some aspects of prognosis in the epilepsies: a review

Epilepsiu, 34(6): 1007-1016, 1993 Raven Press, Ltd., New York 0 International League Against Epilepsy

Some Aspects of Prognosis in the Epilepsies: A Review

J. W. A. S. Sander

Epilepsy Research Group, University Department of Clinical Neurology, Institute of Neurology, Queen Square, London, and National Hospitul-Chalfont Centre for Epilepsy, Gerrards Cross, Bucks, England

Summary: The traditional view that epilepsy is usually a chronic condition in which the prognosis is consistently poor has been challenged in the last 2 decades. Evidence from population-based studies and from intervention studies in newly diagnosed patients has produced a wealth of information of a much better prognosis. It is now generally accepted that as many as 70-80% of people developing seizures for the first time will eventually achieve terminal remission, whereas the remaining 20- 30% will continue to have recurrent seizures despite all treatment. Despite the high recurrence rate after a first

epileptic seizure, remission usually occurs early and for most persons, epilepsy is a short-lived condition. The exact role of antiepileptic drugs (AEDs) in this good outcome, however, remains open to debate, because the natural history of the untreated condition is largely unknown. In this article, factors that may influence the prognosis of the epilepsies, including the problems of diagnosis, are reviewed. Special emphasis is given to the issue of spontaneous remission and the question of prognosis of different epileptic syndromes. Key Words: Epi- lepsy-Epileptic syndromes-Prognosis-Remission.

Prognosis is defined as the chance of recovery from a condition. Strictly, in epilepsy this means the chance of terminal remission once a patient has established a pattern of recurrent epileptic seizures. Several aspects must be considered, however, when assessing the prognosis of epilepsy. These include the likelihood of seizure recurrence after a first epileptic attack; the underlying etiology of this attack; the role of antiepileptic drug (AED) treatment in outcome; the risk of recurrence of seizures after AED discontinuation; the likelihood of remission after epilepsy surgery, and the mortality of epilepsy. The entire nature of epileptic seizures, which are a symptom rather than a distinct illness, the difficulty of their diagnosis, and their unpredict- ability must also be considered.

This article provides an overview of the prognosis of epileptic seizures. Issues considered are: (a) a brief historical overview of the prognosis of epilepsy; (b) the problem of diagnosis (is it epilepsy?); (c) recurrence after a first seizure; (d) the natural history of treated epilepsy; (e) untreated epilepsy (is there spontaneous remission?); and (f) the heterogeneity of epilepsy: the outcome of different epileptic syndromes. Outcome after epilepsy surgery and

Received June 1992; revision accepted November 1992. Address correspondence and reprint requests to Dr.

J . W. A. S. Sander at National Hospital-Chalfont Centre for Epilepsy, Gerrards Cross, Bucks SL9 9NR, England.

mortality associated with epileptic seizures are out- side the scope of this review.

The operational definition of epilepsy currently accepted is the occurrence of more than one nonfebrile, nonacute seizure in a lifetime. In practice, the diagnosis of epilepsy is applied to a number of conditions that have in common only a tendency to recurrent epileptic seizures. In this article, however, the terms epilepsy and epileptic seizures are used interchangeably. The term chronic epilepsy, as used in this article, is defined as epilepsy still active 5 years after onset.

THE PROGNOSIS OF EPILEPSY: A HISTORICAL OVERVIEW

Many publications have dealt with the prospects of remission once a patient has epilepsy, but only a few of the publications have had significant impact. Gowers, in 1881, set the pace with his celebrated quotation: “The spontaneous cessation of the disease is an event too rare to be reasonably antici- pated in any given case” and this is still the central theme of a number of articles dealing with epilepsy outcome (Elwes et al., 1988; Elwes and Reynolds, 1990). Rodin (1968), 87 years later, reinforced Gow- ers’ view of epilepsy as an ailment of guarded outcome, portraying it “as a chronic condition charac- terised by a tendency to seizure relapse” (Rodin,

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1968). Gowers’ and Rodin’s views, and also those of the investigators who wrote in the period between the publications of these luminaries, were heavily biased towards hospital attenders, a population in which patients with chronic and severe epilepsy are overrepresented.

This gloomy view of the prognosis of the epilepsies began to be dispelled soon after Rodin’s work was released (Rodin, 1968), as the results of general population-based studies began to be published. The Rochester, Minnesota, U.S.A. group reported in 1979 that in a retrospective community-based study as many as 76% of patients achieved long- term remission (Annegers et al., 1979). Soon after, similar findings were reported in another community-based study in Tonbridge, England (Goodridge and Shorvon, 1983). These population studies showed that more than two thirds of patients would achieve remission, a far cry from the reserved prognosis once given to epileptic seizures.

Indications of a good outcome had already been provided by epidemiologic surveys, which had shown incidence rates for epilepsy to be between 20 and 70 per 100,000 per year, so that lifetime prevalence (cumulative incidence) of epileptic seizures could be between 2 and 5%, whereas concomitant prevalence rates for active epilepsy were consistently -0.5% (Crombie et al., 1960; Pond et al., 1960; Gudmundsson, 1966; Hauser and Kurland, 1975). Thus, these epidemiologic data clearly showed that most patients who develop epileptic seizures have an excellent prognosis for eventual seizure control.

Intervention studies in patients with newly diagnosed epilepsy performed by the King’s College Hospital group, at about the same time as these population-based studies demonstrated that, when treated, most newly diagnosed patients with epilepsy soon entered long-term remission (Shorvon et al., 1978; Shorvon and Reynolds, 1982; Elwes et al., 1984, 1985). Shorvon (1984) stressed that most of the work before 1979 had overrepresented hospital patients with chronic epilepsy and had failed to appreciate the temporal aspects of seizure recurrence which was a major compounding factor for the understanding of the prognosis of epileptic seizures; he suggested that failure to provide early seizure treatment may facilitate evolution of epilepsy into an intractable condition. The evidence for this prop- osition was circumstantial and based entirely on seizure patterns in newly diagnosed patients, many of whom had a relatively short-lived condition after initiation of treatment.

It is now generally accepted that as many as 70- 80% of persons developing seizures for the first

time will eventually achieve remission, whereas the remaining 20-30% will continue to have recurrent seizures despite all treatment. Remission occurs early, and in most persons epilepsy is a short-lived condition. However, uncertainties remain; among them are the issues of predictability of remission (who will achieve remission and when?), and the role of treatment in outcome (is treatment curative?).

THE PROBLEM OF DIAGNOSIS: IS IT EPILEPSY?

The first issue with regard to the prognosis of epilepsy concerns diagnosis. Epileptic seizures are very pleomorphic, although usually stereotyped for a given individual. Most patients with seizure disorders do not have physical manifestations, unlike in most ailments, and seizures are of a transient and unpredictable nature. Most of the time, the disorder is “not there,” and thus can be diagnosed only his- torically or by chance observation of a seizure (Sander and Shorvon, 1987). Epileptic seizures remain basically a clinical diagnosis and thus depend fundamentally on discretionary judgment which may vary depending on the observer.

Diagnosis of epilepsy is particularly difficult in the early stages of the condition. In 21% of patients enrolled in a population-based study, the diagnosis was still unclear 6 months after patients’ entry to the study (Sander et al., 1990~) . In the Rochester study, time from first seizure to diagnosis was >2 years in >30% of patients (Hauser and Kurland, 1975). In addition, in specialized clinics, as many as 10-20% of patients referred with seemingly intractable chronic seizures, have been estimated not to have true epileptic attacks (Lesser, 1985). Common sources of confusion are syncope or psychogenic attacks. In the case of the latter, a compounding factor is that some patients may also have organic seizures or have had epilepsy in the past.

It is now generally accepted that 2&30% of patients who develop epilepsy will eventually be classified as having chronic epilepsy. Inclusion of patients with nonepileptic attacks in the latter group may inflate the proportion of chronic cases artifi- cially. In many prognostic studies of epilepsy, this question of uncertain diagnosis has not been fully addressed and may introduce substantial bias. In any assessment of the outcome of epileptic seizures, the problem of diagnosis should be seriously considered.

RECURRENCE AFTER A FIRST SEIZURE The orthodox viewpoint that single seizures

should not be equated with epilepsy originates from

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PROGNOSIS IN THE EPILEPSIES 1009

the findings of earlier recurrence studies which in- dicated that a considerable proportion of patients with a single seizure had no further attacks. Re- ported estimates of the risk of a second attack have varied from 27% to 80% (Thomas, 1959; Costeff, 1965; Saunders and Marshall, 1975; Annegers et al., 1978; Blom et al., 1978; Cleland et al., 1981; Hauser et al., 1982; Goodridge and Shorvon, 1983; Elwes et al., 1985; Hopkins et al., 1988; Hart et al., 1990). Most hospital-based estimates have fallen in the lower end of this range whereas estimates in population-based studies and studies in which patients were enrolled within 24 h of an attack lie at the higher end of the range. The main reasons for this variation are selection bias in the patient population chosen for a study and the effect of time of entry to the study.

The risk of seizure recurrence is much higher in the first weeks or months after an epileptic initial attack. Consequently, if there is a long interval between the first seizure and registration in a recurrence study, a second seizure may already have occurred and the patient therefore will not be in- cluded. This was clearly evident in a hospital-based study that reported a recurrence rate after a single tonic-clonic seizure of 15% among patients registered 8 weeks after the first seizure as compared with 50% of patients registered within 4 weeks (Hopkins et al., 1988).

A prospective general population-based study performed in the United Kingdom, in which scru- pulous care was taken to avoid selection bias, provided comprehensive information on this issue (Hart et al., 1990). Recurrence rates were determined by actuarial analysis for 564 unselected patients with nonfebrile seizures. Overall, 67% of patients had recurrence within 12 months of a first attack and 78% had recurrence in 36 months. Sei- zures associated with a neurologic deficit presumed present at birth had a 100% rate of relapse in the first 12 months, whereas seizures associated with a CNS lesion acquired postnatally carried a risk of relapse of 75% by 12 months and 85% by 36 months. Seizures occurring with an acute insult to the brain or in the context of an acute precipitant carried a risk of relapse of 40% by 12 months and 46% by 36 months. Only 86 patients were treated after a first attack and their recurrence rate was 50% by 12 months and 57% by 36 months. Patients were not randomly assigned to treatment, and treatment probably was started in patients in whom the risk of relapse was perceived to be high. Any comparison of treated and untreated patients should therefore be made with caution. The study also confirmed that the risk of recurrence after a first attack is not

constant; most recurrences occurred in the first 6 months, and the risk decreased the longer a patient remained free from attacks.

The risk of a further seizure after a first attack is greater than was previously accepted. This has im- plications for management of single seizures and also casts doubt on the value of distinguishing between single seizures and epilepsy. If it is meaning- ful in an individual, it is only so when the time elapsed since the first attack is known. The distinction between single seizure and epilepsy may be valid only for acute symptomatic seizures, although even in this group a significant proportion of patients will have further seizures.

THE NATURAL HISTORY OF TREATED EPILEPSY

Newly diagnosed epilepsy Usually, in the developed world, when a patient

has had two or more unprovoked seizures, a diagnosis of epilepsy is made and AED treatment is initiated. Several hospital-based prospective inter- ventional studies reported the effect of treatment in newly diagnosed cases (Callaghan et al., 1978, 1985; Shorvon et al., 1978; Feely et al., 1979; Strandjord and Johanessen, 1980; Shakir et al., 1981; Turnbull et al., 1982; Elwes et al., 1984; Matt- son et al., 1985; Duncan and Shorvon, 1986). Al- though there are differences in case ascertainment between these studies, outcome is usually discussed in terms of seizure remission defined as a period of 1, 2, or 5 years of total freedom from seizures. Patients are thus categorized in two cate- gories: those in remission and those not in remission. Overall, 1-year remission rates reported in these studies varied between 58 and 95%, with most studies reporting between 65 and 80%. The prognosis for control of partial seizures is not as good; in one large study in which patients were grouped by seizure type, complex partial seizures were controlled in only 1643% of patients, whereas for those with only secondarily generalized attacks control was achieved in 48-53% at 1 year (Mattson et al., 1985). Most studies have reported outcome in newly diagnosed cases to be less favorable in patients with multiple seizure types and associated neurologic deficit, behavioral, or psychiatric distur- bance. One study also associated a worse prognosis with a family history of epilepsy and a high frequency of tonic-clonic seizures before treatment (Elwes et al., 1985).

Two retrospective general population-based studies have also ascertained the remission of seizures

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I010 J . W . A. S . SANDER

in patients who had been diagnosed as having epilepsy sometime in the past and had been started on treatment. In Rochester, an analysis was made of outcome of all patients with epilepsy registered by the Mayo clinic record linkage system (Annegers et al., 1979). Remission was defined as a 5-year period without attacks. Twelve months after diagnosis, 42% of patients entered a remission period; by 10 years, 65% were in remission. By 15 years after onset, 76% were in 5-year remission. In Tonbridge, a study of a general practice population showed similar results; overall, 73% of the patients were in remission, defined as 2 years seizure-free (Good- ridge and Shorvon, 1983). In both studies, most patients who entered remission did so in the first 2 years; as time elapsed, the prospect of entering remission decreased. i n the Rochester study, 42% of patients entered remission after the first year, a further 22% entered remission in the next 9 years, and only a further 11% entered remission in the subsequent 10 years. In the Tonbridge study, for a patient whose epilepsy was still active (defined as one seizure at least in the previous 2 years) at 5 years the probability of being in a 2-year remission 5 years later was only 33% and was 38% 10 years later, in contrast to patients who were seizure-free at 5 years, for whom these percentages were 100 and 95%.

Thus, population- and hospital-based studies show high remission rates with initial AED treatment in newly diagnosed cases; overall 70-80% of patients will enter remission once AED treatment is initiated. No report has yet associated this good outcome with any particular AED. Although some individuals do respond better to a particular AED, all first-line AEDs appear to be equally effective on a population basis. in many of these patients who enter long-term remission, epilepsy appears to run a self-limiting course.

Chronic epilepsy Most patients who have a first epileptic seizure

will soon have a second seizure. Usually, after this recurrence, treatment is started and is followed by a remission in most patients. However, 20-30% of patients will continue to have seizures. All hospital studies of newly diagnosed epilepsy have consistently demonstrated the existence of this hard core of patients who do not enter remission. Further confirmation of this is derived from community studies: 20-30% of patients with epilepsy do not enter any substantial remission period and continue to have epileptic seizures regardless of treatment with all AEDs (Annegers et al., 1979; Goodridge and Shorvon, 1983). Thus, both community and

hospital studies indicate that a substantial minority of patients will continue to have seizures. They have chronic epilepsy. The good outcome of treatment in patients with newly diagnosed epilepsy con- trasts sharply with endeavors to treat patients with established chronic epilepsy. The traditional rather pessimistic view of prognosis in epilepsy was based on studies of these chronic cases, usually from hospital-based clinics. Rodin (1968) comprehensively reviewed the literature on the prognosis of chronic epilepsy. His conclusion that only 20% of these chronic patients would have periods of seizure freedom and that even short-term remission was unlikely to occur in most of these patients remains an important observation. Epilepsy in most cases runs true to form from its onset.

It is often said that the hope of persons with chronic epilepsy for full seizure control lies in novel AEDs or in the possibility of surgical intervention. The latter approach is possible in only a very small proportion of patients, and currently available new AEDs have not lived up to expectation. Only a small percentage of persons with chronic epilepsy have been rendered seizure-free by addition of vigabatrin, a relatively new drug in the antiepileptic armory (Anonymous, 1989; Mumford and Dam, 1989; Sander et al., 19906), although it must be hoped that the advent of other novel AEDs may be more beneficial.

Drug discontinuation and seizure relapse Seventy to 80% of patients receiving AED treat-

ment will eventually become seizure-free, but whether the remission is the result of AED therapy remains to be seen. Because of the possible long- term side effects of AEDs, it is common clinical practice to consider drug discontinuation after a patient enters a substantial remission period, but risk of relapse exists when AEDs are discontinued. Sev- eral studies have addressed this issue (Juul-Jensen, 1964; Sakamoto et al., 1978; Thurston et al., 1982; Todt, 1984; Bouma et al., 1987; Oller-Daurella and Oller, 1987; Overweg et al., 1987; Aarts et al., 1988; Callaghan et al., 1988; Matricardi et al., 1989; MRC AED Withdrawal Group, 1991). The probability of relapse has varied between 1 1 and 41%.

In the largest and best-designed of all studies of AED discontinuation, 1,013 patients in long-term remission were randomized to either continuing treatment or to slow discontinuation of medication (MRC AED Withdrawal Group, 1991). The risk of relapse was 41% in the first 2 years without AED treatment, whereas the probability of relapse in the group randomized to continuing treatment was 22% in the first 2 years after randomization. The differ-

Epilepsia, Vol. 34, NO. 6 , 1993


ences between these two groups were maximal between 1 and 2 years; after this, the risk of seizure relapse is actually greater in those who continue treatment. Some other factors (e.g., noncompli- ance, voluntary discontinuation of medication), however, may be playing a role, and this finding should be viewed with caution. Nevertheless, discontinuation of medication in some of these patients may only be anticipating a relapse that would occur anyway, whereas in other patients it may indicate that remission is indeed dependent on AEDs.

Most of the studies described herein failed to dif- ferentiate between patients who entered a period of remission at some time after initiation of AED treatment and those who remained in remission from onset of treatment. These two groups may have a different prognosis for seizure recurrence after drug discontinuation, and if future studies are to extend our understanding in this area the onset and time course of remission must also be clearly reported.

Patterns of remission Study of the temporal course of seizure activity

has been rather neglected despite the importance of such data for assessment of prognosis. Shorvon and Sander (1986) studied the temporal course of epilepsy and patterns of seizure remission in two very different populations. The first group consisted of 108 unselected patients identified in the community with a median history of epilepsy of 17 years (range 5-74 years). The second group consisted of 181 patients with chronic epilepsy attending a specialized clinic, also with a median history of epilepsy of 17 years (range 5-57 years). Three patterns of remission were readily identified: (a) burst pattern, which consisted of a period of seizure activity followed by a remission (at least 2 years) that continued to the time of the survey; (b) intermittent pattern, which consisted of a period of seizure activity followed by a remission of at least 2 years, with a subsequent relapse; and (c) continuous pattern, in which no remission occurred.

Of patients with a history of epilepsy in the community, 65% had a burst pattern of seizures and readily entered long-term remission. About one quarter had continuing epilepsy from onset; in the remaining 12% of patients, remission was followed by relapse which was often associated with discontinuation of medication. In contrast, in the group with chronic epilepsy, only 22% had experienced remission at any time in their history and the rest had continuing seizures without remission from the very onset of epilepsy. Thus, epilepsy usually runs true to form from its very onset, in both groups. The concept of epilepsy as a chronic remitting and re-

lapsing condition applied only to a minority of patients.

UNTREATED EPILEPSY: IS THERE SPONTANEOUS REMISSION?

The natural history of untreated epileptic seizures is largely unknown. Studies of outcome in epilepsy have almost invariably been of the treated condition. Effective treatment for epileptic seizures has been available since 1857, when bromide therapy was introduced, long before the concept of longitu- dinal studies of unselected populations came to light. Consequently, two important questions remain unanswered: the possibility of spontaneous remission and the effect of early treatment on outcome.

Recently, circumstantial evidence about these issues has emerged from studies of untreated populations in rural areas of the developing world, where AED treatment is not commonly available. Patients with epilepsy in developing countries may have had the condition untreated for long periods of time, which differs from the situation in developed countries where treatment is usually started at onset of the condition.

In a truly chronic condition, which never recov- ers, cumulative incidence should approach prevalence, the difference being explained by differential death rates in the cases (Sander and Shorvon, 1987). In epilepsy, in the developed world, the difference between the two rates is now largely attrib- uted to AED-induced remission. The incidence rates for epilepsy apparently are higher in developing countries, mainly due to acute infection, para- sitic infections, and poor pre- and peri-natal care (Shorvon and Farmer, 1988). Assuming, however, that incidence rates for epilepsy are similar in both the developed and developing world and that failure to provide early treatment for epilepsy may facilitate evolution of epilepsy into an intractable condition (Shorvon, 1984, 1987; Reynolds, 1987), one would expect higher prevalence rates in the developing world. Indeed, studies originating in developing countries have reported high prevalence rates for epilepsy (Jilek-Aall, 1965; Osuntokun et al., 1982; Goudsmit et al., 1983; Gracia et al., 1990). One problem with these studies, however, is that all were small-scale studies of selected or isolated populations with high rates of degenerative diseases or epileptic syndromes.

Very interesting data derive from a cross- sectional population-based study performed in the highlands of Northern Ecuador, where meticulous care was taken with case ascertainment (Placencia

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et al., 1992a). Of a total estimated population of 75,000 persons, 72,121 were screened in a house-to- house survey. A cascade system of diagnosis was used to identify 88 1 people with a definite history of epilepsy. Of the patients, 55% had active epilepsy; the remaining 45% were in remission, defined as being at least 2 years seizure-free. Owing to case ascertainment bias, patients in long-term remission are usually underrepresented in this type of study, and the result should be considered as a minimum estimate of patients in remission in this community. Only 15% of all cases identified were receiving treatment at the time of the survey, and only 29% had ever received AED treatment. Nevertheless, 46% of the untreated cases were in long-term remission. Therefore, 28% of the original sample entered remission, regardless of AED treatment. This finding is corroborated by the epidemiologic findings. In this largely untreated population, a projected incidence of epilepsy of 122 per 100,000 per year was determined and the lifetime prevalence rate was estimated to be 1.9%. However, the prevalence rate for active epilepsy was only 0.67% (Placencia et al., 1992b).

In a population study of 18,954 persons in Nige- ria, a similarly low prevalence rate (0.53%) for active epilepsy was reported (Osuntokun et al., 1987); only 4% of the prevalent cases were receiving treatment at the time of the survey. Further data were reported in an Ethiopian study of 60,820 persons; a prevalence rate of 0.52% was established, and only 1.6% of the 316 patients with active epilepsy identified had ever received AED treatment (Tekle- Haimanot et al., 1990). In large-scale population- based studies in China (Li et al., 1985) and in India (Bharucha et al., 1988; Koul et al., 1988), similar prevalence rates were reported. These rates in largely untreated populations in areas where AED treatment for epilepsy is usually not available are very similar to rates of the developed countries. One explanation is that epilepsy carries a higher mortality rate in the developing world, although it is very unlikely that this would account for the entire difference. Another explanation is that case ascertainment for active seizures was not optimal, but cases in remission rather than active cases often are likely to be missed in such studies (Schoenberg, 1983; Sander and Shorvon, 1987). A more plausible explanation is that some of the patients do enter remission, which may suggest that, contrary to Gowers’ thought (1881), spontaneous remission may occur in a significant number of patients.

The efficacy of treatment in patients who had not previously received AED treatment was described in a prospective study performed in an area of rural

Kenya (Feksi et al., 1991). Three hundred two patients aged 6-65 years were recruited; all had active GTC. Patients were randomized to one of two AEDs (carbamazepine or phenobarbital), and stan- dard therapeutic regimens were used. Two hundred forty-nine patients completed the study, of whom 53% became seizure-free in the second 6 months of therapy as compared with the baseline pre- treatment 6-month period; a further 26% of the patients had a substantial (>50%) reduction in seizures. These findings were similar to those reported by other investigators in newly diagnosed patients in the developed world (Callaghan et al., 1978, 1985; Shorvon et al., 1978; Feely et al., 1979; Shakir et al., 1981; Elwes et al., 1984). Two hundred two (81%) of the patients completing the study were AED naive (Feski et al., 1991), many were chronic cases (52% had had epilepsy >5 years) and had fre- quent seizures (38% had had >lo0 seizures). The outcome of treatment was uniformly good in these patients, and neither duration of the condition or number of seizures before treatment was a predictor of outcome.

These results suggest that treatment can be as effective in AED-naive patients with long histories as in AED-naive patients with short histories and offer evidence against the view that chronic epilepsy will develop unless treatment is initiated early. Similar observations were also made in a study in the rural highlands of Northern Ecuador in South America (Placencia et al., 1990) and in a study in Malawi (Watts, 1989, 1992). The role of treatment in epilepsy is intriguing and it may well be that treatment, in some patients at least, by induc- ing remission diminishes the chances of subsequent relapse; however, disease duration before treatment is initiated does not appear to lessen this possibility.

The findings of these uncontrolled studies described are only circumstantial evidence that spontaneous remission may occur and that early treatment is not necessarily a predictor of good outcome. The ideal method to test these hypotheses would be to allocate patients developing cryptogenic epilepsy randomly to three groups [early treatment (treatment after a first attack), the present clinical practice (treatment after a second attack), and delayed treatment (withholding treatment as long as possible)] and to compare long-term prognosis. To achieve adequate statistical power in such a study, at least 1,500 patients would have to be enrolled in each group. At present, it is common clinical practice to offer AED treatment to most patients developing epilepsy for the first time; therefore, ethical considerations may hamper such

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a study. As more circumstantial evidence becomes available, however, the prospect of such a study may become increasingly more acceptable.

HETEROGENEITY OF EPILEPSY: EPILEPTIC SYNDROMES AND PROGNOSIS

Epilepsy is characterized by recurrent epileptic seizures and, by definition, a single seizure is not considered “epilepsy” (although this may be an ar- bitrary definition). Myriad different conditions may express themselves solely by occurrence of recurrent epileptic seizures, thus qualifying for the label of epilepsy. Recently, in recognition of this possibility, the International League Against Epilepsy is- sued a comprehensive proposal for the classification of the epilepsies and epileptic syndromes and, although the classification has limitations, its use should be encouraged (Commission, 1989).

Epilepsy is therefore a collection of syndromes and conditions rather than an illness or a process; failure to appreciate this may be responsible for some of the misconceptions about prognosis. Use of the term epilepsy, in population studies at least, is itself misleading: the term should be “the epilepsies ,” as many different background etiologies and syndromes may be responsible for the seizures. These different conditions and syndromes may have different outcomes but are often grouped to- gether. Some subjective distinctions are made, however. Acute symptomatic seizures (those occurring in the context of an acute illness or metabolic disorder) are usually not considered under the label of epilepsy, although this distinction is sometimes spurious. Neither are febrile seizures considered epilepsy, despite having clear epileptic phenomenology.

Once the diagnosis of an epileptic seizure is firmly established, a syndromic or conditional diagnosis should always be attempted. This may be difficult: A syndrome is characterized by a clustering of signs and symptoms consistently occurring to- gether (Commission, 1985). Some of the epileptic syndromes are clear-cut. Most, however, may have considerable overlap or may be based on a rather loose association of clinical features. There may be disagreement about the precise limits of a syndrome, and different etiologies may exist for the same syndrome. In many cases, a syndromic diagnosis can be made only retrospectively. Identifica- tion of a putative etiology for the seizures usually is not possible in more than half of the cases; e.g., in a large unselected population of patients with newly diagnosed epilepsy, as many as 62% of attacks were labeled as cryptogenic even after at least 6 months of follow-up (Sander et al., 1990a). Often the only

discernible sign is recurrence of epileptic seizures. In most patients, remission occurs early in the condition, rendering a retrospective syndrome diagnosis difficult.

Some syndromes may not yet have been defined; e.g., -7% of persons with chronic partial seizures enter remission once treatment with vigabatrin, a new GABAminergic drug, is initiated (Reynolds 1990; Sander et al., 19906). In a small subgroup of patients, epilepsy may be caused by low levels of GABA (a yet-undefined syndrome or condition?), and such patients may belong to a population different from that of patients with chronic epilepsy who do not respond. Evidence for secondary epileptogenesis in some animal models of partial epilepsy is convincing (Goldensohn, 1984; Engel and Cahan, 1986); but such evidence in humans is not persuasive at this time. Specific epileptic syndromes, in which this is a prominent feature, may have yet to be defined.

With regard to outcome, the epileptic syndromes and conditions could easily be classified in four different prognostic groups (Shorvon, 1991 ; Trevisol- Bittencourt and Sander, 1991; Duncan and Shor- von, 1992). These broad groups are to some extent static and self-contained, and migration from one group to another is unlikely unless new factors arise, e.g., exposure to a novel AED, surgical intervention, or widening of a lesion or of damage. Patients developing epileptic seizures will fall into one of the following prognostic groups, and this is likely to be predetermined by the epileptic condition they represent.

1 . Excellent prognosis. In the group with excellent prognosis, syndromes and conditions are self-limiting and very benign. They may comprise -20-30% of all persons who develop epileptic attacks. Usually, only a few seizures occur. Patients commonly do not require AED treatment as spontaneous remission is the rule. Conditions include benign neonatal seizures, benign partial epilepsy (rolandic epilepsy, benign occipital epilepsy, benign frontal epilepsy), benign myoclonic epilepsy of in- fancy, and some of the epilepsies with seizures precipitated by specific modes of activation (acute symptomatic seizures, drug-induced seizures, febrile convulsions).

2. Good prognosis. Epilepsies in the group with good prognosis are usually benign and short- lived and may comprise -3040% of all people who develop epileptic attacks. Seizures are easily controlled with AEDs, although spontaneous remission is possible in some cases. Once remission is achieved, it is permanent,

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3.

4.

and AEDs can be successfully tapered. In this group, AEDs may be curative or suppressant until the epileptic diathesis resolves spontane- ously. Conditions include childhood absence epilepsy, epilepsy with generalized tonic clonic seizures (GTC) on awakening, nonspe- cific FTC seizures in patients with no neurologic signs, and some of the localization- related epilepsies (both cryptogenic and symptomatic types). Uncertain prognosis. The group with uncertain prognosis has a long-term tendency to seizures. This group is probably the smallest and may comprise - 10-20% of all persons who develop epileptic attacks. AEDs in this group are suppressive of seizures rather than curative. Patients may achieve remission but tend to relapse if AEDs treatment is discontinued. Treatment with AEDs is usually a lifetime prospect. Conditions include juvenile myoclonic epilepsy and the bulk of the localization-related epilepsies (both cryptogenic and symptomatic). Some patients in the latter group may be amenable to surgical intervention, however, with subsequent change in prognostic group. Bad prognosis. The prognosis for seizure control is guarded in this group, which may comprise ~ 2 0 % of all persons who develop epileptic attacks. AEDs in this group are palliative rather than suppressive of seizures. Persons in this group have a continuous tendency for seizures despite intensive treatment with all AEDs, although occasionally they may move to the uncertain prognosis group when treated with a novel AED. Some patients in this group may also be amenable to surgical intervention, with subsequent change in prognostic group. Conditions include seizures associated with neurologic deficit present from birth (tuberous sclerosis, Sturge-Weber syndrome, malforma- tions, cerebral palsy), epilepsia partialis con- tinua, progressive myoclonic epilepsies, and other progressive neurologic diseases, West syndrome, Lennox-Gastaut syndrome and other syndromes in which atonic/tonic seizures are a prominent feature, localization- related seizures associated with gross struc- tural lesions, and some localization-related cryptogenic epilepsies.

The concept of syndromes is not yet universally accepted. Epilepsy has been suggested to be a progressive biologic process based on decreasing inter- vals between seizures (Elwes et al., 1988), but the evidence for this is not persuasive. A quasicontin-

uous spectrum of causation involving environmen- tal and genetic factors has been suggested for the generalized epilepsies (Berkovic et al., 1987). This is a neat theoretical concept, but in practice, with regard to outcome, different generalized epilepsies will still fall into one of the prognostic groups; therefore this becomes a philosophical issue. Thus, the outcome of epilepsy is determined to a large extent by its syndromic classification. Studies reporting outcome should be encouraged to classify all reported cases according to the ILAE proposal for classification of the epilepsies and epileptic syndromes (Commission, 1989). Not all epileptic syndromes are yet clearly delineated, however, and ef- forts are urgently needed to improve such delineation.

CONCLUSIONS

Our knowledge and understanding of the prognosis of epilepsy has advanced significantly in the last 2 decades; however, in two areas, more data are urgently required. First, more studies focusing on the prognosis of individual epileptic syndromes are warranted, including studies that will result in better delineation of epileptic syndromes as yet ill defined. Second, there is urgent need for a controlled clinical trial randomizing patients with cryptogenic seizures at the time of a first epileptic attack to either treatment or no treatment. The necessity of such a study to assess the role of treatment in epilepsy cannot be overemphasized.

Acknowledgment: I thank my colleagues Drs. J. S. Duncan, Y. M. Hart and S. D. Shorvon for helpful dis- cussion of some of the concepts discussed in this article. Sanofi Pharma is thanked for support.

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RESUME L’opinion traditionnelle selon laquelle 1’Cpilepsie est habitu-

ellement une maladie chronique dans laquelle le pronostic est toujours dkfavorable, a CtC contestte pendant les deux dernitres dCcennies: des ttudes bas6es sur les populations et les Ctudes portant sur des patients nouvellement diagnostiquks ont produit de nombreuses informations tendant a prouver que le pronostic est bien meilleur. On accepte maintenant gCnCralement environ 70 B 80% des patients prCsentant des crises pour la premitre fois bCnCficieront d’une rCmission finale, tandis que les 20 Q 30% des patients autres continueront a presenter des crises indCpen- damment de tout traitement. MalgrC le taux ClevC de recurrence aprts une premikre crise, la remission survient habituellement de faCon prkcoce; pour la majorit6 des patients, 1’6pilepsie est une maladie de courte duree. Le r6le exact des medicaments anti- Cpileptique dans ce bon pronostic reste controversk, car I’Cvo- lution naturelle de la maladie sans traitement est en grande partie ignorCe. Dans ce travail, les facteurs qui peuvent influencer le pronostic des Cpilepsies, incluant les probltmes du diagnostic, sont passCs en revue. L’auteur insiste sur les rCmissions spon- tanCes et sur le pronostic differentiel des diffkrents syndromes Cpileptiques.

(P. Genton, Marsielle)

RESUMEN En las dos ultimas dkcadas se ha cuestionado el concept0

tradicional de que la epilepsia es, generalmente, una condici6n cr6nica con un pron6stico generalmente pobre. Segdn 10s estudios basados en la poblacion o 10s estudios de intervenci6n en casos de diagnostic0 “de-novo” se ha conseguido una informa- ci6n importante que evidencia un pronostico mas favorable. En la actualidad se acepta que, al menos un 70-80% de personas que desarrollan ataques por primera vez en su vida, consiguen una remision total mientras que 10s restante 2&30% continuan te- niendo ataques recurrentes a pesar del tratamiento. A pesar del elevado n6mero de recurrencias tras un primer ataque, la remi- si6n generalmente occure precozmente y, en la rnayoria de 10s casos, la epilepsia constituye uan condition de corta duracibn. El papel exacto que las drogas antiepiltpticas juegan en este resultado es debatible puesto que la historia natural de casos no trdtados es desconocida. En esta communicaci6n se revisan 10s factores que pueden influenciar el pron6stico de la epilepsia in- cluyendo 10s problemas diagn6sticos. Los autores otorgan un Cnfasis especial a la remisi6n espontanea y a1 problema del pro- n6stico segun 10s diferentes tipos de sindromes epilCpticos.

(A. Portera-Sanchez, Madrid)

Epilepsia, Vol. 34, No. 6, 1993

some aspects of prognosis in the epilepsies: a review

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