Epilepsy: A Comprehensive Textbook
2nd Edition
© 2008 Lippincott Williams & Wilkins
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Chapter 7
The Natural History and Prognosis of Epilepsy
Ettore Beghi
Josemir W. Sander
Introduction
For the majority of people with epilepsy, the condition is treatable and the term prognosis generally refers to the probability of attaining seizure freedom after treatment has been started, during treatment, and after drug withdrawal. Little is known about the natural history of the untreated condition as most patients, particularly in industrialized countries, are treated. There are only a few reports, mostly from resource-poor countries, on the prognosis of untreated epilepsy.
Methodologic Issues
As with most other chronic conditions, the prognosis of epilepsy depends on the characteristics of the population concerned, the case definition, the spectrum of severity of the condition, the duration of follow-up, and the choice of prognostic predictors, including treatment. More specifically, the design of an ideal study on the prognosis of epilepsy should include the following:
  • Well-defined criteria for the inclusion of patients.
  • Standard (homogeneous) definitions of the prognostic predictors and outcome measures.
  • Adequate duration of follow-up and proper statistical methods to adjust for those lost to follow-up and limited periods of observation.
Ideally, patients should be enrolled at a similar point in the course of the disease (e.g., the time of diagnosis or the time of the index event) and should be representative of the general population of people with epilepsy. Many patients do not seek medical advice until seizures have recurred; using these people as the population under study will exclude those who have had only one seizure and may well influence the prognosis. Additionally, most studies of the prognosis of epilepsy have been carried out in specialized services, generally including predominantly people with complex, difficult to control epilepsy; thus, selection bias may well affect the prognosis of epilepsy.
Homogeneous (preferably standard) definitions for the most common prognostic indicators should be encouraged. For example, there are inconsistent reports that a family history of epilepsy increases the risk of seizure recurrence; this may be explained by the fact that family history is difficult to ascertain and may be unreliable. Details should also be given of all the putative prognostic predictors considered, to provide a comprehensive overview of the prognosis of the disease and to give the best explanation of the results after controlling for the known prognostic indicators. Prolonged follow-up is required and attempts should be made to obtain information on the outcome in all patients. Outcome measures should be clearly defined and, where possible, reliable indicators should be used. Proper statistical methods (including multivariate analysis models) should be employed to assess the independent role of each prognostic predictor. Most of the differences among studies on the prognosis of epilepsy can be explained by the different methodology, with particular reference to the study design (retrospective or prospective; community based or specialized clinic based), the target population (children and/or adults), the timing of enrollment (interval between first seizure and enrollment), the type of seizure (generalized tonic and/or clonic, partial, and other), the length of follow-up, and the use of antiepileptic drugs.
Overall Prognosis of Epilepsy
The overall prognosis of epilepsy is favorable in the majority of patients. There are several pieces of evidence that support this conclusion. First, reports from several resource-poor countries (where people with epilepsy are largely untreated) give prevalence rates that tend to be broadly similar to those of industrialized countries.3,7,8,21,22,28,31,48,50,52,59,64,65,69,71 Prevalence rates for active epilepsy are usually between 4 and 10 per 1,000 in both settings. In most resource-poor countries the incidence of epilepsy is higher than that in industrialized countries.27,30,36,42,43,48,50 Incidence rates in developed countries tend to fall within the range of 30 to 60 cases per 100,000, while most reports from resource-poor countries give figures in excess of 70 per 100,000. The increased mortality of epilepsy in resource-poor countries explains only part of the difference between incidence and prevalence. The most likely explanation for the similarity of the prevalence rates, therefore, is spontaneous remission in some people. Additionally, contrary to old reports,49 studies done in newly diagnosed patients have consistently shown that 55% to 68% of cases achieve prolonged seizure remission (Table 1).35
Table 1 Population-based Studies on the Prognosis of Epilepsy
Country Population % (Duration) remission Source Follow-up (yr) Notes
United States All ages 55% (10-y) at 20 y Records linkage 33 Included isolated seizures
United Kingdom All ages 69% (5-y) at 9 y General practitioners 9 Included isolated seizures
Sweden Adults 58% (5-y) at 11 y Multiple 10 Included isolated seizures
France All ages 62% (complete) at 5 y Neurologists 5 Included isolated seizures
Switzerland All ages 68% (complete) at 10 y Neurologists 10 Included isolated seizures
Ecuador All ages 21% (complete) at 4 y Hospitals 4 Only two or more seizures
Holland Children 62% (2-y) at 5 y Hospitals 5 Included isolated seizures
Canada Children 55% (complete) at 7 y (average) Child neurologists >20 Included isolated seizures
Finland Children 68% (5-y) at 30 y Multiple >30 Only two or more seizures
Source: Jallon P. In: Jallon P, Berg AT, Dulac O, et al., eds. Prognosis of Epilepsies. Montrouge: John Libbey; 2003.
Early Prognosis of Unprovoked Seizures and Epilepsy
Prognosis after the First Unprovoked Seizure
The risk of relapse after a first unprovoked seizure has been reported to range from 23% to 71%5 and from 14% to 68% when actuarial methods are used. The rates at 2 and 5 years are 21% to 69% and 34% to ≥71%, respectively. Population-based studies2,29 provide more homogeneous relapse rates at 1 (36% to 37%) and 2 years (43% to 45%). In a systematic review of 16 reports,11 the average overall recurrence risk was 51% (95% confidence interval [CI], 49% to 53%). By 2 years, the recurrence risk was 36% and 47% in prospective and retrospective studies, respectively. After a first unprovoked seizure, the probability of a relapse decreases with time; about
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50% of recurrences occur within 6 months of the initial seizure and 76% to 96% within 2 years.11
Risk Factors for Relapse of a First Unprovoked Seizure
The two most consistent predictors of recurrence are a documented etiology of the seizure (as opposed to idiopathic or cryptogenic seizures) and an abnormal (epileptiform and/or slow) electroencephalogram (EEG) pattern.11 The pooled recurrence risk in patients with an idiopathic or cryptogenic first seizure is 32% (95% CI, 28% to 35%), compared with 57% (95% CI, 51% to 63%) for a remote symptomatic seizure (i.e., a seizure with an underlying, nonacute brain problem). The recurrence risk ranges from 27% (95% CI, 21% to 33%) with a normal EEG tracing to 58% (95% CI, 49% to 66%) with an EEG showing epileptiform abnormalities. Epileptiform abnormalities tend to be associated with a higher risk of seizure recurrence than do nonepileptiform abnormalities. The pooled 2-year recurrence risk is lowest for an idiopathic or a cryptogenic first seizure with a normal EEG (24%; 95% CI, 19% to 29%), intermediate for a remote symptomatic seizure (48%; 95% CI, 34% to 62%) with normal EEG or an idiopathic/cryptogenic seizure with an abnormal EEG (48%; 95% CI, 40% to 55%), and highest with a remote symptomatic seizure with an abnormal EEG (65%; 95% CI, 55% to 76%). Seizures occurring during sleep tend to be associated with a higher risk of recurrence in both children and adults.34,57,68 Partial seizures, which are usually associated with a documented brain injury, are also correlated with a higher risk of recurrent seizures, even after controlling for etiology and EEG abnormalities.2,15 A positive correlation between seizure relapse and family history of seizures has only been confirmed in patients with idiopathic or cryptogenic first seizures in one study.33 A history of prior acute symptomatic seizures has occasionally been found to increase the risk of relapse, while evidence is inconclusive or lacking for sex, age, and presentation with status epilepticus.11
Treatment, Risk of Recurrence, and Long-term Prognosis of a First Seizure
There are at least five published randomized studies assessing the effects of treatment of the first unprovoked seizure.16,20,23,25,44,46 The results of these studies consistently show that treatment of the first seizure seems to reduce the risk of short-term relapse but is apparently ineffective on the chance of long-term seizure remission. A large multicenter Italian trial23 (the FIRST study) of 397 children and adults was conducted to assess the effectiveness of treatment of the first seizure on the risk of relapse and the long-term prognosis of epilepsy. Patients seen within 7 days after a first witnessed unprovoked tonic–clonic seizure with or without partial onset were randomized to be treated or to be left untreated until the time of a second seizure. The mean period of observation was 274 days in patients given immediate treatment and 309 days in patients who did not receive treatment. Overall, 36 of 204 treated patients and 75 of 193 untreated patients were referred for seizure relapse. In this trial, the cumulative time-dependent risk of recurrence in treated patients was 17% at 12 months and 25% at 24 months, and in untreated patients was 41% and 51%, respectively. The differences tended to disappear, however, when the end-point was the chance of initiating a 2-year remission. The cumulative probability of long-term remission in the two treatment groups tended to be similar from the second year of follow-up until 15 years after randomization.41a The results of this study were confirmed by an even larger pragmatic randomized European trial (the MESS study) comparing immediate and deferred treatment for early epilepsy and single seizures.44 Patients aged at least 1 month were randomized if both the clinician and the patient were uncertain whether to proceed with treatment. In this trial, 722 patients were randomized to immediate treatment and 721 to deferred treatment. Of these, 404 and 408, respectively, had a single seizure at randomization. Immediate treatment prolonged the time to the first relapse (risk ratio [RR] 1.5; 95% CI, 1.2 to 1.8) and increased the proportion of patients achieving immediate 2-year remission (64% vs. 52%) (p = 0.023). However, at the 2-year follow-up, 32% of those with immediate treatment had had a recurrence compared with 39% of those with deferred treatment. In addition, 92% versus 92% patients achieved 2-year remission at 5 years and 95% versus 96% at 8 years, respectively. The results of these trials tend to confirm several observational reports that the long-term prognosis of the first seizure is substantially unaffected by immediate treatment. However, the comparative effects of the treatment of the first seizure and treatment only on relapse on the chance of long-term remission (without drugs) have not yet been assessed.
Prognosis of Untreated Epilepsy
With one exception,37 the prognosis of untreated epilepsy has been assessed only in resource-poor countries where epilepsy is
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largely untreated (treatment gap ranging from 70% to 94%). In a population-based study conducted in Ecuador,48 the cumulative annual incidence rate was 190 per 100,000 and the prevalence rate of active epilepsy was 7 per 1,000, which implies a remission rate of at least 50%. Similar prevalence rates of active epilepsy (5 per 1,000) were found in Nigeria,47 where only 4% of patients were treated at the time of the survey, and in Ethiopia.65 In a smaller study conducted in Malawi,70 duration of active epilepsy was similar to that of industrialized countries. All these findings lend support to the hypothesis that spontaneous remission of untreated epilepsy is a common event. In a field study conducted in Warsaw in the 1970s, almost one third of those who had never been treated, including some who had previously had frequent generalized seizures, had been free of seizures for more than 5 years.72 A small study in Finland, conducted in those with untreated epilepsy, found the probability of remission to be 42% by 10 years after the onset of epilepsy.37
Prognosis of Newly Diagnosed Epilepsy
In industrialized countries treatment of epilepsy is generally started at the time of diagnosis, which is not usually made until at least two unprovoked seizures have occurred. In fact, after a second unprovoked seizure the risk of a third seizure has been estimated as 73%, and after a third seizure the risk of a fourth seizure has been estimated as 76%.32 Population-based studies on the long-term prognosis of treated epilepsy report a 58% to 65% cumulative 5-year remission rate at 10 years.1,18 This number rises to about 70% by 20 years following seizure onset.1 The 5-year remission rate at 10 years is 61% in adults41 and the 3- to 5-year remission rate at 12 to 30 years in children is 74% to 78%.24 In a Finnish cohort of patients with childhood-onset epilepsy, after over 30 years of follow-up 64% of cases were in 5-year terminal remission, of whom 74% were off medications.60
Principal Prognostic Predictors
The etiology of the epilepsy is by far the strongest prognostic predictor for seizure recurrence. In general, idiopathic epilepsy has a better chance of seizure remission than symptomatic or cryptogenic epilepsy. In the population-based study from Rochester, Minnesota, people with symptomatic epilepsies were found to have a significantly lower chance of 5-year remission than those with idiopathic epilepsies (30% vs. 42% at 15 years).1 Within the group of those with symptomatic epilepsies, patients with neurologic dysfunction present at birth had the lower chance of remission (46% and 30% off drugs at 20 years). Lower, albeit less significant, remission rates in patients with symptomatic epilepsies were also found in the United Kingdom, Sweden (adults), and Finland (children).35 A documented etiology of epilepsy has also been found to be a significant predictor of seizure intractability in childhood-onset epilepsy.62 In the Connecticut study of childhood-onset epilepsy, early predictors of intractability included known etiology, high initial seizure frequency, and focal EEG slowing.9 Other prognostic indicators of 5-year remission in the Rochester, Minnesota, population included absence of EEG epileptiform abnormalities (odds ratio [OR] 1.6) and absence of generalized tonic–clonic seizures.55 In the UK National General Practice Study of Epilepsy (NGPSE), the only independent predictor of 1-year and 2-year remission was the number of seizures experienced by the patient in the 6 months after the first seizure.18,43 When other prognostic predictors are taken into consideration, there is no evidence that age at onset of seizures affects seizure outcome. With the exception of epilepsies associated with rare inherited sex-linked disorders, sex has not been indicated as a significant prognostic predictor.
Prognosis of Epilepsy Syndromes
An epileptic syndrome is a symptom complex that is characterized by a fairly uniform clinical and electrographic picture. In addition to seizure type, defining features of epileptic syndromes also include family history, age at onset, presumed etiology, and EEG and neuroimaging findings.19 To some extent, particularly in children, different epileptic syndromes have various and sometimes distinct outcomes and responses to treatment. It has been suggested52 that epilepsy syndromes can be classified into four prognostic groups:
  • Excellent prognosis (about 20% to 30% of the total) with high probability of spontaneous remission: These include neonatal seizures, benign partial epilepsies, benign myoclonic epilepsy in infancy, and epilepsies provoked by specific modes of activation.
  • Good prognosis (about 30% to 40%) with easy pharmacologic control and possibility of spontaneous remission: These include infantile absence epilepsy, epilepsies with generalized tonic–clonic seizures secondary to specific conditions, and some partial epilepsies.
  • Antiepileptic drug–dependent prognosis (about 10% to 20%), which may respond to drugs, but tend to relapse after treatment withdrawal: These include juvenile myoclonic epilepsy and most partial epilepsies (symptomatic or cryptogenic).
  • Guarded prognosis (about 20%) in which seizures tend to recur despite intensive treatment: These include epilepsies associated with congenital neurologic defects, progressive neurologic disorders, and some symptomatic or cryptogenic partial epilepsies.
The prognosis of specific epilepsy syndromes may be significantly different and reflects, at least in children, the inherent severity of epilepsy more than the quality of the therapeutic approach.58
Antiepileptic Drugs and Seizure Outcome
Antiepileptic drugs (AEDs) are often successful in suppressing seizures, but they do not seem to alter the long-term prognosis of epilepsy. In addition, in the FIRST and MESS studies44,46 there was evidence of less than optimal outcome of seizures in about 20% of patients with newly diagnosed epilepsy.
There are virtually no reports on the comparative efficacy of old and new AEDs on the long-term outcome of epilepsy, and there is no evidence to suggest that the newer medications are more efficacious.4,40 Although individuals seem to present differing responses to the available drugs, all first-line AEDs seem to be equally effective at a community level. In a single-center hospital-based study of 470 patients diagnosed, treated, and followed for a mean period of 5.6 years, 47% of cases became seizure free with the first prescribed drug.39 There was no significant difference in the proportion of cases with inadequate seizure control among those treated with carbamazepine, valproate, or lamotrigine. The majority of seizure-free patients required only a moderate daily dose of AED.
Prognosis of Epilepsy after Treatment Withdrawal
A long-term population-based study has shown that 5-year terminal remission of epilepsy (without drugs) is 61%.1
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Discontinuation of drug treatment is thus a valuable option in patients with epilepsy who are seizure free for 2 years or longer. In a critical review of 28 studies accounting for 4,615 cases, most of whom had at least 2 years of seizure remission, the proportion of patients with relapses during or after treatment withdrawal ranged from 12% to 66%.63 Using life-table analysis, the cumulative probability of remaining seizure free in children was 66% to 96% at 1 year and 61% to 91% at 2 years. The corresponding values in adults were 39% to 74% and 35% to 57%, respectively. The relapse rate was highest in the first 12 months (especially in the first 6 months) and tended to decrease thereafter. In a meta-analysis of 25 studies, the pooled relapse risk was 25% (95% CI, 21% to 30%) at 1 year and 29% (95% CI, 24% to 34%) at 2 years.10
In the only randomized trial on the effects of AED withdrawal on seizure relapse, 22% of patients randomized to continued treatment had relapsed by 2 years, while 41% of patients randomized to slow drug withdrawal had relapsed.45 This differential risk of relapse was maximal between 1 and 2 years and declined thereafter. After 2 years, the risk of subsequent relapse was the same for both treatment groups. The risk of recurrence was also similar in patients who relapsed after withdrawal of AEDs and in those who relapsed while remaining on treatment.17
Factors Predicting Seizure Relapse after Treatment Withdrawal
A number of factors have been associated with favorable or unfavorable seizure outcome after treatment discontinuation. Factors consistently indicating a higher-than-average risk of seizure relapse include adolescent-onset epilepsy, partial seizures, presence of an underlying neurologic condition, and abnormal EEG findings (in children). Factors associated with a lower-than-average risk were childhood-onset epilepsy, idiopathic generalized epilepsy, and (in children) normal EEG. Selected epilepsy syndromes (e.g., benign epilepsy with centrotemporal spikes and juvenile myoclonic epilepsy) may be associated with significantly different outcomes after treatment withdrawal.63 In the Medical Research Council AED withdrawal study, independent predictors of relapse included history of partial seizures, primarily or secondarily generalized tonic–clonic seizures, or myoclonic seizures; use of more than one AED; seizures after treatment start; and a shorter seizure-free period at randomization.45 In a meta-analysis of 25 studies, those with adolescent age at onset of seizures had a 1.34-fold increased risk of relapse (95% CI, 1.00 to 1.81) compared with those with adult age at onset.10 Patients with remote symptomatic seizures had a 1.55-fold increased risk of relapse (95% CI, 1.21 to 1.98). An abnormal EEG prior to drug discontinuation was associated with a 1.45-fold increased risk of relapse (95% CI, 1.18 to 1.79). In the same review, prognosis following drug withdrawal was similar whether a 2-year or a 4-year seizure-free interval was considered. Additionally, a randomized trial comparing a 6-week taper with a 9-month taper after 2-year seizure remission in children with epilepsy showed no difference in recurrence risk at 2 years.66
Psychosocial Outcome
People with epilepsy are more likely to be unemployed than people in the general population, with unemployment rates ranging from 24% to 36%.51 In a population-based study of adults who had childhood-onset epilepsy, independent predictors of low socioeconomic status included poor fine-motor performance (OR 14.8), poor short-term outcome after treatment (OR 9.8), and presence of psychoneurotic symptoms (OR 3.2).61 In that study, 15% required little assistance in daily living activities and about 50% were socially disabled, of whom 60% had moderate to severe handicap. School achievement in children and adolescents with epilepsy is lower than that in the general population. Low achievement may occur even when epilepsy is not associated with other neurologic sources of impairment.41 A lower intellectual level is the most likely explanation for underachieving at school. Learning disabilities and cognitive dysfunction are commonly reported in children with epilepsy.13 Factors associated with underachieving at school include epilepsy, use of AEDs, and psychosocial factors. The strongest independent predictors of underachieving at school include early onset of seizures and cumulative number of seizures.54 Alteration of cognition might reflect a chronic adverse effect of AEDs, but the negative effects of the drugs are only one of several factors that may influence cognition. In addition, subjective complaints of cognitive deficits (e.g., memory problems or attention) may also reflect aspects of adverse effects other than those concerning specific cognitive functions (e.g., mood and anxiety).14 Although intuitive, the correlation between underachieving at school and psychosocial factors is not supported by studies with robust methodology.
Lower rates of marriage and fertility (even after adjustment for marriage) have also been reported in people with epilepsy when compared with the general population.53 Several sociocultural limitations may explain the lower likelihood of marriage in the presence of epilepsy. Although adverse treatment effects may be implicated, the cause of decreased fertility remains unclear.
In the absence of seizures (with or without treatment), the risk of accidents and injuries is clearly decreased compared with those with ongoing seizures, and tends to be close to that of the general population.38,67 In a multicenter cohort study conducted in six western European countries (Italy, Germany, England, Holland, Spain, and Portugal) and three eastern European countries (Russia, Estonia, and Slovenia), 951 children and adults with early idiopathic, cryptogenic, or remote symptomatic epilepsy and 909 matched controls were followed prospectively for 17,484 and 17,206 person-months, respectively.6,67 Two hundred and seventy accidents were reported by 199 people with epilepsy (21%) compared with 149 accidents reported by 124 controls (13%). About one quarter of accidents in people with epilepsy were seizure related. The most common accidents in people with epilepsy were, in decreasing order of frequency, contusions, wounds, fractures, abrasions, and brain concussions. Contusions followed by wounds and sprains or strains predominated in the controls. In people with epilepsy, about one third of brain concussions, contusions, and fractures were seizure related compared with one fifth of burns and less than one sixth of wounds. Most accidents occurred at home, followed by traffic, sports and other leisure activities, work, and school. About one half of domestic accidents were seizure related. About one third of school accidents and one quarter of traffic accidents were seizure related. Apart from brain concussions, accidents occurring both in patients with epilepsy and in nonepileptic controls were mostly trivial. The proportion of road accidents attributable to seizures in people with active epilepsy is extremely low, ranging from 0.02% to 0.2%.12,56
Summary and Conclusions
In the past, studies from tertiary referral centers offered a picture of epilepsy as a chronic, progressive, unremitting disorder.26,49 Epidemiologic evidence indicates that the poor prognosis observed in earlier studies was largely the result of selection bias. More recently, the results of epidemiologic studies and randomized clinical trials have greatly changed our
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understanding of the nature and natural history of seizures and of epilepsy. On this basis, one can assume that epilepsy is a fairly benign condition in the majority of cases, with a good prognosis for seizure control and, ultimately, discontinuation of AEDs. However, epilepsy is a heterogeneous clinical condition and many different syndromes have been recognized. The outcome is determined to some extent by the type of epilepsy. Factors influencing the prognosis of epilepsy include etiology, EEG abnormalities, presence of generalized tonic–clonic seizures, the number of seizures experienced after the onset of treatment, and the syndromic pattern. Antiepileptic drugs are successful in suppressing seizures, but do not alter the long-term prognosis of epilepsy. The available compounds seem to be equally effective, about 50% of patients being satisfactorily controlled by the first drug, given as monotherapy. In contrast to the medical prognosis, the psychosocial prognosis of epilepsy is at best fair, reflecting the negative aspects of the disease on the daily living activities and the quality of the patient’s life. The heterogeneous spectrum of the disease, the adverse treatment effects, and stigma may all concur in affecting the psychosocial outcome of epilepsy.
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