21,22] The lack of medical facilities in many resource-poor countries may result in misclassification of some cases, particularly of acute symptomatic seizures [23] Despite this, it is likely that the incidence of epilepsy in resource-poor countries is higher than in the industrialized world In industrialized countries, there is evidence of a decrease in the incidence in children and a simultaneous increase in the elderly over the last three decades [23,24] In children this is not fully understood and speculation has centred on the role of the adoption of healthier life styles by expectant mothers, improved prenatal care, and enhanced immunization programmes This may have led to a decrease in neuronal migration defects, to a reduction in the incidence of birth hypoxia and the reduction of central nervous system viral infections [2,3,23] In the elderly, the increased incidence seems to be related to improved survival in persons with CVD This seems paradoxical, however, as the incidence of CVD has decreased significantly over the last two decades [2,3,25 27 ] The prevalence Prevalence refers to the number of diseased persons in a defined population at one point in time, divided by the number of persons in that population, and is expressed as the number of cases per 1000 people in the population A plethora of studies has been made of the prevalence of epilepsy in many different settings and it has usually been found to be between 4 and 10/1000 persons [1,2 4,16,21,28,29 32 ] Part of the variation in prevalence can be explained by the methodological differences used to assess it A few studies, primarily conducted in resource-poor countries, have given prevalence rates well above this range [2,3] These have usually been small-scale studies from isolated geographic areas where unique genetic or environmental factors may be important Most large-scale studies of populations in resource-poor countries have reported prevalence rates for active epilepsy between 6 and 10/1000; many of these studies have, however, reported different rates for urban and rural areas, usually with higher rates in the latter [2,3,21,33] The differences seem unlikely to be

The epidemiology of epilepsy revisited Sander 167 artifactual or attributable to differential case ascertainment between regions as many of these studies used identical methods, study design and diagnostic confirmation in each area No clear aetiological reason for these variations in the prevalence in contiguous areas has yet been identified Lifetime prevalence rates are much higher than prevalence rates of active epilepsy, and it is generally agreed that up to 5% of a population will experience nonfebrile seizures at some point in life [2,3]; this finding applies to both industrialized and resource-poor countries In resource-poor countries, however, where antiepileptic drug (AED) treatment is not usually available, the incidence is at least double that of industrialized countries [34,35,36 ] From the difference between lifetime prevalence and the prevalence of active epilepsy it is apparent that most patients developing epilepsy will either cease to have seizures or die [37] It is likely that in most patients the condition remits Epilepsy, however, is associated with increased mortality particularly, but not exclusively, in symptomatic cases [38,39,40 ] Patients with chronic epilepsy are most at risk but the impact of mortality on the prevalence of epilepsy and the extent to which the difference in lifetime and point prevalence rates is due to mortality has not yet been fully appraised The prognosis Prognosis in this context is taken as the prospect of attaining complete seizure freedom once a pattern of recurrent seizures has been established The overall prognosis for full seizure control is very good, with more than 70% of patients achieving long-term remission, the majority within 5 years of diagnosis [37,41] Few predictors of a good outcome are known with confidence, but they may include age of onset, number of seizures in the early stages of the condition, early response to AEDs and some specific EEG findings [37,42,43,44 ] The finding of the prognostic significance of the number of early seizures is in accordance with studies showing that most patients who enter remission do so early, and that the prospect of entering remission decreases as time elapses [43] Other factors, including seizure type, seemed to be unimportant or to be variables associated with another prognostic factor It has been suggested that, in any individual patient, outcome and response to treatment is inherent and therefore seizure control in some severely affected patients may be impossible from the onset [43] Most prognostic studies have not used strict aetiological stratification, which may limit the identification of other predictors [23] AEDs are highly successful in suppressing seizures in most patients, but their influence on the natural history remains unknown [37,45,46 ] In the developed world the overall good prognosis for seizure control is often attributed to the widespread and early use of AEDs The suggestion has been made, however, that a significant number of patients developing an epileptic syndrome will enter a permanent remission regardless of AED treatment [2,37] Support for this proposition has come from analysis of epidemiological data arising from the resource-poor countries where, despite the lack of AEDs, a significant number of patients enter long-term remission [37,47] In addition, it is well recognized that a number of epileptic syndromes have an excellent outcome independent of AED treatment This would be in keeping with the suggestion that prognosis is inherent and dependent on the background process responsible for the epilepsy [37] Two important issues need to be addressed as they may have a major impact on the number of patients with socalled chronic epilepsy, ie patients who have not responded to AED therapy These are the roles of misdiagnosis and substandard management It is now generally accepted that 20 30% of patients developing epilepsy will eventually be classified as sufferers of chronic epilepsy [37] Between 10 and 20% of patients referred to clinics with refractory epilepsy may have been misdiagnosed, however In one recent study 13% of those referred to a single consultant with a diagnosis of refractory seizures did not have the condition and 44% were significantly improved by optimal treatment [48] Another recent study suggested that management was substandard in up to 20% of patients with newly diagnosed epilepsy [49 ] The inclusion of these patients may artificially inflate the proportion of chronic cases Prognosis for life: the mortality of epilepsy In the industrialized world, it has consistently been shown that people with epilepsy, despite an overall good prognosis for seizure control, have a greater risk of death compared with those without epilepsy [3,38,39,40,50,51 ] This increased risk is most evident in people with chronic epilepsy, particularly the young, and those with symptomatic epilepsy Trauma, suicide, pneumonia, status epilepticus and seizures have been identified as causes of death in people with epilepsy more frequently than in the general population [52 54,55 ] Sudden unexpected death in epilepsy (SUDEP) is also being increasingly recognized as a cause of death, especially in persons with severe epilepsy [56,57 ] The mechanism for SUDEP is unknown Suggestions have been made that substandard care may contribute to the risk but this needs to be formally ascertained [58,59] Little is known about the mortality in resource-poor countries, although circumstantial evidence seems to propose that it is even higher This may explain, at least in part, the

168 Seizure disorders discrepancy between the higher incidence and the relatively low prevalence of active epilepsy in resourcepoor countries [2] Shortcomings in knowledge One of the major shortcomings in the epidemiology of epilepsy is that the great majority of descriptive epidemiological studies of epilepsy have been carried out in industrialized countries and there is a dearth of data from resource-poor countries [23] Most studies have used a retrospective or cross-sectional design and this is likely to have introduced considerable bias With few exceptions, current descriptive studies, particularly of incident cohorts, have not classified epilepsy according to strictly defined putative aetiologies or risk factors [60,61 ] Studies that have attempted to classify aetiologies have done so in broad aetiological groupings (symptomatic, cryptogenic and idiopathic) There is, therefore, a dearth of information on the descriptive epidemiology of individual epileptic syndromes The range of aetiologies, risk factors, relative and attributable risk for epilepsy in the general population is also not known Little is known about the role of AED treatment on the outcome of epilepsy It has been suggested that antiseizure drugs may have little affect on the long-term prognosis This is an area that requires further work, as if this lack of effect of seizure suppressant drugs on longterm prognosis is true on a wider basis, a change in the routine management of epilepsy may be warranted If patients with an inherently good prognosis could be identified at the onset of their condition, the option of no treatment or only very short courses of symptomatic treatment (to avoid seizure-related morbidity and mortality) could become clear alternatives If, by the same token, inherently bad prognosis syndromes could be identified earlier, more aggressive management may limit the progression of the disorder until such time that antiepileptogenic drugs are identified [62] Conclusion There is little justification for further cross-sectional studies of prevalence [23] Studies comparing the prevalence of epilepsy in different countries are unlikely to be helpful unless they are clearly hypothesis driven Prospective studies of incidence in different settings should be strongly encouraged to establish the magnitude of possible geographic differences in incidence; the contribution of different aetiologies and risk factors to geographic variations in incidence; and syndromespecific incidence rates [23] These studies should be conducted in diverse locations using similar methodology with standardized definitions and diagnostic workup, including when possible neuroimaging and neurogenetic techniques Studies involving a retrospective incidence design (incidence estimation based on prevalence cases) should be avoided Analytical case control studies of identified cases should be performed on incidence cohorts whenever possible to identify the full spectrum of aetiologies and risk factors Long-term prospective, population-based (rather than clinic-based) outcome studies of people with specific epileptic syndromes and risk factors are urgently warranted [23] These should be studies of incident cases, but special attention should be given to the issue of diagnostic accuracy and full case ascertainment and follow up be assured Studies of the role of AED treatment on the prognosis and determinants of the outcome for terminal remission and intractability are also urgently warranted In addition, studies of the incidence of SUDEP and risk factors in different settings are strongly to be encouraged References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest 1 Jallon P Epilepsy and epileptic disorders, an epidemiological marker? Contributions of descriptive epidemiology Epileptic Disord 2002; 4:1 13 This is a review of methodological problems and current knowledge in this area 2 Sander JW, Shorvon SD Epidemiology of the epilepsies J Neurol Neurosurg Psychiatry 1996; 61:433 443 3 Bell GS, Sander JW The epidemiology of epilepsy: the size of the problem Seizure 2001; 10:306 314 4 Rwiza HT, Kilonzo GP, Haule J, et al Prevalence and incidence of epilepsy in Ulanga, a rural Tanzanian district: a community-based study Epilepsia 1992; 33:1051 1056 5 Commission on Tropical Diseases of the International League Against Epilepsy Relationship between epilepsy and tropical diseases Epilepsia 1994; 35:89 93 6 Molyneux ME Impact of malaria on the brain and its prevention Lancet 2000; 355:671 672 7 Bergen DC Preventable neurological diseases worldwide Neuroepidemiology 1998; 17:67 73 8 Waruiru CM, Newton CR, Forster D, et al Epileptic seizures and malaria in Kenyan children Trans R Soc Trop Med Hyg 1996; 90:152 155 9 Pal DK, Carpio A, Sander JW Neurocysticercosis and epilepsy in developing countries J Neurol Neurosurg Psychiatry 2000; 68:137 143 10 Nicoletti A, Bartoloni A, Reggio A, et al Epilepsy, cysticercosis, and toxocariasis: a population-based case-control study in rural Bolivia Neurology 2002; 58:1256 1261 This is a most interesting study that suggests toxocariasis may be an important risk factor for partial epilepsy in resource-poor countries 11 Anderson VE, Hauser WA, Rich SS Genetic heterogeneity and epidemiology of the epilepsies Adv Neurol 1999; 79:59 73 12 Johnson MR, Sander JW The clinical impact of epilepsy genetics J Neurol Neurosurg Psychiatry 2001; 70:428 430 13 Berkovic SF, Scheffer IE Genetics of the epilepsies Epilepsia 2001; 42 (Suppl 5):16 23 This is an authoritative review of the genetics of epilepsy with particular emphasis on ion channels

The epidemiology of epilepsy revisited Sander 169 14 Anderson E, Berkovic S, Dulac O, et al ILAE genetics commission conference report: molecular analysis of complex genetic epilepsies Epilepsia 2002; 43:1262 1267 This report summarizes knowledge on the complex subject of the genetics of epilepsy and makes recommendations for future research 15 Zarrelli MM, Beghi E, Rocca WA, et al Incidence of epileptic syndromes in Rochester, Minnesota: 1980 1984 Epilepsia 1999; 40:1708 1714 16 MacDonald BK, Cockerell OC, Sander JW, et al The incidence and lifetime prevalence of neurological disorders in a prospective community-based study in the UK Brain 2000; 123:665 676 17 Kotsopoulos IA, Merode T, Kessels FG, et al Systematic review and metaanalysis of incidence studies of epilepsy and unprovoked seizures Epilepsia 2002; 43:1402 1409 This is comprehensive review and a meta-analysis of reported incidence rates for epilepsy 18 Heaney DC, MacDonald BK, Everitt A, et al Socioeconomic variation in incidence of epilepsy: prospective community based study in south east England BMJ 2002; 325:1013 1016 This is the first study to show in an incident cohort that epilepsy is more likely to affect people in the more deprived segments of the population 19 Gaitatzis A, Purcell B, Carroll K, et al Differences in the use of health services among people with and without epilepsy in the United Kingdom: socio-economic and disease-specific determinants Epilepsy Res 2002; 50:233 241 This study suggests that epilepsy increases comorbidity 20 Lindsten H, Stenlund H, Edlund C, et al Socioeconomic prognosis after a newly diagnosed unprovoked epileptic seizure in adults: a population-based case-control study Epilepsia 2002; 43:1239 1250 This is a study of the socioeconomic impact of epilepsy in an incident cohort 21 Placencia M, Shorvon SD, Paredes V, et al Epileptic seizures in an Andean region of Ecuador: incidence and prevalence and regional variation Brain 1992; 115:771 782 22 Lavados J, Germain L, Morales A, et al A descriptive study of epilepsy in the district of El Salvador, Chile Acta Neurol Scand 1992; 85:249 256 23 ILAE Commission of Epidemiology and Prognosis The epidemiology of the Epilepsies: future directions Epilepsia 1997; 38:614 618 24 Everitt AD, Sander JW Incidence of epilepsy is now higher in elderly people than children BMJ 1998; 316:780 25 Buntinx F, Devroey D, Van Casteren V The incidence of stroke and transient ischaemic attacks is falling Br J Gen Pract 2002; 52:813 817 This study shows a decrease in the incidence of stroke over the last three decades in Belgium 26 Hallstrom B, Norrving B, Lindgren A Stroke in Lund-Orup, Sweden: improved long-term survival among elderly stroke patients Stroke 2002; 33:1624 1629 This study shows a considerable increase in survival in CVD 27 Muntner P, Garrett E, Klag MJ, et al Trends in stroke prevalence between 1973 and 1991 in the US population 25 to 74 years of age Stroke 2002; 33:1209 1213 This study shows an important decrease in the incidence of stroke in the USA over the last three decades 28 Olafsson E, Hauser WA Prevalence of epilepsy in rural Iceland: a populationbased study Epilepsia 1999; 40:1529 1534 29 Rocca WA, Savettieri G, Anderson DW, et al Door-to-door prevalence survey of epilepsy in three Sicilian municipalities Neuroepidemiology 2001; 20:237 241 This study suggests a relatively low prevalence of epilepsy in Sicily 30 Al Rajeh S, Awada A, Bademosi O, et al The prevalence of epilepsy and other seizure disorders in an Arab population: a community-based study Seizure 2001; 10:410 414 This study in Saudi Arabia finds prevalence rates within the expected range 31 Gomes MM, Zeitoune RG, Kropf LA, Beeck ES A house-to-house survey of epileptic seizures in an urban community of Rio de Janeiro, Brazil Arq Neuropsiquiatr 2002; 60:708 711 This study in Brazil finds prevalence rates within the expected range 32 Onal AE, Tumerdem Y, Ozturk MK, et al Epilepsy prevalence in a rural area in Istanbul Seizure 2002; 11:397 401 This study in Turkey finds prevalence rates within the expected range 33 Aziz H, Ali SM, Frances P, et al Epilepsy in Pakistan: a population-based epidemiologic study Epilepsia 1994; 35:950 958 34 Scott RA, Lhatoo SD, Sander JW The treatment of epilepsy in developing countries: where do we go from here? Bull World Health Organ 2001; 79:344 351 35 Meinardi H, Scott RA, Reis R, Sander JW The treatment gap in epilepsy: the current situation and ways forward Epilepsia 2001; 42:136 149 36 Coleman R, Loppy L, Walraven G The treatment gap and primary health care for people with epilepsy in rural Gambia Bull World Health Organ 2002; 80:378 383 This is an interesting account of the practical problems encountered when delivering epilepsy care in a resource-poor country 37 Sander JW Some aspects of prognosis in the epilepsies: a review Epilepsia 1993; 34:1007 1016 38 Lhatoo SD, Johnson AL, Goodridge DM, et al Mortality in epilepsy in the first 11 to 14 years after diagnosis: multivariate analysis of a long-term, prospective, population-based cohort Ann Neurol 2001; 49:336 344 39 Shackleton DP, Westendorp RG, Kasteleijn-Nolst Trenite DG, et al Survival of patients with epilepsy: an estimate of the mortality risk Epilepsia 2002; 43:445 450 This is a study showing increased mortality amongst clinic patients in Holland 40 Morgan CL, Kerr MP Epilepsy and mortality: a record linkage study in a UK population Epilepsia 2002; 43:1251 1255 This is a study showing increased mortality amongst clinic patients in Wales, UK 41 Cockerell OC, Johnson AL, Sander JW, et al Prognosis of epilepsy: a review and further analysis of the first nine years of the British National General Practice Study of Epilepsy, a prospective population-based study Epilepsia 1997; 38:31 46 42 Kwan P, Brodie MJ Early identification of refractory epilepsy N Engl J Med 2000; 342:314 319 43 MacDonald BK, Johnson AL, Goodridge DM, et al Factors predicting prognosis of epilepsy after presentation with seizures Ann Neurol 2000; 48:833 841 44 Kwan P, Brodie MJ Effectiveness of first antiepileptic drug Epilepsia 2001; 42:1255 1260 This is a study of the efficacy and tolerability of the first antiepileptic drug in newly diagnosed epilepsy 45 O Donoghue M, Sander JW Does early anti-epileptic drug treatment alter the prognosis for remission of the epilepsies? J R Soc Med 1996; 89:245 248 46 Hauser WA, Lee JR Do seizures beget seizures? Prog Brain Res 2002; 135:215 219 Very challenging paper, suggesting that in some patients seizures modify brain function increasing the risk for further seizures 47 Shinnar S, Berg AT Does antiepileptic drug therapy alter the prognosis of childhood seizures and prevent the development of chronic epilepsy? Semin Pediatr Neurol 1994; 1:111 117 48 Smith D, Defalla BA, Chadwick DW The misdiagnosis of epilepsy and the management of refractory epilepsy in a specialist clinic Q J Med 1999; 92:15 23 49 Lhatoo SD, Sander JW, Shorvon SD The dynamics of drug treatment in epilepsy: an observational study in an unselected population based cohort with newly diagnosed epilepsy followed up prospectively over 11 14 years J Neurol Neurosurg Psychiatry 2001; 71:632 637 This long-term study of AED treatment in a large incidence cohort in the UK suggests that the treatment is substandard in at least one in five 50 Rafnsson V, Olafsson E, Hauser WA, et al Cause-specific mortality in adults with unprovoked seizures: a population-based incidence cohort study Neuroepidemiology 2001; 20:232 236 This is a study of the causes of death in patients with epilepsy in Iceland 51 Camfield CS, Camfield PR, Veugelers PJ Death in children with epilepsy: a population-based study Lancet 2002; 359:1891 1895 This is a very important study of mortality in children with epilepsy and it shows that associated neurological disabilities are a major marker for premature death 52 Logroscino G, Hesdorffer DC, Cascino GD, et al Long-term mortality after a first episode of status epilepticus Neurology 2002; 58:537 541 This is a study of long-term mortality in patients with status epilepticus in Rochester, Minnesota 53 Sillanpaa M, Shinnar S Status epilepticus in a population-based cohort with childhood-onset epilepsy in Finland Ann Neurol 2002; 52:303 310 This is a study of the incidence of status epilepticus in a cohort of patients followed for over 30 years in Finland 54 Wu YW, Shek DW, Garcia PA, et al Incidence and mortality of generalized convulsive status epilepticus in California Neurology 2002; 58:1070 1076 This is a study of the mortality in status epilepticus 55 Nilsson L, Ahlbom A, Farahmand BY, et al Risk factors for suicide in epilepsy: a case control study Epilepsia 2002; 43:644 651 This is an important case control study of the risk factors for suicide in people with chronic epilepsy in Sweden Temporal lobe epilepsy was not found to be a risk factor, contrary to what is often said

170 Seizure disorders 56 Walczak TS, Leppik IE, d Amelio M, et al Incidence and risk factors in sudden unexpected death in epilepsy: a prospective cohort study Neurology 2001; 56:519 525 This case control study in the USA suggests that seizure severity is the major risk factor 57 Donner EJ, Smith CR, Snead OC Sudden unexplained death in children with epilepsy Neurology 2001; 57:430 434 This is the largest series of SUDEP in the paediatric age group 58 Pedley TA, Hauser WA Sudden death in epilepsy: a wake-up call for management Lancet 2002; 359:1790 1791 59 Hanna NJ, Black M, Sander JW, et al The national sentinel clinical audit of epilepsy related death: epilepsy death in the shadows London: The Stationery Office; 2002 60 Sidenvall R, Heijbel J, Blomquist HK, et al An incident case-control study of first unprovoked afebrile seizures in children: a population-based study of preand perinatal risk factors Epilepsia 2001; 42:1261 1265 Meticulous care was taken in this study with diagnostic accuracy and in carrying out standardized investigations 61 Liu RS, Lemieux L, Bell GS, et al A longitudinal quantitative MRI study of community-based patients with chronic epilepsy and newly diagnosed seizures: methodology and preliminary findings Neuroimage 2001; 14:231 243 This is the first population-based study in which sophisticated magnetic resonance imaging techniques were used in the initial assessment of patients with newly diagnosed epilepsy and a control group in the community 62 Walker MC, White HS, Sander JW Disease modification in partial epilepsy Brain 2002; 125:1937 1950