WHY DOES EPILEPSY BECOME INTRACTABLE?

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STUDIES OF PROGNOSIS IN EPILEPSY

Preventive Medicine

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WHY DOES EPILEPSY BECOME INTRACTABLE? Prevention of Chronic Epilepsy E. H. REYNOLDS

R. D. C. ELWES

S. D. SHORVON

University Department of Neurology, King’s College Hospital, Denmark Hill, London SE5

Summary

and our own hospitalbased studies suggest that the prognosis for seizure control is very good in most patients with epilepsy. However, chronic epilepsy develops in about 25%. The pattern of chronicity is established early in the course of treatment. Factors associated with a high risk of chronicity include additional neurological, psychological, and social handicaps and also partial seizures. In addition a process of evolution of chronic epilepsy may occur by a mechanism proposed by Gowers a century ago. Chronic epilepsy is very difficult to control and may best be prevented by more effective treatment at the onset of the disorder.

Community-based

INTRODUCTION

PATIENTS with chronic intractable epilepsy are common in adult and paediatric hospital clinics. In most Western countries special multidisciplinary centres or clinics have been established or at least recommended for these patients.1 Although many of them have other handicaps in addition to chronic epilepsy, some of these problems such as psychological difficulties or brain damage will have arisen from earlier uncontrolled seizures. Why and how does epilepsy become intractable? An understanding of this question would have implications for preventive medicine. We emphasise that we are not asking the question why do people develop epilepsy? Rather, we are concerned with why, after the onset of the first few seizures, most patients with epilepsy are well controlled on treatment but others progress to long-term epilepsy which is seemingly unresponsive to all currently available medication? Do patients with intractable epilepsy have inherently more "severe" epilepsy or is there a process of escalation which can be prevented or reversed at its onset? Our interest in this question has arisen from our own prospective studies of new referrals to a neurological clinic over a period of 10 years,2-5 and recent community-based studies6,7 of epilepsy, which reveal a rather different picture of prognosis than the older hospital and institution based studies.8 SIZE OF THE PROBLEM

The prevalence of epilepsy will vary according to the definition adopted. If only patients with continuing "active" epilepsy are included the prevalence rate varies between 3 - 3 and 6 - 2 per thousand. If, however, patients with a previous history of seizures or a single seizure are included the prevalence rate may rise up to 20 per thousand, even after the exclusion of febrile convulsions. The most widely accepted views about the prognosis of epilepsy are those derived from the careful and comprehensive xeview of published reports by Rodin.8 Although different types of epilepsy have a varying outcome the overall picture of prognosis presented is a rather gloomy and unsatisfactory one, based as it is almost wholly on studies

in

hospitals

or

institutions.

For

example,

several

investigations$-13 suggest that as few as 30-40% of epileptic patients achieve even a 2-year remission (see accompanying table). Furthermore the longer patients are followed up, the lower the remission rate, which may fall to as low as 10% at 10 years. Rodin8 concludes that 80% of patients with epilepsy are likely to have a chronic seizure disorder, although this may include short-term remissions. However, more recent community-based studies suggest a rather more optimistic prognosis. Annegers et al6 identified all newly diagnosed cases of epilepsy presenting in Rochester, Minnesota, between 1935 and 1974. In those followed for at least 20 years 7007o were in 5-year remission and 50% of the total had successfully discontinued medication. In a survey of a general practice population in south-east England, Goodridge and Shorvonfound that 69% were in 4-year remission after 15 years of follow-up. In contrast to hospitalbased studies both community studies showed that the remission rate improved with increasing duration of followup. We have prospectively followed for up to 10 years (median 5 - 6 years) 106 successive new previously untreated patients

with epilepsy referred to an adult neurological clinic at a district hospita1.4,5 At the end of follow-up 82% had entered 2-year remission. For the first time the prognosis in a hospital-based investigation accords with community-based findings. The reason for the much more favourable outcome in our own and community-based studies is the inclusion of all patients from the onset of their epilepsy. There is little doubt that, if it were not for our systematic attempt to follow up all our new referrals to a hospital clinic, most of those who were well controlled would have returned to their own general practitioners. This would have contributed to making the prognosis in the community better than that associated with hospital clinics which progressively accumulate patients with chronic intractable epilepsy with an increasingly unfavourable prognosis. Overall, the latter patients may amount to no more than 25% of the epileptic population, but because epilepsy is so common they constitute an enormous problem. FACTORS INFLUENCING PROGNOSIS

Several

important factors are generally agreed to influence adversely the prognosis of epilepsy-ie, partial or mixed seizure types; presence of an abnormal neurological or mental state examination, or a low IQ; and the number of seizures and duration of epilepsy before referral. There is less agreement about the influence of age of onset of epilepsy, of electroencephalographic abnormalities, and of genetic and other factors. In our own

prospective studies

of new referrals

we

have

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confirmed that neurological, psychological, and social handicaps have the most striking influence on prognosis, and that partial attacks and the number and duration of seizures before treatment also contribute to a less favourable outcome. However, although patients with these adverse factors will in general do less well, most will also go into remission. For example, 67% of patients with partial seizures and 84% of patients with neurological handicap entered a 1-year remission within 5 years. It appears therefore that other factors must contribute to the development of chronic intractable epilepsy. In our studies of new referrals we have for the first time observed the evolution of chronic epilepsy in patients followed prospectively from the onset of their disorder. A remarkable feature was that in most patients the pattern of chronicity was established within the first one or two years of treatment.3-5 In other words the longer-term prognosis may be determined in part by the initial response to treatment. This is illustrated in fig 1 which shows the actuarial percentage of patients who did not respond to optimum single-drug therapy and who continued to have chronic epilepsy despite the addition of a second drug or other alterations to their treatment. Of 21% who did not respond to treatment, all did so within the first two years, with the exception of two late failures in the fourth year.

A further aspect of the evolution of chronic epilepsy is illustrated in fig 2, which shows the 1-year remission rates in all our patients, as well as in those patients who were continuing to have seizures after 1 year and after 2 years of treatment. The actuarial curve for the whole series exemplifies the good prognosis for most patients, with 92% entering 1-year remission. The two subsequent curves show the progressive decline in remission rate with increasing duration of continuing epilepsy. Of those patients still having seizures during the first year of treatment, 77% achieved 1-year remission, and for those having seizures after 2 years of treatment the corresponding remission rate was 42%. Thus,

the longer seizures continue on treatment the less likely is remission to occur. Rodin 8 also emphasised in his studies of patients with chronic epilepsy that the longer the history of epilepsy before referral the poorer were the prospects for seizure control. In their retrospective community study Goodridge and Shorvon’ also noted that most patients entered remission early and that the longer the epilepsy remained active the less likely was eventual remission. MECHANISMS OF INTRACTABILITY

The picture that is emerging from the studies discussed above is that for most patients the outlook for seizure control is extremely good with high remission rates in the early years of treatment. However, in about a quarter of patients epilepsy becomes chronic and because most remissions occur shortly after starting treatment the pattern of chronicity is usually established early in the course of the disease. Certain higher risk factors for chronicity have been identified, such as neurological and psychological handicaps and partial seizures, but these seem insufficient in themselves to provide a

I-Actuarial percentage by duration of follow-up of patients in whom optimal single-drug treatment failed.

Fig

Fig 2-Influence patients

of duration of

epilepsy

achieving one-year remission.

’IBlumber

at

risk.

on

actuarial percentage of

complete explanation.

How should we view the evidence, in patients with chronic epilepsy and in new referrals, that the longer the history of continuing seizures, the worse the prognosis for seizure control? Do chronic patients simply have inherently more "severe" epilepsy-so "severe" that they cannot be controlled by currently available medication? The concept of "severe" epilepsy is a difficult one, the clarification of which would require prolonged observation of untreated patients, which for ethical reasons is unlikely to be undertaken. Furthermore there is little doubt that in many individual patients epilepsy may appear to be either "severe" or "mild" at different times. We prefer to regard epilepsy as a process, modified by constitutional and environmental factors, which in most patients remits either spontaneously or under the influence of anticonvulsant treatment. In chronic epilepsy this process evolves progressively or erratically and is seemingly little modified by modern drug therapy. That remission is not always simply a matter of drug treatment is illustrated by the well-known tendency of some seizure types, such as petit mal or certain benign focal epilepsies of childhood, to remit spontaneously. One mechanism which -might underlie the evolution of chronic epilepsy was suggested by Gowers14 a century ago. He commented that "When one attack has occurred, whether in apparent consequence of an immediate excitant or not, others usually follow without any immediate traceable cause. The effect of a convulsion on the nerve centres is such as to render the occurrence of another more easy, to intensify the predisposition that already exists. Thus every fit may be said to be, in part, the result of those which have preceded it, the cause of those which follow it". Gowers was clearly attracted to this hypothesis which appears in the second paragraph of

954

his first chapter, although it has received little notice until now. He presented evidence from his own careful observations that the prognosis for seizure control was inversely proportional to the duration of the disorder. He emphasised the very favourable prognosis in patients with a seizure disorder of less than one year (83% "arrested") (fig 2) and the relatively high probability that seizures would not be controlled if the disorder had been present for more than 5 years. Thus the observations of Rodin in patients with chronic epilepsy and our own in new referrals are entirely in accord with Gowers’ view of the inverse relations between duration of epilepsy and subsequent prognosis, and his hypothesis of seizures begetting further seizures.

seizures. There is a clear need for new drugs or new strategies of management. These patients present a formidable challenge and the best hope for the future may be in the prevention of the evolution of chronic epilepsy. We thank our colleagues who have assisted in our studies over the past 10 years. These include Dr A. W. Galbraith, Dr D. Chadwick, Dr C. Dellaportas, Dr S. Brown, and Dr M. McGowan. Dr A. L. Johnson gave statistical advice.

Correspondence should

be addressed

to

E. H. R.

REFERENCES 1. Shorvon SD.

Specialized services for the non-institutionalized patient with epilepsy: developments in the US and the UK. Health Trends 1983; 15: 40-45 2 Reynolds EH, Chadwick D, Galbraith AW One drug (phenytoin) in the treatment of epilepsy Lancet 1976; i: 923-26. 3. Shorvon SD, Reynolds EH. Early prognosis of epilepsy. Br Med J 1982, 285: 1699-701.

RDC, Johnson AL, Shorvon SD, Reynolds EH. The early prognosis of epilepsy Parsonage M, Grant R, Craig A, Ward AA, eds. Proceedings of the 14th Epilepsy International Symposium 1983. New York: Raven Press (in press). 5. Elwes RDC, Shorvon SD, Johnson AL, Reynolds EH. Remission and relapse in newly diagnosed epileptic patients. Unpublished. 6 Annegers JF, Hauser WA, Elveback LR. Remission of seizures and relapse in patients with epilepsy Epilepsia 1979; 20: 729-37 7. Goodridge DMG, Shorvon SD. Epilepsy in a population of 6000 1. Demography, diagnosis and classification, and the role of the hospital services. 2. Treatment and prognosis. Br Med J 1983; 287: 641-47. 8. Rodin EA The prognosis of patients with epilepsy. Springfield, Illinois: Thomas 4. Elwes

CONCLUSIONS AND IMPLICATIONS

Patients with intractable epilepsy utilise most of the allocated for epilepsy services. They are vulnerable to polytherapy, drug interactions, chronic toxicity, and other unsatisfactory aspects of treatment. 15 Our evidence suggests that most chronic patients can be identified within the first or second, year of treatment. Can the early escalation into chronic epilepsy in these patients be prevented? Would more effective therapy at the onset reduce the risk of intractable epilepsy? For example, it is current practice in most instances not to treat after a single seizure. Certainly some patients have no further attacks, or very few. However, most patients do go on to have further attacks.7,14 Should they all be treated to prevent the risk of chronic epilepsy? How vigorously should treatment be instituted among newly referred patients who have had more than one attack and in whom the need for treatment is generally agreed? Should they all be given optimum doses of an anticonvulsant from the start, instead of beginning with a small dose which is gradually increased according to clinical progress, as is frequently practised? Poor compliance and withdrawal seizures are a major difficulty in anticonvulsant therapy.16 What steps should be taken to improve compliance at the onset of treatment, to prevent this factor contributing to the evolution of chronic epilepsy? To what extent does anticonvulsant therapy influence the natural history of epilepsy? Ethical considerations have inhibited the comparison of anticonvulsants and placebo at the onset of epilepsy. Gowers14 was certainly impressed with the impact of bromides on epilepsy. The striking fall in seizure frequency with current anticonvulsants in new referrals, high remission rate on treatment, and the relatively high relapse rate on withdrawal of therapyl7 all suggest to us that the drugs are having some effect. Would more effective control at the onset improve the prospect of a natural remission? These unanswered and to a large extent unasked questions about the evolution and treatment of chronic epilepsy suggest that much more research should be directed at the start and early years of therapy. Until recently all trials of anticonvulsant therapy have been in chronic epileptic patients, and in most studies 16 the duration of epilepsy was not even documented despite the century-old evidence, cited here, of the influence of duration on prognosis, and thus on the effect of any therapy. Finally, what treatment can we offer to the numerous patients with chronic epilepsy who continue to attend our clinics, usually undergoing frequent and fruitless additions to or changes of drug therapy? Even after simplification and rationalisation of therapy with the optimum use of one or two drugs18most patients will continue to have at least some resources

In:

1968.

study of epilepsy in its clinical, social and genetic aspects. Acta Psychiat Neurol Scand 1950; suppl 63: 1-69. Strobos RRJ. Prognosis in convulsive disorders. Arch Neurol 1959; 1: 216-25 Kiorboe E. The prognosis of epilepsy. Acta Psychiat Neurol Scand 1960; suppl 150·

9. Alstroem CH. A

10. 11.

166-78. 12 Trolle E. Drug therapy of epilepsy. Acta Psychiat Neurol Scand 1960; suppl 150 187-99. 13. Juul-Jensen P. Epilepsy A clinical and social analysis of 1020 adult patients with epileptic seizures. Acta Neurol Scand 1964, suppl 5: 1-148. 14. Gowers WR. Epilepsy and other chronic convulsive diseases London Churchill, 1881. 15 Reynolds EH. Unsatisfactory aspects of drug treatment of epilepsy. Epilepsia 1976; 17: 13-15. 16. Shorvon SD, Johnson AL, Reynolds EH. Statistical and theoretical considerations in the design of anticonvulsant trials. In: Dam M, Gram L, Penry JK, eds. Advances in epileptology New York- Raven Press, 1981: 123-28. 17. Thurston JH, Thurston DL, Hixon BB, Keller AJ. Prognosis in childhood epilepsy Additional follow-up of 148 children 15-23 years after withdrawal of anticonvulsant therapy. N Engl J Med 1982; 306: 831-36. 18. Reynolds EH, Shorvon SD Monotherapy or polytherapy for epilepsy? Epilepsia 1981, 22: 1-10

Public Health OUTBREAK OF INFANTILE GASTROENTERITIS DUE TO TYPE 40 ADENOVIRUS SHUNZO CHIBA SHUJI NAKATA IZUMI NAKAMURA KOHKI TANIGUCHI SHOZO URASAWA KEI FUJINAGA TOORU NAKAO

.

Department of Paediatrics, Sapporo Medical College, Department of Molecular Biology, Sapporo Medical and Department of Hygiene,

Institute,

College Cancer Research Sapporo Medical College, Sapporo, Hokkaido, Japan

characterisation was strain of adenovirus (EAd) performed isolated from an outbreak of gastroenteritis which occurred in an orphanage in the City of Sapporo, in the room housing the eldest children, who ranged in age from 14 to 22 months. 7 of the 11 children housed in that room had diarrhoea between July 11 and July 22, 1982. All 7 shed adenoviruses detectable by electron microscopy in their stools. Immune electron microscopy showed that all patients as well as the healthy contacts sharing the room underwent seroconversion to EAd. There was no homology, or very slight homology, between

Summary

Genetic and

antigenic

on a