Epidemiology, classification, natural history, and genetics of epilepsy

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EPILEPSY OCTET

Epidemiology, classification, natural history, and genetics of epilepsy S. D. SHORVON

Incidence and

prevalence

Incidence and prevalence studies of epilepsy have been reported from many countries but comparisons are often difficult because investigators have adopted different definitions of epilepsy, case-ascertainment methods, and classification schemes; selection bias is also important.1 Nevertheless, most studies have found incidence rates of 20-70/100 000 per year (range 11-134/100 000 per year) and point prevalence rates of 4-10/1000 in the general population (range 1-5-30/1000). Incidence varies considerably with age; rates are greatest in early childhood, reach a nadir in early adult life, and rise again in elderly people. Prevalence rates show a similar but less pronounced age-related pattern (ref 2 and Sander JWAS et al, unpublished data from the UK National General Practice Study of Epilepsy, see figure). Most studies show a slight excess of epilepsy among males. Another interesting statistic is the lifetime (or total) prevalance, which is the measure of the number of people in a population who have ever had epilepsy; estimates vary from 2 to 5% (the latter according to the World Health Organisation) of the population. Thus perhaps as many as 1 in 20 of the population will have had an epileptic seizure at some point in their lives and (at a conservative estimate) 1 in 200 will have epilepsy. These calculations indicate that epilepsy is the most prevalent serious neurological condition: the prevalence rate is 10 times that of multiple sclerosis and 100 times that of motoneuron disease. These epilepsy figures exclude febrile convulsions, which occur in about 5% of children.3 The importance of definition of the disorder in assessment of prevalence rates is illustrated by the study of epilepsy in a population of 6000 persons in Tonbridge, Kent/.5 in which lifetime prevalence was 20-3/1000 (single seizures and seizures with acute illness were included but not febrile seizures), 10-5/1000 for those with active epilepsy and/or on treatment (the usual defmition of "epilepsy"); and 5-3/1000 for those with active epilepsy alone (one or more seizures in the preceding 24 months). Epilepsy is slightly more common in the lower socioeconomic groups, and US mortality data (albeit an unreliable source) suggest that the prevalence of epilepsy may be significantly higher in blacks than in whites in that country.6Geographic variation has been hard to assess because of the lack of standard

techniques,’ but ongoing ICBERG (International Community Based Epilepsy Research Group) studies may provide more accurate figures. Major geographic differences seem unlikely, so in this respect epilepsy differs from other neurological conditions such as multiple sclerosis. Aetiological differences in general have only a moderate effect on prevalence rates, but higher rates in Latin America may reflect high local prevalence of neurocysticercosis.8

Age-specific incidence cumulative incidence and prevalence rates in Rochester, Minnesota, (1935-1974) from Hauser et al. 26

Characteristics of

epilepsy in the general population

Widely different distributions of seizure types have been reported in population studies of epilepsy, but this variability probably reflects differences in methods of ascertainment. Although many studies have found generalised epilepsy to be most common, those with rigorous neurological inquiry have usually shown that ADDRESS: Institute of Neurology, Queen Square, London WC1 N 3BG, UK (Dr S. D. Shorvon, FRCP).

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and secondarily generalised seizures for about 60% of prevalent cases.2,9 Primary generalised tonic-clonic seizures may account for about 30%,and generalised absence (petit mal) and myoclonus for less than 5%. In the UK, the National General Practice Study of Epilepsy (NGPSE) is a prospective cohort population-based study, now in its fifth year, in which epidemiological and natural history data are being collected in an unselected population. In this cohort of new cases, the index attack (the attack initiating diagnosis) was a secondarily generalised seizure in 36%, a primary generalised tonic-clonic seizure in 33%, a complex partial seizure in 16%, a simple partial seizure in 4%, an absence in 1%, and myoclonus in 1 %. Since the aetiology of epilepsy is often multifactorial, exact attribution of cause is often impossible. About 60-70% of all epilepsies have no clear cause, and are best referred to as the cryptogenic epilepsies; these cases should not be confused with the syndromes of primary generalised epilepsy or the other well-defined epileptic syndromes. In the NGPSE cohort, aetiologies at diagnosis were: cerebrovascular in 15%, cerebral tumour in 6%, alcoholrelated in 6%, and post-traumatic in 2%; other causes were rare. The contribution of perinatal damage to the development of epilepsy is very difficult to assess, but recent case-controlled evidence suggests that this factor may be less important than is often assumed. Although the range of severity of epilepsy and its associated disabilities in the population as a whole is unknown, estimates from one US government sourcelo suggest that about a third of prevalent cases have less than 1 seizure a year, a third between 1 and 12 seizures a year, and a third more than 1 seizure a month (and 20% more than 1 seizure a week). At a very rough approximation, about 40% of all patients have epilepsy alone and the rest have concomitant behavioural, neurological, or intellectual disturbance. Although antiepileptic drug therapy is widely available, many patients with active epilepsy are untreated. In the Tonbridge survey,6 over 40% of those with active epilepsy were not on treatment on the day of the survey. In many developing countries the treatment gap is much greater—eg, it has been estimated that only 6% of patients in the Philippines or Pakistan or 20% of patients in Ecuador are receiving treatment at any one time."

Classification

complex partial account

TABLE I-INTERNATIONAL CLASSIFICATION OF SEIZURE TYPE

Epilepsy can be classified in several ways—eg, by clinical events (usually seizure type), electroencephalographic (EEG) changes, aetiology, pathophysiology, anatomy, or age. Since epilepsy is often best regarded as a symptom condition per se, and since the essential is pathophysiology often obscure, classification is inevitably arbitrary. In 1969, the International League Against Epilepsy (ILAE) attempted to introduce a scheme for universal application. This scheme, revised in 1981 and widely adopted, is a classification of seizure type (table I) in which EEG data are taken into account whereas aetiology, age, and anatomical site are ignored.12 More recently, in recognition of the fact that a seizure-type classification does not account for other aspects of the heterogeneity of epilepsy, the ILAE devised a new scheme-the Classification of the Epilepsies and Epileptic Syndromes and related seizure disorders13-which is now also widely used and is an attempt to categorise the epilepsies more rather than

as a

comprehensively. ILAE classification of seizure type (1981): In this scheme seizures are divided into three groups: generalised; partial (focal); and unclassifiable. Generalised seizures are further divided into tonic-clonic (grand mal), absence (petit mal), myoclonic, atonic, and clonic seizures, and partial seizures into simple partial and complex partial categories (according to the preservation or alteration of consciousness (simple and complex, respectively). Generalised seizures are those in which epileptic discharges involve both cerebral hemispheres widely and simultaneously from the onset of the seizure, whereas partial seizures are those in which epileptic activity is confined to a focal area of the brain. The epileptic activity of partial seizures (simple or complex) may spread to become generalised, in which case the seizure is said to be secondarily generalised. Subdivisions of the classification are shown in table 1. ILAE classification of the epilepsies and epilepsy syndromes and related seizure disorders (1989): This classification (table n) takes into account seizure type, EEG, and prognostic, pathophysiological, and aetiological data. It retains the division of epilepsy into generalised and partial (now called localisation-related) categories, with each category subdivided into symptomatic and idiopathic varieties. Two new categories are addedepilepsies and syndromes undetermined, whether focal or generalised, and special syndromes. This scheme is complex and may well confuse non-taxonomists, but it is a serious attempt to incorporate more than simple seizure type data into a comprehensive classification.

Natural history of epilepsy The natural history of untreated epilepsy is almost entirely unknown because effective treatment has been available for many years: bromides were introduced in 1857, phenobarbitone in 1912, and phenytoin in 1938, all before modem epidemiological methods were developed. The traditional view is that the prognosis of treated epilepsy is poor, and in a review of hospital and institutional studies in 1968, Rodin14 concluded that in 80% of all cases epilepsy is chronic (characterised by continuing seizures). However, this opinion is unduly pessimistic because it neglects the

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TABLE II-INTERNATIONAL CLASSIFICATION OF EPILEPSIES AND EPILEPTIC SYNDROMES AND RELATED SEIZURE DISORDERS

had entered remission within a year of diagnosis, and the longer the epilepsy remained active the less were the chances of subsequent remission. In the Tonbridge study, longitudinal patterns of epilepsy were also studied (remission was defined as 2 years without seizures); 65% of the population had epilepsy which continued for less than 5 years, then remission occurred without subsequent relapse; 13% had epilepsy in which remission occurred and was followed by relapse; and 22% had epilepsy that had never remitted. A similar study of remission/relapse patterns was carried out in 181 patients with severe chronic active epilepsy (mean duration of illness 17 years) and a history of remission was found in only 22 %? One conclusion from these studies is that there are two distinct subgroups among patients with newly developing epilepsy-one group will have a short-lived condition, which is usually mild, and the other a condition which is likely to be chronic and in which seizures may continue indefinitely, despite treatment. These subgroups have different characteristics, and it may be possible to differentiate them early in the course of the illness.

Recurrence after first seizure Recurrence after a first seizure is more common than previously recognised. Older hospital-based studies were subject to selection bias; they underestimated the proportion of patients with second seizures because the risks of recurrence are greatest within a few weeks or months of the first attack and because epilepsy is often diagnosed only after several attacks have occurred.15,18,19 Elwes et al20 noted a 71 % risk of recurrence after a generalised convulsion, and in the NGPSE (Hart YM et al, unpublished data from NGPSE) there was a recurrence rate for all seizures of 78%. In other population-based studies recurrence rates of 67% were found in Rochester and 82% in Tonbridge.4,5 Although second seizures are common, the Tonbridge survey showed that in most cases the total number of seizures was often small and the epilepsy short lived.5 Because of this high recurrence rate,the usual distinction between true epilepsy and single seizures seems rather meaningless. However, in many cases epilepsy is shortlived, and the term pre-epilepsy has been suggested for new cases in which epilepsy has not yet become chronic or established

(Hart YM et al, unpublished). influence of selection bias, which is inherent in crosssectional studies based on chronic hospital populations. A simple comparison of prevalence and incidence figures will show that in most cases the epilepsy must remit (and that mean duration of illness is about 10 years); the condition should be studied longitudinally from its onset to assess outcome

comprehensively.15 .

Longitudinal population-based studies of outcome and patterns of epilepsy Two studies have looked retrospectively at the course of epilepsy (treated and untreated) from the time of diagnosis. In a survey of 465 patients from Rochester, Minnesota,16 50% had been in remission (5 years without a seizure) 20 years after

were off treatment and a further in remission and on treatment. Only 30% continued to have seizures. In the Tonbridge survey,4,5 15 years after the onset of epilepsy only 19 % of patients had had a seizure in the preceding 24 months. In both studies those entering remission tended to do so early in the course of the disease. Thus, 42% in Rochester and 47% in Tonbridge

20%

were

diagnosis and

Prognostic factors Since epilepsy is not a homogeneous entity various factors influence prognosis.14,15 Patients with a good prognosis, who often have mild epilepsy, are those with seizures precipitated by alcohol, drugs, or metabolic disturbance; benign syndromes (eg, benign rolandic epilepsy); rare generalised seizures; or adult-onset idiopathic seizures. Patients with the poorest prognosis are those with evidence of diffuse cerebral disorder (often with intellectual or behavioural disturbance); early onset seizures; partial or mixed seizure types; progressive neurological disorders (eg, cerebral tumour, progressive myoclonus epilepsy); or severe epileptic syndromes (eg, Lennox Gastaut syndrome, West syndrome). The length of active epilepsy is also importantthe longer the seizures continue after the onset of treatment the worse the ultimate prognosis. Does early treatment affect prognosis? It has been

suggested that early treatment may not only

suppress seizures in the short term but also prevent the

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evolution

newly developing seizures to chronic epilepsy. 5,152122 This proposition is based on the temporal patterns of epilepsy-that chronic epilepsy is difficult to treat, with perhaps 80% of patients having continuing seizures, in pronounced contrast to newly diagnosed patients started on treatment in whom immediate seizure control is obtained in over 60%; that the chances of long remission are greatest in the early years of treatment; and that relapse after remission is uncommon. Some experimental data (eg, kindling) add circumstantial evidence to this proposition. However, another explanation of these clinical patterns of epilepsy is that the disorder, from its onset, is inherently mild or severe, and that the mild cases remit naturally early in their course. Whilst the clinical observations are undoubted, the exact role of early treatment has

not

of

been resolved.

Genetics An assessment of the genetic contribution to epilepsy is complicated by the heterogeneity of the condition and by the many possible genetic influences.23 Primary generalised epilepsies have a strong genetic contribution 24 (it has been argued that these disorders have an autosomal dominant inheritance with age-specific penetrance, although a polygenic inheritance is also possible). These epilepsies are categorised by the triad of generalised grand mal, absence, and myoclonic seizures; 3 Hz spike and wave EEG traits; photosensitivity; a strong diurnal seizure pattern; and a characteristic clinical course. Whether this group can be subdivided into different clinical syndromes with different inheritance patterns is uncertain, although the gene for juvenile myoclonus syndrome has been localised to chromosome 6.25 Epilepsy is an important feature of more than 140 single-gene disorders, mostly autosomal recessive in nature, in two-thirds of which mental retardation is also present. These conditions account for less than 1 % of all epilepsies, tuberous sclerosis being the most common. Epilepsy is also common in patients with congenital malformations—eg, Sturge-Weber syndrome-for which no specific mode of inheritance has been established and occurs in patients with chromosomal defects, although no particular chromosome has been associated with seizure disorders. In about 60% of patients with epilepsy no cause can be determined. These cryptogenic epilepsies are a heterogeneous group, in which polygenic influences may exist but have not been clearly characterised.23,26

7. Chandra V, Bharucha N, Schoenberg B, Feskanich D. National mortality data for death due to, and all death related to, epilepsy in the United States. In: Porter R, Mattson RH, Ward AA, et al, eds. Advances in Epileptology: XVth Epilepsy International Symposium. New York: Raven, 1984: 531-34. 8. Acha PN, Aguilar FG. Studies on cysticercosis in Central America. Am J Trop Med Hyg 1964; 13: 48-53. 9. Juul-Jensen P, Foldsprang A. Natural history of epileptic seizures. Epilepsia 1983; 24: 297-312. 10. Commission for the Control of Epilepsy and its Consequences. 1978 Plan for Nationwide Action on Epilepsy, vols 1-4. DHEW publication no (NIH) 78-279. Bethesda: US Department of Health, Education and Welfare, 1978. 11. Shorvon SD, Farmer PJ. Epilepsy in developing countries: a review of epidemiological, sociocultural and treatment aspects. Epilepsia 1988; 29 (suppl 1): S36-53. 12. The Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981; 22: 489-501. 13. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for the revised classification of epilepsies and epileptic syndromes Epilepsia 1989; 30: 389-98. 14. Rodin EA. The prognosis of patients with epilepsy. Springfield, Illinois: Thomas, 1968. 15. Shorvon SD. The temporal aspects of prognosis in Epilepsy. J Neurol Neurosurg Psychiatry 1984; 47: 1157-65. 16. Annegers JF, Hauser WA, Elveback L. Remission of seizures and relapse in patients with epilepsy. Epilepsia 1979; 20: 729-37. 17. Sander JWAS, Shorvon SD. Remission periods and prognosis in epilepsy. In: Wolf P, Dam M, Janz D, et al eds. Advances in Epileptology: XVIth Epilepsy International Symposium. New York: Raven 1987: 353-56. 18. Hauser WA, Anderson VE, Loewenson RB, McRoberts SM, Seizure recurrence after a single uprovoked seizure N Engl J Med 1982; 307: 522-28. 19. Hopkins A, Garman A, Clarke C. The first seizure in adult life: value of clinical features, electroencephalography, and computed tomographic scanning in prediction of seizure recurrence Lancet 1988; i: 721-26. 20. Elwes RDC, Chesterman P, Reynolds EH. Prognosis after a first untreated tonic clonic seizure Lancet 1985; ii: 752-53. 21. Shorvon SD. Do anticonvulsants influence the natural history of epilepsy? In: Warlow C, Garfield J, eds. More dilemmas in the management of the neurological patient. Edinburgh: Churchill Livingstone, 1987: 8-13. 22. Shorvon SD. The drug treatment of epilepsy: towards more effective assessment and therapeutics. MD thesis. University of Cambridge, 1982. 23. Anderson VE, Hauser WA, Penry JK. The genetic basis of the epilepsies. New York: Raven, 1982. 24. Shorvon SD. Constitutional epilepsy. In: Swash M, Oxbury J, eds. Diseases of the nervous system. Edinburgh: Churchill Livingstone (in

press) 25. Meierkord H. Advances in genetics and their application to epilepsy In: Trimble MR, ed. Chronic epilepsy: its prognosis and management. Chichester: Wiley, 1989: 243-55. 26. Hauser WA, Annergers JF, Anderson VE. Epidemiology and genetics of epilepsy In: Ward AA, Penry JK, Purpura D et al, eds. Epilepsy. New York: Raven, 1983: 274.

From The Lancet

I thank the National Fund for Crippling Diseases, the Sir Jules Thome Charitable Trust, and the Brain Research Trust for support of the clinical, epidemiological, and prognostic research.

REFERENCES JWAS, Shorvon SD. Incidence and prevalence studies in epilepsy and their methodological problems: a review J Neurol Neurosurg Psychiatry 1987; 50: 829-39. 2. Hauser WA, Kurland LT. The epidemiology of epilepsy in Rochester, Minnesota, 1935 through 1967. Epilepsia 1975; 16: 1-66. 3. Nelson KB, Ellenberg JH. Predicators of epilepsy in children who have experienced febrile seizures. N Engl J Med 1976; 295: 1029-33. 4. Goodridge DMG, Shorvon SD. Epileptic seizures in a population of 6000. 1: demography, diagnosis and classification. Br Med J 1983; 287: 1. Sander

641-44.

Goodridge DMG, Shorvon SD. Epileptic seizures in a population of 6000. 2: treatment and prognosis. Br Med J 1983; 287: 645-47. 6. Haerer AF, Anderson DW, Schoenberg BS. Prevalence and clinical features in a biracial US population. Epilepsia 1986; 27: 66-75. 5.

Execution by electricity The

ghastly details accompanying the account of the execution by electricity of the convict Kemmler are such as to strike with horror every humane mind. The technical errors in carrying out the execution and the want of sufficient care in arranging the adjustments necessary to the effective discharge of the shock have resulted in a failure so manifest as to lead Dr Schrady to make use of the following expression: "The execution was brutal, worse than hanging. The failure to kill at first application was barbarous. Its scientific uncertainty and the expense it involves lead me to believe that this will be the first and last electrical execution." We have more than once expressed our disapprobation of the employment of such a measure for the carrying out of the extreme penalty of the law, and shall take an early opportunity of recurring to the subject.

(Aug 9, 1890)