Epilepsia. 2.42729-737, 1979.
Raven Press, New York
Remission of Seizures and Relapse in Patients with Epilepsy *John F. Annegers, tW.Allen Hauser, and *Lila R. Elveback *Department of Medical Statistics and Epidemiology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55901; and ?Department of Neurology, Columbia University College of Physicians and Surgeons. New York, New York 10032
Summary: In a longitudinal study of patients with epilepsy in Rochester, Minnesota, we found that the probability of being in remission (at least 5 consecutive years seizure-free, and continuing) at 20 years after diagnosis was 70%. The rates for remission we encountered were generally higher than those previously reported. We believe that the better prognosis in our series results from inclusion of all incidence cases in a defined population, beginning at the initial diagnosis of epilepsy. Prognosis for remission of epilepsy is poor in patients with' associated neurologic dysfunction identified from birth. Patients with idiopathic seizures and survivors of postnatally acquired epilepsy have better prospects for eventual remission. The probability of remission is highest in patients with generalized-onset seizures diagnosed before 10 years of age. Prognosis is less favorable for those with partial complex seizures and adultonset epilepsy.
This study was concerned with three questions: (1) What are the chances that patients with epilepsy will have remissions of their seizures? (2) Does the likelihood of remission vary by seizure type, sex, age at onset, or predisposing cause? (3) What are the prospects for discontinuing anticonvulsant medication, as well as being seizurefree, sometime in the future? We attempted to answer these questions by a follow-up study of a cohort of patients with epilepsy.
agnosed cases of epilepsy in the population of Rochester, Minnesota. A total of 618 patients received their initial diagnoses of epilepsy while residents of Rochester between 1935 and 1974. All have had at least two seizures that did not seem to be provoked by an acute cause. Thus, this series excludes more than 1,OOO Rochester residents who had had only febrile convulsions or other convulsions associated with acute illnesses and 159 patients who had had only one seizure without an apparent cause. The METHODS patients we have included were followed The medical records linkage system of (through medical records and by follow-up the Mayo Clinic was used to identify all di- inquiries) from the date of diagnosis of
Received: August 10, 1979. Key words: Epilepsy-Prognosis-Remission-Relapse-Natural
729
history.
730
J . F. ANNEGERS ET A L .
epilepsy, which frequently was the time of a second seizure. For purposes of this study, remission of epilepsy was defined as a seizure-free period of 5 years. Accordingly, remission status could not be attained until 5 years or more after diagnosis. Relapse was defined as the occurrence of one or more seizures after a patient had entered remission status. We also considered the prospect for successful discontinuance of anticonvulsant medication in conjunction with remission of epilepsy. Of the 618 Rochester patients with epilepsy first diagnosed between 1935 and 1974, 93 died within 5 years of diagnosis, and 50 have been followed less than 5 years. Among the 475 cases followed at least 5 years, information concerning subsequent seizures and anticonvulsant medication was judged inadequate in 18 cases, which were excluded from this analysis. Thus, our study was concerned with 457 cases, of which 328 were followed at least 10 years and 141 at least 20 years. The net probabilities of remission have been determined by actuarial methods (Kaplan and Meier, 1958). Deaths without remission were treated as withdrawals from observation. The rate of remission during each year after diagnosis has been determined. The remission curves represent the cumulative effects of these rates. The results at each time interval after diagnosis represent the patients who survived to that time. Data on the following graphs will be presented for three separate remission criteria: (1) ever having achieved remission status, (2) being in remission at a particular time after initial diagnosis of epilepsy, and (3) being seizure-free and off medication for 5 years or more. The number of patients in each group is the number followed at least 5 years after diagnosis.
8o
r
Years after diagnosis FIG. 1. Remissions among all 457 cases. Remission ever: percentage of patients who achieved remission status. In remission: percentage who have been seizure-free during last 5 years or more. Without seizures or medication: percentage during last 5 years or more.
after diagnosis; the probabilities refer to completion of 5 consecutive seizure-free years. (Another interpretation may be based on subtraction of 5 years from each point on the time scale, which makes the ordinate correspond to the probability of entering a 5-year period free of seizures. For example, at 1 year after diagnosis, 42% of the eligible patients had entered a seizure-free period that was to extend for 5 years, and at 2 years 51% had entered.) The longer patients continued to have seizures after the date of initial diagnosis, the lower the probability of a subsequent remission. The estimates of prognosis for seizure remission apply only from time of diagnosis.
Remission of Epilepsy All Patients FINDINGS Among all 457 patients followed for 5 The prognosis for all patients is presented years or more, the estimated probability of in Fig. 1. The time scale begins at 5 years having achieved remission ( 5 consecutive Epilepsie, Vol. 20, December 1979
REMISSION A N D RELAPSE IN EPILEPSY
731
100seizure-free years) within 10 years after diagnosis was 65%, and within 20 years 76%. The net probability of being in remission currently (5 years or more, and continuing) 80 at 10 years after diagnosis was 61%, and at 20 years 70%. The difference, of course, was due to occurrences of relapse after 5C .$ year remission had been achieved. Both .? 60 curves became stable at 10 to 15 years after E e diagnosis, and the percentage of remission .E did not change between 20 and 30 years. The probability of being without seizures for 5 years while not taking anticonvulsant medication is represented by the lowest curve. The initial slope of this curve is much less than the slope for remission alone, but it continues to rise throughout the 20-year period. Thus, at 20 years after the initial diagnosis of epilepsy, approxi1 I I 10 15 20 mately 30% of patients continued to have Years after diagnosis seizures, approximately 20% continued to FIG. 2. Percentage in remission, by etiology. take anticonvulsant medication but had been free of,seizures for at least 5 years, and approximately 50% had been without years was 74% (Fig. 2). The 73 patients with seizures or anticonvulsant medication for at secondary epilepsy had slightly lower rates least 5 years. of remission in the early years, but eventually the prospects for remission among surAnalysis by Subgroups vivors became similar to those among the Within the epilepsy series, groups idiopathic patients. The 49 patients with categorized on the basis of etiology of sei- neurologic dysfunction from birth had only zures, seizure type, age at diagnosis, and sex had differing rates of remission. Etiology of epilepsy. According to pre6Or . sumed etiology, we classified the patients into three groups: (1) patients with idiopathic epilepsy or without a known pre- C disposing cause; (2) patients with second- .? u) 40ary epilepsy, i.e., those with central ner- .2 8 vous system lesions acquired postnatally t from trauma, brain tumors, cerebrovascu- .s lar disease, infection, or chronic degenera- c -secondary 5 seizures tion; and (3) patients with major neurologic or medication 5 seizures loL ---idiopathic dysfunction of uncertain cause but preor medication sumed to have been present at birth and -.-. neuro daficit F saizures medication manifested by gross neurologic deficit I I I (spasticity, hemiparesis) or mental retarda10 15 20 tion (IQ less than 70). Years after diagnosis For the idiopathic group of 335 patients, FIG. 3. Percentage in remission, by etiology and the probability of being in remission at 20 medication status. 00.
w
Epilepsia, Vol. 20, December 1979
732
J . F. ANNEGERS ET A L .
a 46% probability of being in remission at 20 years. The probability of being in remission without medication at 10 years after diagnosis was 36% in the idiopathic group, but less than 20% in the secondary group (Fig. 3). By 15 years after diagnosis, the probabilities rose to 42% for the idiopathic group and 30% for the secondary group; at 20 years it reached 47% for the idiopathic group and 54% for the symptomatic group. In contrast, the probability for patients with neurologic deficits to be seizure-free and off medication at 10 years after diagnosis was less than 15%, and only 30% were expected to achieve this status by 20 years after diagnosis. Seizure type. All patients were classified according to seizure type on the basis of clinical history (Hauser and Kurland, 1975). The 335 patients with idiopathic epilepsy included 33 with absence seizures (with or without generalized tonic-clonic seizures), 91 with generalized tonic-clonic seizures, 33 with myoclonic seizures, 111 with partial complex seizures, 56 with partial elementary seizures, and 11 with mixed types or unclassified seizures. Among the patients with idiopathic epilepsy, the remission rates were higher for those with generalized tonic-clonic seizures than for those with seizures focal at onset. At 20 years after diagnosis, the probability of being in remission was 85% for the subgroup with generalized tonic-clonic seizures and 80% for the subgroup with absence seizures (with or without tonic-clonic seizures), whereas for the patients with partial complex seizures the probability of being in remission was only 65% (Fig. 4). The probability of being in remission and being without medication at 20 years after diagnosis was greater than 50% for those with generalized-onset seizures, but only 35% for those with partial complex seizures. Age at diagnosis. Among the group with idiopathic epilepsy, younger patients were
Epilepsia, Vol. 20, December 1979
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I
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I 20
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FIG. 4. Percentage of idiopathic patients in remission, by seizure type and medication status.
more likely to become seizure-free (Fig. 5). At 10 years after diagnosis, the probability of being in remission was 75% for those whose epilepsy was diagnosed before 10 years of age, 68% for those with epilepsy diagnosed between ages 10 and 19 years, and 63% for those with diagnosis between ages 20 and 59 years. If we consider discontinuance of medication as well, remission differences by age group were even greater (Fig. 6). At 10 years after diagnosis, the probability of having had no seizure and no medication for at least 5 years was 51% for those with diagnosis before 10 years of age, 40% for those with diagnosis at aged10 to 19 years, 28% for those with diagnosis at ages 20 to 59 years, and only 6% for those with diagnosis at age 60 years or later. Age and seizure type. Remission curves for patients with idiopathic epilepsy, analyzed both by age group (under or over 20 years at diagnosis) and by seizure type (focal- or generalized-onset), are presented in Fig. 7. Among the group younger at diagnosis, those with focal-onset seizures had
733
REMISSION A N D RELAPSE IN EPILEPSY
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generalized group, the probability of being higher remission rates during the first few in remission at 20 years after diagnosis was years after diagnosis. However, because of better for those with generalized seizures. a low rate of late remissions in the focal Initial diagnosis after 20 years of age engroup and continuing remissions in the tailed a less favorable prognosis, but here, too, the patients with generalized seizures had considerably better prospects of eventual remission than did those with focal seizures. Sex. There was little difference in prospect for remission between males and females (Fig. 8). Females had slightly higher rates of remission of seizures in the early years following d'agnosis, but the I , probabilities of remissiO Jbecame similar in these two groups by 20 years after diagnosis. The difference in prospect of remission remains small when discontinuation of medication is included as a criterion. 0:
Period of Diagnosis To examine possible changes over time, I I I we subdivided the group of idiopathic pa10 15 20 tients by dates of diagnosis: 1935 through Years after diagnosis FIG. 6. Percentage of idiopathic patients seizure-free 1959 and 1960 through 1974. Between these subgroups, the difference in proportions of without medication for the 5 preceding years, by age.
Epilepsie, Vol. 20. December 1979
734
J . F. ANNEGERS ET AL.
1
I 15
I
5 6
10
20
Years after diagnosis FIG. 8. Percentage of idiopathic patients in remission, by sex and medication status.
patients experiencing remission of seizures was small. In the more recent subgroup, slight differences were found between 10 and 15 years after diagnosis, but the observation was based on few cases.
achieved remission status. Since we would expect only one new case of epilepsy to occur during this number of person-years of follow-up, virtually all of the recurrences were considered relapses. The mean annual incidence rate of relapse was 1.6%. Roughly two-thirds of the patients who experienced relapse were not taking anticonvulsant medication, but the relapses rarely occurred soon after discontinuance of such medication. The probability of a relapse in the first 5 years after entering remission status was 8%. It became 15% by the 10th year after remission and 24% by 20 years (Fig. 9). Among the patients with idiopathic seizures, the probability of relapse by 20 years was 6% for absence seizures, 21% for generalized tonic-clonic seizures, and 32% for partial complex seizures. The likelihood of relapse increased with advance in age at diagnosis (Fig. 10). The probability of relapse by 20 years after remission was 13% among those less than 9 years of age at diagnosis, 22% among those aged 10 to 19 years at diagnosis, and 32% among those over age 20 years at diagnosis.
Relapse Among our 305 patients who achieved DISCUSSION remission (followed up for a total of 2,750 Seizures are only one of many factors person-years), 45 had seizures after having that contribute to the overall morbidity in
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FIG. 10. Percentage of idiopathic patients suffering relapse after entry into remission status, by age.
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patients with epilepsy, but remission of seizures is the most obvious measure of the course of the disease. The attainment of total control of seizures is the object sought by most patients with epilepsy, and seizure control, combined with discontinuation of all anticonvulsant medication, is an endpoint suggesting total freedom from the epilepsy syndrome and its stigmata. Comparison with Other Reports The remission rates noted in our study were greater k t i m those usually reported by other authors, most of whom have said that approximately one-third of all patients enter remission of seizures. This holds true despite the fact that those studies (generally from neurologic clinics) have used a seizure-free interval of only 2 or 3 years as a criterion for remission and generally have disregarded medication status (Rodin, 1972).
In the present series, 70% of all patients followed up for 20 years were seizure-free for 5 years or more at that time, and 50% of the cohort had not taken medication for at least 5 years. There are several factors to account for this large discrepancy: Iength of :follow-up, case selection, and beginning the :assessment with new cases. Although the duration of patient
follow-up in our series was greater than in other series, this longer follow-up was only partially responsible for the higher remission rates. Although the probability of remission continued to increase for 15 years beyond diagnosis, patients who continued to have seizures (even if infrequently) 15 years after diagnosis seemed to have little chance of eventually achieving remission status. The present series of cases identified from the community included a wide variety of patients with epilepsy, from mild to most severe. Series from neurologic clinics are, unfortunately, weighted toward a less favorable prognosis. The most important factor is that the prognostic assessment began at the time epilepsy was diagnosed, frequently the time of a second seizure. Other studies have accepted patients later in the course of disease, after the annual rates of remission had diminished considerably. To illustrate, for all patients in our series the net probability of achieving remission within 10 years after diagnosis was 65%. However, for patients who were not in remission 5 years after diagnosis, the probability of achieving remission during the next 10 years was only 33%. And although it is impossible to establish selection factors important in referral to
Epilepsie, Yo/. 20, December 1979
736
J . F. ANNEGERS ET AL.
specialty clinics, such as those where other prognostic studies have been carried out, persistence of seizures over time must be one factor that would induce a general practitioner or pediatrician to relinquish care to a specialty clinic. The lower rate of remission among our patients with partial complex seizures may be related to a less complete identification of cases rather than to an actual difference in remission with this symptom complex. The interval between onset and diagnosis for patients with partial complex seizures usually was longer. Patients who have partial complex seizures for only 1 or 2 years without further symptoms may be missed in a study such as ours. Thus, the difference in prognosis for patients with partial complex seizures may be related to identification of those whose seizures are more severe or occur over a longer period. Comparison of Groups The similarity of remission curves for the groups with symptomatid and idiopathic epilepsy was surprising. One might think that individuals with identifiable cause for brain damage are more likely to have gross structural lesions and less likely to achieve ultimate resolution of symptoms from an epileptogenic focus than individuals without gross neurologic deficits. It is possible that epileptogenic foci tend to mature or “burn themselves out,” regardless of the underlying cause or presumed site of brain lesion. However, this comparison ignores the higher mortality among patients with secondary epilepsy. The prospects of both surviving and being seizure-free are considerably less for those with secondary epilepsy.
tory of the disease but also a reflection of medical practice, based on the physician’s prior concepts of the disease and on factors related to occupation and home environment. For example, clinicians are taught that certain types of seizures (particularly absence seizures and generalized tonicclonic childhood seizures) may remit. Therefore, the practicing physician may feel free to try withdrawal of medication in selected cases after puberty has been reached. This may explain, in part, why discontinuance of medication was more frequent among patients in whom the onset of seizures had occurred in childhood. Patients who may require chronic medication for other diseases (particularly the elderly) and patients who are handicapped by central nervous system disturbance and so are under close medical supervision may be less likely to discontinue anticonvulsant medication. Certainly elderly individuals who enter custodial care, for whatever reasons, have little likelihood for discontinuance of medication unless gross toxic side effects occur. This situation does not permit the attempts at self-regulation through which some independent patients achieve gradual reduction and discontinuance of medications without a physician’s advice.
Secular Change It has been suggested by some that the likelihood of remission of epilepsy has increased over the past few years (Okuma, 1978). Although our series does not seem to demonstrate this trend, many confounding factors must be considered. There may be a specific cohort effect. In the first 25 years, and the last I5 years, there may have been different (yet unidentified) mechanisms unDiscontinuance of Medication derlying the ‘‘idiopathic” seizure disorders Although adding discontinuance of medi- diagnosed. Other changes in the disease cation to freedom from seizures may be a may be occurring. Analysis for secular more exacting definition of remission, the changes has disclosed a decreasing incidata become difficult to interpret. Medica- dence rate for epilepsy in Rochester, partion is not only a factor in the natural his- ticularly for children, over the past 10 years
Epilepsia, Vol. 20, December 1979
REMISSION A N D RELAPSE IN EPILEPSY
(Hauser et al., 1977). If this is a real trend, the reduction in number of the cases with highest remission rates may produce a false picture of total remission rates unless age is taken into account. The incidence of epilepsy in the Rochester population has declined during the last 15 years of the study, and the number of patients with single seizures has increased. However, if treatment following an initial seizure prevents some patients from meeting our definition of epilepsy (i.e., having two or more seizures), some mild cases that would have qualified for inclusion in the earlier years may not have qualified in the later interval. The smaller proportion of mild cases during the last 15 years could be the reason for the lower rate of remission in the first year of eligibility in more recent years. ACKNOWLEDGMENTS
The authors wish to thank Mr. Charles S. Davis for his programming assistance and Ms Shirley A. Fortney for preparation of the manuscript. ,
REFERENCES Hauser WA, Annegers JF, and Kurland LT. Is the incidence of epilepsy declining? A m J Epidemiol 106:246, 1977 (abstract). Hauser WA and Kurland LT. The epidemiology of epilepsy in Rochester, Minnesota, 1935 through 1%7. Epilepsia 16: 1-66, 1975. Kaplan EL and Meier P. Nonparametric estimation from incomplete observations. J A m Sfafisfical ASSOC53:457-481, 1958. Okuma T. Natural history and prognosis of epilepsy. Presented at the 9th International Symposium on Epilepsy, Vancouver, September 12, 1978. Rodin EA. Medical and social prognosis in epilepsy. Epilepsia 13: 12 1 - 13 1, 1972.
&SUME A I'occasion d'une ttude longitudinale des malades tpileptiques de Rochester (Minesota) nous avons trouvt que la probabilitt d'une remission (au moins 5 anntes constcutives sans crises) 20 anntes aprks le diagnostic etait de 70%. Ce taux est plus Clevt que ceux prtctdemment rapportts. Nous pensons que le meilleurs pronostic dans notre strie tient A ce que nous avons inclus tous les cas incidents dans une population dtfinie, A partir du diagnostic initial d'tpi-
737
lepsie. Le pronostic concernant la remission est moins bon pour les patients qui prtsentent des troubles neurologiques associks d'origine obstktricale; il est meilleurs pour les patientsavec des crises idiopathiques ou ayant une tpilepsie acquise aprks la naissance. Ce pronostic est le meilleur pour les malades qui prtsentent des crises gkntralistes d'emblte diagnostiqutes avant I'tige de 10 ans ; il est moins favorables chez ceux qui prtsentent des crises partielles A stmiologie complexe et chez ceux dont I'tpilepsie est survenue A I'tige adulte. (J.-L. Gastaut, Marseilles)
RESUMEN En un estudio longitudinal de enfermos con epilepsia realizado en Rochester, Minnesota, encontramos que la probabilidad de estar en remisidn (por lo menos 5 ados consecutivos sin ataques y continuar asi), 20 ados despuds del diagndstico, era de un 70%. Las cifras de remisiones son generalmente m8s elevadas que las publicadas previamente. Pensamos que el mejor prondstico de nuestras series se basa en la inclusidn de todos 10s casos que inciden en una poblacidn definida desde el momento del diagndstico de epilepsia. El prondstico con respecto a la remisidn de la epilepsia es pobre en 10s pacientes con disfuncidn neuroldgica asociada identificada desde el nacimiento. Tienen mejor posibilidad de eventual remisi6n aquellos enfermos con ataques idioplticos y 10s supervivientes de epilepsia adquirida en el period0 postnatal. La mayor posibilidad de remisidn la tienen 10s enfermos con ataques de comienzo generalizado diagndsticados antes de 10s 10 ados. El prondstico es menos favorable en 10s que presentan ataques parciales complejos y epilepsia de comienzo en edad adulta. (A. Portera Sanchtz, kildrid)
ZUSAMMENFASSUNG In einer Langzeitstudie iiberpatienten mit Epilepsie in Rochester, Minnesota, fander wir daO die Wahrscheinlichkeit einer Remission (mindestens 5 und mehr Jahre Anfallsfreiheit) 20 Jahre nach der Diagnosestellung bei 70% lag. Die Remissionsrate lag allgemein hdher als in friheren Arbeiten angegeben wird. Wir glauben, da8 die bessere Prognose in unserer Gruppe dadurch zustande kommt, daO, bei einer definierten Population, alle Fllle mit dem Zeitpunkt der Diagnosestellung Epilepsie in die Studie aofgenommen wurden. Die Prognose bzgl. Anfallsfreiheit ist schlecht bei Patienten mit zusatzlich neurologischen Stdrungen, die seit Geburt bestehen. Sie ist besser bei Patienten mit idiopathischen Anfalen und bei ilberlebenden einer postnatal erworbenen Epilepsie. Die Wahrscheinlichkeit einer Remission ist besonders hoch bei Patienten mit generalisierten Anfalen, die vor dern 10. Lebensjahr diagnostiziert wurden. Weniger giinstig ist die Prognose bei Patienten mit partiellen Anfiillen rnit komplexer Symptomatik und Beginn im Erwachsenenalter. ( G . Mittermaier, Heidelberg)
Epilepsia, Vol. 20, December 1979
Raven Press, New York
Remission of Seizures and Relapse in Patients with Epilepsy *John F. Annegers, tW.Allen Hauser, and *Lila R. Elveback *Department of Medical Statistics and Epidemiology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55901; and ?Department of Neurology, Columbia University College of Physicians and Surgeons. New York, New York 10032
Summary: In a longitudinal study of patients with epilepsy in Rochester, Minnesota, we found that the probability of being in remission (at least 5 consecutive years seizure-free, and continuing) at 20 years after diagnosis was 70%. The rates for remission we encountered were generally higher than those previously reported. We believe that the better prognosis in our series results from inclusion of all incidence cases in a defined population, beginning at the initial diagnosis of epilepsy. Prognosis for remission of epilepsy is poor in patients with' associated neurologic dysfunction identified from birth. Patients with idiopathic seizures and survivors of postnatally acquired epilepsy have better prospects for eventual remission. The probability of remission is highest in patients with generalized-onset seizures diagnosed before 10 years of age. Prognosis is less favorable for those with partial complex seizures and adultonset epilepsy.
This study was concerned with three questions: (1) What are the chances that patients with epilepsy will have remissions of their seizures? (2) Does the likelihood of remission vary by seizure type, sex, age at onset, or predisposing cause? (3) What are the prospects for discontinuing anticonvulsant medication, as well as being seizurefree, sometime in the future? We attempted to answer these questions by a follow-up study of a cohort of patients with epilepsy.
agnosed cases of epilepsy in the population of Rochester, Minnesota. A total of 618 patients received their initial diagnoses of epilepsy while residents of Rochester between 1935 and 1974. All have had at least two seizures that did not seem to be provoked by an acute cause. Thus, this series excludes more than 1,OOO Rochester residents who had had only febrile convulsions or other convulsions associated with acute illnesses and 159 patients who had had only one seizure without an apparent cause. The METHODS patients we have included were followed The medical records linkage system of (through medical records and by follow-up the Mayo Clinic was used to identify all di- inquiries) from the date of diagnosis of
Received: August 10, 1979. Key words: Epilepsy-Prognosis-Remission-Relapse-Natural
729
history.
730
J . F. ANNEGERS ET A L .
epilepsy, which frequently was the time of a second seizure. For purposes of this study, remission of epilepsy was defined as a seizure-free period of 5 years. Accordingly, remission status could not be attained until 5 years or more after diagnosis. Relapse was defined as the occurrence of one or more seizures after a patient had entered remission status. We also considered the prospect for successful discontinuance of anticonvulsant medication in conjunction with remission of epilepsy. Of the 618 Rochester patients with epilepsy first diagnosed between 1935 and 1974, 93 died within 5 years of diagnosis, and 50 have been followed less than 5 years. Among the 475 cases followed at least 5 years, information concerning subsequent seizures and anticonvulsant medication was judged inadequate in 18 cases, which were excluded from this analysis. Thus, our study was concerned with 457 cases, of which 328 were followed at least 10 years and 141 at least 20 years. The net probabilities of remission have been determined by actuarial methods (Kaplan and Meier, 1958). Deaths without remission were treated as withdrawals from observation. The rate of remission during each year after diagnosis has been determined. The remission curves represent the cumulative effects of these rates. The results at each time interval after diagnosis represent the patients who survived to that time. Data on the following graphs will be presented for three separate remission criteria: (1) ever having achieved remission status, (2) being in remission at a particular time after initial diagnosis of epilepsy, and (3) being seizure-free and off medication for 5 years or more. The number of patients in each group is the number followed at least 5 years after diagnosis.
8o
r
Years after diagnosis FIG. 1. Remissions among all 457 cases. Remission ever: percentage of patients who achieved remission status. In remission: percentage who have been seizure-free during last 5 years or more. Without seizures or medication: percentage during last 5 years or more.
after diagnosis; the probabilities refer to completion of 5 consecutive seizure-free years. (Another interpretation may be based on subtraction of 5 years from each point on the time scale, which makes the ordinate correspond to the probability of entering a 5-year period free of seizures. For example, at 1 year after diagnosis, 42% of the eligible patients had entered a seizure-free period that was to extend for 5 years, and at 2 years 51% had entered.) The longer patients continued to have seizures after the date of initial diagnosis, the lower the probability of a subsequent remission. The estimates of prognosis for seizure remission apply only from time of diagnosis.
Remission of Epilepsy All Patients FINDINGS Among all 457 patients followed for 5 The prognosis for all patients is presented years or more, the estimated probability of in Fig. 1. The time scale begins at 5 years having achieved remission ( 5 consecutive Epilepsie, Vol. 20, December 1979
REMISSION A N D RELAPSE IN EPILEPSY
731
100seizure-free years) within 10 years after diagnosis was 65%, and within 20 years 76%. The net probability of being in remission currently (5 years or more, and continuing) 80 at 10 years after diagnosis was 61%, and at 20 years 70%. The difference, of course, was due to occurrences of relapse after 5C .$ year remission had been achieved. Both .? 60 curves became stable at 10 to 15 years after E e diagnosis, and the percentage of remission .E did not change between 20 and 30 years. The probability of being without seizures for 5 years while not taking anticonvulsant medication is represented by the lowest curve. The initial slope of this curve is much less than the slope for remission alone, but it continues to rise throughout the 20-year period. Thus, at 20 years after the initial diagnosis of epilepsy, approxi1 I I 10 15 20 mately 30% of patients continued to have Years after diagnosis seizures, approximately 20% continued to FIG. 2. Percentage in remission, by etiology. take anticonvulsant medication but had been free of,seizures for at least 5 years, and approximately 50% had been without years was 74% (Fig. 2). The 73 patients with seizures or anticonvulsant medication for at secondary epilepsy had slightly lower rates least 5 years. of remission in the early years, but eventually the prospects for remission among surAnalysis by Subgroups vivors became similar to those among the Within the epilepsy series, groups idiopathic patients. The 49 patients with categorized on the basis of etiology of sei- neurologic dysfunction from birth had only zures, seizure type, age at diagnosis, and sex had differing rates of remission. Etiology of epilepsy. According to pre6Or . sumed etiology, we classified the patients into three groups: (1) patients with idiopathic epilepsy or without a known pre- C disposing cause; (2) patients with second- .? u) 40ary epilepsy, i.e., those with central ner- .2 8 vous system lesions acquired postnatally t from trauma, brain tumors, cerebrovascu- .s lar disease, infection, or chronic degenera- c -secondary 5 seizures tion; and (3) patients with major neurologic or medication 5 seizures loL ---idiopathic dysfunction of uncertain cause but preor medication sumed to have been present at birth and -.-. neuro daficit F saizures medication manifested by gross neurologic deficit I I I (spasticity, hemiparesis) or mental retarda10 15 20 tion (IQ less than 70). Years after diagnosis For the idiopathic group of 335 patients, FIG. 3. Percentage in remission, by etiology and the probability of being in remission at 20 medication status. 00.
w
Epilepsia, Vol. 20, December 1979
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J . F. ANNEGERS ET A L .
a 46% probability of being in remission at 20 years. The probability of being in remission without medication at 10 years after diagnosis was 36% in the idiopathic group, but less than 20% in the secondary group (Fig. 3). By 15 years after diagnosis, the probabilities rose to 42% for the idiopathic group and 30% for the secondary group; at 20 years it reached 47% for the idiopathic group and 54% for the symptomatic group. In contrast, the probability for patients with neurologic deficits to be seizure-free and off medication at 10 years after diagnosis was less than 15%, and only 30% were expected to achieve this status by 20 years after diagnosis. Seizure type. All patients were classified according to seizure type on the basis of clinical history (Hauser and Kurland, 1975). The 335 patients with idiopathic epilepsy included 33 with absence seizures (with or without generalized tonic-clonic seizures), 91 with generalized tonic-clonic seizures, 33 with myoclonic seizures, 111 with partial complex seizures, 56 with partial elementary seizures, and 11 with mixed types or unclassified seizures. Among the patients with idiopathic epilepsy, the remission rates were higher for those with generalized tonic-clonic seizures than for those with seizures focal at onset. At 20 years after diagnosis, the probability of being in remission was 85% for the subgroup with generalized tonic-clonic seizures and 80% for the subgroup with absence seizures (with or without tonic-clonic seizures), whereas for the patients with partial complex seizures the probability of being in remission was only 65% (Fig. 4). The probability of being in remission and being without medication at 20 years after diagnosis was greater than 50% for those with generalized-onset seizures, but only 35% for those with partial complex seizures. Age at diagnosis. Among the group with idiopathic epilepsy, younger patients were
Epilepsia, Vol. 20, December 1979
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FIG. 4. Percentage of idiopathic patients in remission, by seizure type and medication status.
more likely to become seizure-free (Fig. 5). At 10 years after diagnosis, the probability of being in remission was 75% for those whose epilepsy was diagnosed before 10 years of age, 68% for those with epilepsy diagnosed between ages 10 and 19 years, and 63% for those with diagnosis between ages 20 and 59 years. If we consider discontinuance of medication as well, remission differences by age group were even greater (Fig. 6). At 10 years after diagnosis, the probability of having had no seizure and no medication for at least 5 years was 51% for those with diagnosis before 10 years of age, 40% for those with diagnosis at aged10 to 19 years, 28% for those with diagnosis at ages 20 to 59 years, and only 6% for those with diagnosis at age 60 years or later. Age and seizure type. Remission curves for patients with idiopathic epilepsy, analyzed both by age group (under or over 20 years at diagnosis) and by seizure type (focal- or generalized-onset), are presented in Fig. 7. Among the group younger at diagnosis, those with focal-onset seizures had
733
REMISSION A N D RELAPSE IN EPILEPSY
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generalized group, the probability of being higher remission rates during the first few in remission at 20 years after diagnosis was years after diagnosis. However, because of better for those with generalized seizures. a low rate of late remissions in the focal Initial diagnosis after 20 years of age engroup and continuing remissions in the tailed a less favorable prognosis, but here, too, the patients with generalized seizures had considerably better prospects of eventual remission than did those with focal seizures. Sex. There was little difference in prospect for remission between males and females (Fig. 8). Females had slightly higher rates of remission of seizures in the early years following d'agnosis, but the I , probabilities of remissiO Jbecame similar in these two groups by 20 years after diagnosis. The difference in prospect of remission remains small when discontinuation of medication is included as a criterion. 0:
Period of Diagnosis To examine possible changes over time, I I I we subdivided the group of idiopathic pa10 15 20 tients by dates of diagnosis: 1935 through Years after diagnosis FIG. 6. Percentage of idiopathic patients seizure-free 1959 and 1960 through 1974. Between these subgroups, the difference in proportions of without medication for the 5 preceding years, by age.
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J . F. ANNEGERS ET AL.
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patients experiencing remission of seizures was small. In the more recent subgroup, slight differences were found between 10 and 15 years after diagnosis, but the observation was based on few cases.
achieved remission status. Since we would expect only one new case of epilepsy to occur during this number of person-years of follow-up, virtually all of the recurrences were considered relapses. The mean annual incidence rate of relapse was 1.6%. Roughly two-thirds of the patients who experienced relapse were not taking anticonvulsant medication, but the relapses rarely occurred soon after discontinuance of such medication. The probability of a relapse in the first 5 years after entering remission status was 8%. It became 15% by the 10th year after remission and 24% by 20 years (Fig. 9). Among the patients with idiopathic seizures, the probability of relapse by 20 years was 6% for absence seizures, 21% for generalized tonic-clonic seizures, and 32% for partial complex seizures. The likelihood of relapse increased with advance in age at diagnosis (Fig. 10). The probability of relapse by 20 years after remission was 13% among those less than 9 years of age at diagnosis, 22% among those aged 10 to 19 years at diagnosis, and 32% among those over age 20 years at diagnosis.
Relapse Among our 305 patients who achieved DISCUSSION remission (followed up for a total of 2,750 Seizures are only one of many factors person-years), 45 had seizures after having that contribute to the overall morbidity in
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patients with epilepsy, but remission of seizures is the most obvious measure of the course of the disease. The attainment of total control of seizures is the object sought by most patients with epilepsy, and seizure control, combined with discontinuation of all anticonvulsant medication, is an endpoint suggesting total freedom from the epilepsy syndrome and its stigmata. Comparison with Other Reports The remission rates noted in our study were greater k t i m those usually reported by other authors, most of whom have said that approximately one-third of all patients enter remission of seizures. This holds true despite the fact that those studies (generally from neurologic clinics) have used a seizure-free interval of only 2 or 3 years as a criterion for remission and generally have disregarded medication status (Rodin, 1972).
In the present series, 70% of all patients followed up for 20 years were seizure-free for 5 years or more at that time, and 50% of the cohort had not taken medication for at least 5 years. There are several factors to account for this large discrepancy: Iength of :follow-up, case selection, and beginning the :assessment with new cases. Although the duration of patient
follow-up in our series was greater than in other series, this longer follow-up was only partially responsible for the higher remission rates. Although the probability of remission continued to increase for 15 years beyond diagnosis, patients who continued to have seizures (even if infrequently) 15 years after diagnosis seemed to have little chance of eventually achieving remission status. The present series of cases identified from the community included a wide variety of patients with epilepsy, from mild to most severe. Series from neurologic clinics are, unfortunately, weighted toward a less favorable prognosis. The most important factor is that the prognostic assessment began at the time epilepsy was diagnosed, frequently the time of a second seizure. Other studies have accepted patients later in the course of disease, after the annual rates of remission had diminished considerably. To illustrate, for all patients in our series the net probability of achieving remission within 10 years after diagnosis was 65%. However, for patients who were not in remission 5 years after diagnosis, the probability of achieving remission during the next 10 years was only 33%. And although it is impossible to establish selection factors important in referral to
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J . F. ANNEGERS ET AL.
specialty clinics, such as those where other prognostic studies have been carried out, persistence of seizures over time must be one factor that would induce a general practitioner or pediatrician to relinquish care to a specialty clinic. The lower rate of remission among our patients with partial complex seizures may be related to a less complete identification of cases rather than to an actual difference in remission with this symptom complex. The interval between onset and diagnosis for patients with partial complex seizures usually was longer. Patients who have partial complex seizures for only 1 or 2 years without further symptoms may be missed in a study such as ours. Thus, the difference in prognosis for patients with partial complex seizures may be related to identification of those whose seizures are more severe or occur over a longer period. Comparison of Groups The similarity of remission curves for the groups with symptomatid and idiopathic epilepsy was surprising. One might think that individuals with identifiable cause for brain damage are more likely to have gross structural lesions and less likely to achieve ultimate resolution of symptoms from an epileptogenic focus than individuals without gross neurologic deficits. It is possible that epileptogenic foci tend to mature or “burn themselves out,” regardless of the underlying cause or presumed site of brain lesion. However, this comparison ignores the higher mortality among patients with secondary epilepsy. The prospects of both surviving and being seizure-free are considerably less for those with secondary epilepsy.
tory of the disease but also a reflection of medical practice, based on the physician’s prior concepts of the disease and on factors related to occupation and home environment. For example, clinicians are taught that certain types of seizures (particularly absence seizures and generalized tonicclonic childhood seizures) may remit. Therefore, the practicing physician may feel free to try withdrawal of medication in selected cases after puberty has been reached. This may explain, in part, why discontinuance of medication was more frequent among patients in whom the onset of seizures had occurred in childhood. Patients who may require chronic medication for other diseases (particularly the elderly) and patients who are handicapped by central nervous system disturbance and so are under close medical supervision may be less likely to discontinue anticonvulsant medication. Certainly elderly individuals who enter custodial care, for whatever reasons, have little likelihood for discontinuance of medication unless gross toxic side effects occur. This situation does not permit the attempts at self-regulation through which some independent patients achieve gradual reduction and discontinuance of medications without a physician’s advice.
Secular Change It has been suggested by some that the likelihood of remission of epilepsy has increased over the past few years (Okuma, 1978). Although our series does not seem to demonstrate this trend, many confounding factors must be considered. There may be a specific cohort effect. In the first 25 years, and the last I5 years, there may have been different (yet unidentified) mechanisms unDiscontinuance of Medication derlying the ‘‘idiopathic” seizure disorders Although adding discontinuance of medi- diagnosed. Other changes in the disease cation to freedom from seizures may be a may be occurring. Analysis for secular more exacting definition of remission, the changes has disclosed a decreasing incidata become difficult to interpret. Medica- dence rate for epilepsy in Rochester, partion is not only a factor in the natural his- ticularly for children, over the past 10 years
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REMISSION A N D RELAPSE IN EPILEPSY
(Hauser et al., 1977). If this is a real trend, the reduction in number of the cases with highest remission rates may produce a false picture of total remission rates unless age is taken into account. The incidence of epilepsy in the Rochester population has declined during the last 15 years of the study, and the number of patients with single seizures has increased. However, if treatment following an initial seizure prevents some patients from meeting our definition of epilepsy (i.e., having two or more seizures), some mild cases that would have qualified for inclusion in the earlier years may not have qualified in the later interval. The smaller proportion of mild cases during the last 15 years could be the reason for the lower rate of remission in the first year of eligibility in more recent years. ACKNOWLEDGMENTS
The authors wish to thank Mr. Charles S. Davis for his programming assistance and Ms Shirley A. Fortney for preparation of the manuscript. ,
REFERENCES Hauser WA, Annegers JF, and Kurland LT. Is the incidence of epilepsy declining? A m J Epidemiol 106:246, 1977 (abstract). Hauser WA and Kurland LT. The epidemiology of epilepsy in Rochester, Minnesota, 1935 through 1%7. Epilepsia 16: 1-66, 1975. Kaplan EL and Meier P. Nonparametric estimation from incomplete observations. J A m Sfafisfical ASSOC53:457-481, 1958. Okuma T. Natural history and prognosis of epilepsy. Presented at the 9th International Symposium on Epilepsy, Vancouver, September 12, 1978. Rodin EA. Medical and social prognosis in epilepsy. Epilepsia 13: 12 1 - 13 1, 1972.
&SUME A I'occasion d'une ttude longitudinale des malades tpileptiques de Rochester (Minesota) nous avons trouvt que la probabilitt d'une remission (au moins 5 anntes constcutives sans crises) 20 anntes aprks le diagnostic etait de 70%. Ce taux est plus Clevt que ceux prtctdemment rapportts. Nous pensons que le meilleurs pronostic dans notre strie tient A ce que nous avons inclus tous les cas incidents dans une population dtfinie, A partir du diagnostic initial d'tpi-
737
lepsie. Le pronostic concernant la remission est moins bon pour les patients qui prtsentent des troubles neurologiques associks d'origine obstktricale; il est meilleurs pour les patientsavec des crises idiopathiques ou ayant une tpilepsie acquise aprks la naissance. Ce pronostic est le meilleur pour les malades qui prtsentent des crises gkntralistes d'emblte diagnostiqutes avant I'tige de 10 ans ; il est moins favorables chez ceux qui prtsentent des crises partielles A stmiologie complexe et chez ceux dont I'tpilepsie est survenue A I'tige adulte. (J.-L. Gastaut, Marseilles)
RESUMEN En un estudio longitudinal de enfermos con epilepsia realizado en Rochester, Minnesota, encontramos que la probabilidad de estar en remisidn (por lo menos 5 ados consecutivos sin ataques y continuar asi), 20 ados despuds del diagndstico, era de un 70%. Las cifras de remisiones son generalmente m8s elevadas que las publicadas previamente. Pensamos que el mejor prondstico de nuestras series se basa en la inclusidn de todos 10s casos que inciden en una poblacidn definida desde el momento del diagndstico de epilepsia. El prondstico con respecto a la remisidn de la epilepsia es pobre en 10s pacientes con disfuncidn neuroldgica asociada identificada desde el nacimiento. Tienen mejor posibilidad de eventual remisi6n aquellos enfermos con ataques idioplticos y 10s supervivientes de epilepsia adquirida en el period0 postnatal. La mayor posibilidad de remisidn la tienen 10s enfermos con ataques de comienzo generalizado diagndsticados antes de 10s 10 ados. El prondstico es menos favorable en 10s que presentan ataques parciales complejos y epilepsia de comienzo en edad adulta. (A. Portera Sanchtz, kildrid)
ZUSAMMENFASSUNG In einer Langzeitstudie iiberpatienten mit Epilepsie in Rochester, Minnesota, fander wir daO die Wahrscheinlichkeit einer Remission (mindestens 5 und mehr Jahre Anfallsfreiheit) 20 Jahre nach der Diagnosestellung bei 70% lag. Die Remissionsrate lag allgemein hdher als in friheren Arbeiten angegeben wird. Wir glauben, da8 die bessere Prognose in unserer Gruppe dadurch zustande kommt, daO, bei einer definierten Population, alle Fllle mit dem Zeitpunkt der Diagnosestellung Epilepsie in die Studie aofgenommen wurden. Die Prognose bzgl. Anfallsfreiheit ist schlecht bei Patienten mit zusatzlich neurologischen Stdrungen, die seit Geburt bestehen. Sie ist besser bei Patienten mit idiopathischen Anfalen und bei ilberlebenden einer postnatal erworbenen Epilepsie. Die Wahrscheinlichkeit einer Remission ist besonders hoch bei Patienten mit generalisierten Anfalen, die vor dern 10. Lebensjahr diagnostiziert wurden. Weniger giinstig ist die Prognose bei Patienten mit partiellen Anfiillen rnit komplexer Symptomatik und Beginn im Erwachsenenalter. ( G . Mittermaier, Heidelberg)
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