Highlights
- •Two of three patients or more will enter long-term terminal remission.
- •One half will be in remission, one fifth is drug resistant, and one third has a fluctuating course.
- •Changes for social integration and competence are almost comparable with healthy peers.
- •Yet epilepsy has a far-reaching and significant impact on later life.
Abstract
Purpose
To review the long-term outcome of epilepsy in population-based studies.
Method
Analysis of population-based studies.
Results
About two of three patients with new-onset epilepsy will, in the long run, enter five-year terminal remission. Chances for remission are best for those with idiopathic or cryptogenic epilepsy. It is unclear whether the seizure outcome has improved over the last several decades. Social outcome, however, may have become better because of the improved level of knowledge on and public attitudes toward people with epilepsy, and possibly fewer prejudices at home, daycare, school, military and labor market.
Conclusion
While we still do not have a cure for epilepsy for all patients, relief of the medical and social consequences is available for many and hope is on the horizon for people with epilepsy.
Keywords
1. Introduction
The first attempts, in a modern sense, to explore the medical and social outcome of patients with epilepsy were made in the 1950s [
[1]
] and 1960s [] based on patients from hospitals and other institutions. According to those studies and the previous literature from 1901 to 1964 discussed by Rodin [], the five-year terminal remission varied by etiology between 15 and 30%. Yet, studies based on unselected population cohorts are needed to get unbiased and valid data on this chronic disorder. The data are important for the treating doctor, but have usually have also many medical and social implications for the patients and society. The first population-based study, the Rochester Study [[3]
], designed as a record linkage system and linking on one record clinical data derived 1935–1967 from inpatient, outpatient, emergency room contacts and home visits by health professionals at the Mayo Clinic. In long-term follow-up, 40% had entered terminal 5-year remission [[3]
]. In more recent population studies, about two thirds were in 5-year terminal remission [4
, 5
, 6
, 7
]. The improved prognosis can be ascribed, among other things, to advanced externally valid study populations, diagnostic methods and therapeutic armament [5
, 8
, , 10
]. Only a few long-term (more than 10 years), prospective unselected population-based cohort studies have been reported [4
, 5
, 6
, 8
, 11
, 12
, 13
]. The review and discussion of the present paper is mainly, but not only, focused on the contribution of population-based reports.2. Prospective cohort studies
2.1 Population-based long-term studies [11, 12]
The recruitment of study subjects of Brorson [
[11]
] was from the Swedish province of Uppsala (total population of 0–19 years of age, n = 54,000) including general and epilepsy hospital inpatients and outpatients and clients from provincial medico-social board and special school registers, and the EEG laboratory of the university hospital of Uppsala. Excluded were patients with neonatal seizures during the three first days of life; provoked seizures; unprovoked non-convulsive epileptic attacks; and potential study subjects not medically treated for epilepsy. The baseline study sample included 195 children and adolescents aged 0–19 years who had had at least one provoked seizure in 1961–1964 and were thus considered as having active epilepsy. The study is apparently population-based. The baseline paper is a survey reported in Swedish by the national Social Board of Sweden in 1970 and not easily accessible. The prevalence was estimated as 3.5/1000 and the mean annual incidence 50/100,000. On 12-year follow-up [[6]
], 124 (64%) were in 3-year terminal remission.In the Turku study [
[12]
], recently re-named as the Turku Adult Childhood Onset Epilepsy (TACOE) study, the source population consisted of children aged 15 years or less who were living in the catchment area of Turku University Hospital at the end of 1964 (n = 108,019), and had unprovoked seizures [[14]
]. Epilepsy was defined as repeated, unprovoked seizures 24 h apart at the age of 4 weeks to 15 years. Epileptic seizures and syndromes were later re-classified [[15]
] to be in line with the update ILAE definitions [16
, 17
, 18
]. Active epilepsy was defined as onset of epilepsy in 1961–1964 or one or more unprovoked seizures in a child with the diagnosis of epilepsy ascertained before 1961. Children with epilepsy were identified by reviewing the files from the following data sources: inpatient and outpatient clinical and EEG records of hospitals and institutions for mentally retarded or cerebral palsy in the catchment area of Turku University Hospital and any hospitals or institutions the whole southern Finland potentially treating or having treated children with epilepsy; special schools in the area; and community general practitioners’ offices and private offices’ records. Finally, the National Health Service Register data of refundable antiepileptic drugs for epilepsy (but not for other indications) could be reviewed by permission of the public authorities. That method of approach detected five cases not earlier identified, but then proven to fulfill the inclusion criteria. Thus, the enrolment of the subjects was not only based on hospital and institution records, but any public or private health units and, to be on the safe side, on the review of all subjects in the study area who got fully reimbursed antiepileptic drugs for the treatment of epilepsy. The special school and community and private office records did not virtually contribute to the data collection, because all the relevant cases had been identified by the hospital records. This was not unexpected, because there was and still is a rule in Finland that every child with an epileptic or suspected epileptic seizure should be referred to hospital with pediatric or child neurological expertise [5
, 19
]. Access to board-certified pediatrician became possible all over the country since the 1950s to 1960s, when the countrywide network of tertiary care hospitals with pediatric departments was built and enabled specialist care for children despite the place of residence in Finland []. The registers of the national social security institution, based on the legislation largely copied form the British national health service, effective since 1964, has been proved to be a reliable source of data for research purposes in many reports [21
, 22
, 23
, 24
].The review of all the above mentioned records including EEG statements was made by one child neurologist (M.S.) who also clinically examined all the 245 children who were ascertained as children with epilepsy. One hundred and fifty children were ascertained as incident cases, that is, they were first evaluated for epilepsy in 1961–1964. The remaining 95 patients were diagnosed as prevalent cases, whose diagnosis of epilepsy was made before 1961, but who had one or more unprovoked seizure during 1961–1964 [
5
, 12
]. In addition to the reviewed records, EEG and clinical neurological examination data, additional EEG and neuroimaging investigations were performed on clinical grounds, if needed. Ongoing surveillance after the baseline study detected only very few children who fulfilled the inclusion criteria and should have been considered in an epidemiological analysis. On 35-year follow-up, 67% were in five-year remission [5
, 25
].2.2 Community based study [[10]]
The British national general practice study of epilepsy (NGPSE), with the study subjects followed for 25 years [
[26]
], was based on a surveillance process with 275 general practitioners (GPs) recruiting al patients of different ages who had any definite or possible new-onset epileptic seizures during 1984–1987. The method of recruiting patients only covered those living in the community. Subsequently, patients who resided in institutions (institutions for mentally retarded, nursing homes or prisons) were excluded. However, institutions for patients who have epilepsy do exist in the UK [27
, 28
], and it is well-known that institutionalized patients, and those with mental comorbidity in particular, are at markedly higher risk of epilepsy than those living in the community; percentages between 25 and 40% [29
, 30
, 31
, 32
] have been reported. The enrolment method per se then excludes institutionalized patients, because they are virtually invisible to GPs. An obvious weakness in GP-based inclusion method is external and internal validity [[33]
], among other things, over-diagnoses and under-diagnoses [34
, 35
]. A study from Glasgow, UK, found that 799 (69%) of 1156 adults with a diagnosis of epilepsy had never attended local epilepsy clinic and 55% of the population on antiepileptic medication had never received specialist advice [[33]
]. The problem concerns also children with epilepsy in the UK [, 37
]. The study comprised 302 patients with a single unprovoked seizure at presentation and 354 patients with epilepsy (two or more unprovoked seizures) at presentation. In 318 patients, 73% were in 5-year terminal remission at the end of follow-up and 80% in those who could be followed up to the last contact. The 73% is probably calculated up to the last contact or death, whichever came first, and the comparable with the previous studies.Overall, approximately two thirds are in terminal remission (Table 1).
Table 1Five-year terminal remission (5-YTR) reported from population-based and institution-based long-term studies. I = incident cases; P = prevalent cases.
| Study design | Duration of follow-up (years) | 5-YTR (%) on or off medication | Author(s) and year |
|---|---|---|---|
| Population-based, prospective studies | |||
| I&P (n = 227) | 10 | 56 | Sillanpää, 1983 |
| I&P (n = 178) | 20 | 58 | Sillanpää, 1990 |
| I&P (n = 220) | 30 | 64 | Sillanpää et al., 1998 |
| I%P (n = 220) | 40 | 61 | Sillanpää et al., 1998 |
| I (n = 144) | 40 | 67 | Sillanpää et al., 2006 |
| Surviving I&P (n = 133) | 45 | 70 | Sillanpää et al., 2015 |
| Cases with one or more, probably unprovoked seizures (n = 228) | 22 | 68 | Cockerell et al., 1997 |
| Population-based, retrospective studies | |||
| I (n = 475) | 10 | 65 | Annegers et al., 1979 |
| I (n = 141) | 20 | 70 | Annegers et al., 1979 |
| Hospital-based cohort studies | |||
| I (n = 730) | 10 | 79 | Oka et al., 1989 |
| I&P (n = 141) | 10 | 52 | Wakamoto et al., 2000 |
| I&P (n = 75) | 20 | 56 | Wakamoto et al., 2000 |
| I (n = 413) | 15 | 71 | Geerts et al., 2010 |
| I (n = 516) | 21 | 60 | Berg and Rychlik, 2015 |
2.3 Hospital-based studies
Hospital-based studies are, mainly due to their easier feasibility, much more common than population studies. Typically, the hospital studies rely on inpatient and outpatients of one tertiary care hospital. Even in case of multi-institutional recruitment of study subjects, they are approximations of the real prevalence and incidence, because those studies are subject to selection bias and, subsequently, a weak external validity. The risk of a selection bias is still higher, if the study population is based on one laboratory clients. In such a study, no more than 86% of regional physicians indicated they use to order an EEG after a first seizure [
[38]
]. A potential gap between intention and practice was not tested. Among 127 children referred as patients of “first seizure” to a tertiary care First Seizure Clinic, the diagnosis was epileptic in 74%, among patients referred by family physicians only 65% and an EEG done in all 127 children was abnormal in 41% [[39]
]. Without evidence of the validity of the mode of recruitment, the validity and reliability of the enrolment method remains open. Another problem is an inter-observer variation in interpreting EEG records whether they are normal or abnormal. Furthermore, about 10% show a normal first EEG record and may be omitted from the study.3. Mortality
Mortality in subjects with epilepsy is mostly expressed as standardized mortality ratio (SMR). In few population-based studies including patients with one or more newly-diagnosed unprovoked seizures prospectively long-term followed, the overall SMR is from 2 to 3 times as high as expected [
40
, 41
, 42
]. A more than 10-fold excess mortality is associated with a symptomatic etiology of seizures and neurodeficits [[43]
]. The SMRs are higher than in the general population in all etiological categories, even in subjects with idiopathic or cryptogenic etiology [40
, 43
], and higher in children than adults [[44]
]. More than half the fatalities are seizure-related [[43]
] including SUDEP as the most common single seizure-related cause [[45]
]. Excess mortality in people with epilepsy is age-related. While the SMRs are lowering in childhood with increasing age and then plateauing, an increase is found since late adolescence [[40]
]. A shortened life expectancy of two years is to be expected among subjects with idiopathic or cryptogenic epilepsy and up to ten years in those with symptomatic epilepsy [[46]
].4. Long-term medical outcome
4.1 Natural course
Based on the literature review, Sander [
[47]
] suggested the natural course of treated epilepsy to be “excellent” in 20–40%, “good” in 30–40″, “uncertain” in 10–20% and “poor” in 20%. In a study setting, the analysis of the course of epilepsy showed that about half (48%) had remitting course of epilepsy uninterrupted by relapse, one fifth (19%) had remitting-relapsing course (≥5-year relapses interrupted by one or more relapses, but ending in terminal remission), and another fifth (19%) were never in ≥5-year remission (drug resistance), while the remaining 14% had a worsening course (early or late remission followed by drug-resistant epilepsy) [[25]
]. The fluctuating course of epilepsies is so far unexplained [[48]
].4.2 Overall seizure outcome
Overall five-year terminal remission is, according to different population-based reports, very consistently attained by two thirds of patients with childhood-onset or adult-onset epilepsy. Table 1 presents cohort studies reporting five-year terminal remission of seizures on at least ten-year follow-up. During the first 20 years of follow-up, the percentage of patients in five-year terminal remission (5YTR) is lower than on extended follow-up [
5
, 49
], because particularly in children with neurodeficits and severe epilepsy, the mortality rate is high and, on the other hand, chances for survival and seizure freedom are better among children with less severe or no neurological impairments. No significant difference seems to exist, in the long run, in seizure outcome between childhood-onset [5
, 50
, 51
] vs. all-age epilepsy [[69]
]. The prognosis tends to become better, the longer the follow-up period is [5
, 69
]. Outcome is better in cohorts with incident cases [5
, 50
, 51
] than in those with combined incident and prevalent cases [5
, 49
].Long-term seizure outcome after antiepileptic drug withdrawal is favorable in about half of those in 5YTR. Recently, an issue of cure in epilepsy has been raised. Long-term cure, defined as at least 5YTR following withdrawal of antiepileptic medication during sustained remission [
[52]
], was found in 61% of 133 patients with newly diagnosed childhood onset epilepsy followed for 45 years [[53]
]. On multivariate analysis, low (less than weekly) seizure frequency during the first year under treatment; low pretreatment seizure frequency; higher full-scale IQ (71 or more); and idiopathic or cryptogenic vs. symptomatic etiology of seizures proved to be significant and independent predictors of long-term cure [[53]
]. A number of additional independent predictors of 5YTR have been presented including pre-seizure factors; seizure-related factors; and treatment-related factors [[54]
].Time to remission after onset of epilepsy may be even 30 years and is dependent of the number of years with seizures. The higher the proportion of the number of years per follow-up years, the long the time to enter the first five-year remission. One fifth of remitted patients will experience a relapse, but some of them may re-enter remission [
[25]
]. Significant and independent predictors in the phenomenology of the natural course of treated epilepsy include high pre-treatment and early-treatment seizure frequency [53
, 55
, 56
]; delayed time to first remission [[57]
]; and clustering of seizures during treatment [[58]
]. Episodes of status epilepticus have an effect on seizure outcome [[59]
] and are significantly more common in drug-resistant than in drug-responsive epilepsy [[55]
].4.3 Drug therapy
Antiepileptic drug therapy appears helpful in a short-term prognosis, but in long-term follow-up studies, the seizure outcome is obviously the same between drug-treated and those who should have been treated on the basis of the current practice parameters but who were never treated [
[60]
]. Yet, discontinuation of antiepileptic drug therapy leads to relapse in more than one third, and reinstitution of the therapy does not help regain remission in all [[61]
]. Modern antiepileptic drug development has not improved the outcome [[62]
]. Incident drug-resistance need not, however, be irreversible [[63]
], but up to 20% will never enter 5-year remission [[25]
].4.4 Comorbidities and neurodeficits
According to a recent comprehensive report [
[64]
], psychiatric and behavioral disorders are common in children with epilepsy and typically occur in around 35–50%. The disorders including attention-deficit-hyperactivity disorder, autism spectrum disorders, cognitive disorders, depression, and inter-ictal and post-ictal psychoses may badly affect the child's daily activities and quality of life.It is a widely accepted view that symptomatic etiology of seizures is a significant risk factor for not entering remission [
55
, 65
, 66
]. Sustained seizure remission is to be expected in about 60% of patients with symptomatic and in more than 90% of those with idiopathic etiology of childhood-onset seizures [[67]
]. Symptomatic etiology is closely related to an abnormal neurological status and major neurodeficits [11
, 55
, 68
], as defined by Annegers et al. [[69]
]. Epilepsy is diagnosed in 25–40% of patients with mental impairments [29
, 30
, 31
, 32
]. Patients with mental, motor or both impairments enter remission significantly less often than those without any such impairment (35–38%) vs. (72–77%) [[6]
]. Risk for refractory seizures was 4.1-fold in patients with mental comorbidity and 5.6-fold in those with gross motor comorbidity [[55]
].4.5 Seizure type
Twenty years after onset of epilepsy, patients with idiopathic generalized seizures and those with absence seizures had the best outcome of epilepsy syndromes (85% and 80%, respectively), while those with complex partial seizures had a lower remission rate (65%). Patients with generalized seizures remitted in 77%, but those with partial seizures in 59% [
[69]
]. During prolonged follow-up, remission rates tend to become higher. In a Finnish 40-year follow-up study of patients with newly-diagnosed childhood-onset epilepsy, generalized seizures were in remission in 87% and partial seizures in 66% [[61]
].4.6 Specific epilepsy syndromes
Catastrophic epilepsy syndromes of childhood include West syndrome and Lennox–Gastaut syndrome. Among children with West syndrome, remission from infantile spasms reportedly ranges from 24%[
[70]
] and 89%[[71]
] with the higher remission rates largely depending on the duration of follow-up. On 20–35 years of follow-up, 33% of 147 Finnish children surviving at the end of follow-up were in 5-year remission [[72]
]. Patients with Lennox–Gastaut syndrome have a still more gloomy prognosis; only few per cent are in complete remission [[73]
], except for one study that reported 23% of 26 patients to have maintained seizure freedom at 18–35 years of follow-up [[74]
].Among children with childhood absence epilepsy (CAS) (onset at age 4–10), in the long run, typical absence seizures disappear in more than 90% [
[75]
]. Early good effect of therapy is a favorable prognostic sign [[76]
]. However, about half the children may have concurrent generalized tonic–clonic or seizures (GTCS), or CAS may evolve to juvenile myoclonic epilepsy (JME). In both cases, the seizure prognosis is remarkably less favorable. JAS (onset at age 7–17 years) is less frequent than CAS. Adolescents with JAS enter remain in remission on virtually life-long medication in 80%, and combination with GTCS or JME does not significantly affect seizure outcome [[77]
].Benign epilepsy of childhood with centrotemporal spikes (BECTS) denotes an excellent outcome with 95% in complete remission [
78
, 79
]. Extremely few patients have drug-resistant BECTS.5. Social outcome
5.1 Education
While stigmatization is still a problem and prejudices are relieved, they appear to remain a problem.
The less positive attitudes against children with epilepsy make that no more than 75–80% will pass compulsory basic education [
5
, 80
]. Even school children with idiopathic epilepsy in remission are at two-fold risk of failure (relative risk 2.43,95%CI 1.55–3.82) [[5]
]. Yet, when the attitudes of families and teachers are positive, adolescents with uncomplicated childhood-onset epilepsy will enter high school and pass matriculation examination as often as controls [5
, 81
]. Subjects with epilepsy lacked significantly more often vocational education than controls, even though the difference was modest [[5]
]. Adults with epilepsy showed no significant differences by type of education in a case control study derived from seven European countries [[82]
].5.2 Social integration
People with epilepsy meet great challenges on the labor market, although most of them are able to work. In previous studies [, ,
84
], the employment rate is usually reported to be about 60%. However, in more recent reports, the employability rate is given as be about 70% [49
, 85
]. In the population study by Sillanpää et al. [[5]
], compared with the rate of employed of controls (92%), employed were 69% of all patients with uncomplicated epilepsy; 80% of patients with incidence cases in remission off medication; 93% of patients with idiopathic epilepsy in remission without medication. Thus, at best, there is no difference between the employment rates of people with epilepsy and controls. The employment rate of 70% can be maintained among adults with onset of epilepsy when in working life through preventive and rehabilitation measures [[86]
]. While the employability rate was significantly lower among subjects than in controls in the study by Sillanpää et al. [[5]
], Kokkonen et al. [[80]
] reported no significant difference in the employability rates between the subjects and controls.Among both men and women, the marriage rate is lower than in general population [
87
, 88
]. The birth rate was significantly lower among patients off medications during the study period than those on oxcarbazepine (but not on other antiepileptic drugs) [[89]
]. Compared with controls, living in partnership and having children were significantly lower among the subjects (90% vs. 65%, p < 0.001 and 84% vs. 49%, p < 0.001, respectively) [[5]
]. The socioeconomic status was not significantly lower in subjects than controls (52% vs. 65%, p = 0.08) [[5]
]. Epilepsy has a long-term and significant impact on the quality of life [[90]
]. Among adults with childhood onset epilepsy, a perceived quality of life was poorer among subjects on medication, whether in remission or not, than in those whose medication had been withdrawn. Their unemployment rate was higher and the socioeconomic lower than in controls, but that difference did not remain in the comparison between subject in remission off medication and controls. In case of newly diagnosed epilepsy at adult age, most activities beyond work remain unchanged [[91]
].6. Conclusions
Our review of long and ultra-long term population-based studies shows that the outlook is very good for the vast majority of people with new-onset epilepsy. Most will become permanently seizure-free on and off drugs, mostly within a few years of drug treatment, and another important minority will have long periods of seizure remission intermingled with few seizures. Challenges still exist, for an important minority has drug resistant epilepsy, mortality of epilepsy is still a major concern and SUDEP has not been brought to a stop. It is surprisingly uncertain if the seizure and mortality outcomes of epilepsy have actually improved over the last four decades despite the enormous advances in modern antiepileptic drug development, neurostimulation therapy and surgery of epilepsy. Hope is on the horizon, as there is emerging evidence that the social outcome has improved over the last decades, possibly through better social support and a welcomed change in attitude toward people with epilepsy. These are definitely good news for all people with epilepsy.
Conflict of interest statement
None.
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Article info
Publication history
Published online: September 09, 2016
Accepted:
September 4,
2016
Received in revised form:
September 1,
2016
Received:
August 15,
2016
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© 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
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