Advertisement

Long-term outcome of medically treated epilepsy

Open ArchivePublished:September 09, 2016DOI:https://doi.org/10.1016/j.seizure.2016.09.002

      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 [
      • Alström C.H.
      A study of epilepsy in its clinical, social and genetic aspects.
      ] and 1960s [
      • Rodin E.A.
      The prognosis of patients with epilepsy.
      ] based on patients from hospitals and other institutions. According to those studies and the previous literature from 1901 to 1964 discussed by Rodin [
      • Rodin E.A.
      The prognosis of patients with epilepsy.
      ], 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 [
      • Hauser W.A.
      • Kurland L.T.
      The epidemiology of epilepsy in Rochester, Minnesota, 1935 through 1967.
      ], 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 [
      • Hauser W.A.
      • Kurland L.T.
      The epidemiology of epilepsy in Rochester, Minnesota, 1935 through 1967.
      ]. In more recent population studies, about two thirds were in 5-year terminal remission [
      • Sillanpää M.
      Social functioning and seizure status of young adults with onset of epilepsy in childhood. An epidemiological 20-year follow-up study.
      ,
      • Sillanpää M.
      • Jalava M.
      • Kaleva O.
      • Shinnar S.
      Long-term prognosis of seizures with onset in childhood.
      ,
      • Brorson L.O.
      • Wranne L.
      Long-term prognosis in childhood epilepsy: survival and seizure prognosis.
      ,
      • MacDonald B.K.
      • Johnson A.L.
      • Goodridge D.M.
      • Cockerell O.C.
      • Sander J.W.
      • Shorvon S.D.
      Factors predicting prognosis of epilepsy after presentation with seizures.
      ]. The improved prognosis can be ascribed, among other things, to advanced externally valid study populations, diagnostic methods and therapeutic armament [
      • Sillanpää M.
      • Jalava M.
      • Kaleva O.
      • Shinnar S.
      Long-term prognosis of seizures with onset in childhood.
      ,
      • Sillanpää M.
      Children with epilepsy as adults: outcome after 30 years of follow-up.
      ,
      • Sillanpää M.
      Long-term outcome of epilepsy.
      ,
      • Hart Y.M.
      • Sander J.W.A.S.
      • Shorvon S.D.
      National general practice study on epileptic seizures: objectives and study methodology of the largest reported prospective cohort study of epilepsy.
      ]. Only a few long-term (more than 10 years), prospective unselected population-based cohort studies have been reported [
      • Sillanpää M.
      Social functioning and seizure status of young adults with onset of epilepsy in childhood. An epidemiological 20-year follow-up study.
      ,
      • Sillanpää M.
      • Jalava M.
      • Kaleva O.
      • Shinnar S.
      Long-term prognosis of seizures with onset in childhood.
      ,
      • Brorson L.O.
      • Wranne L.
      Long-term prognosis in childhood epilepsy: survival and seizure prognosis.
      ,
      • Sillanpää M.
      Children with epilepsy as adults: outcome after 30 years of follow-up.
      ,
      • Brorson L.
      Socialstyrelsen redovisar: Epileptikervården, Epilepsi hos barn och ungdom.
      ,
      • Sillanpää M.
      Medico-social prognosis of children with epilepsy. Epidemiological study and analysis of 245 patients.
      ,
      • Sillanpää M.
      • Anttinen A.
      • Rinne J.O.
      • Joutsa J.
      • Sonninen P.
      • Erkinjuntti M.
      • et al.
      Childhood-onset epilepsy five decades later. A prospective population-based cohort study.
      ]. 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 [
      • Brorson L.
      Socialstyrelsen redovisar: Epileptikervården, Epilepsi hos barn och ungdom.
      ,
      • Sillanpää M.
      Medico-social prognosis of children with epilepsy. Epidemiological study and analysis of 245 patients.
      ]

      The recruitment of study subjects of Brorson [
      • Brorson L.
      Socialstyrelsen redovisar: Epileptikervården, Epilepsi hos barn och ungdom.
      ] 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 [
      • Brorson L.O.
      • Wranne L.
      Long-term prognosis in childhood epilepsy: survival and seizure prognosis.
      ], 124 (64%) were in 3-year terminal remission.
      In the Turku study [
      • Sillanpää M.
      Medico-social prognosis of children with epilepsy. Epidemiological study and analysis of 245 patients.
      ], 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 [
      • Gastaut H.
      Clinical and electroencephalographical classification of epileptic seizures.
      ]. 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 [
      • Sillanpää M.
      • Jalava M.
      • Shinnar S.
      Epilepsy syndromes in patients with childhood-onset seizures in Finland.
      ] to be in line with the update ILAE definitions [
      • Commission on revised classification of seizures
      Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Commission on classification and terminology of the international league against epilepsy.
      ,
      • Commission on revised classification of epilepsy 1989
      Proposal for revised classification of epilepsies and epileptic syndromes. Commission on classification and terminology of the international league against epilepsy.
      ,
      • Commission on epidemiology prognosis
      Guidelines for epidemiologic studies on epilepsy.
      ]. 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 [
      • Sillanpää M.
      • Jalava M.
      • Kaleva O.
      • Shinnar S.
      Long-term prognosis of seizures with onset in childhood.
      ,
      • Rantala H.
      • Ingalsuo H.
      Occurrence and outcome of epilepsy in children younger than 2 years.
      ]. 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 [
      • Sillanpää M.
      Suomen lastenneurologian historia.
      ]. 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 [
      • Gissler M.
      • Teperi J.
      • Hemminki E.
      • Meriläinen J.
      Data quality after restructuring a national medical registry.
      ,
      • Heinonen R.
      Finns accept the registration of their own data (in Finnish).
      ,
      • Pietilä K.
      • Tenkanen L.
      • Mänttäri M.
      • Manninen V.
      How to define coronary heart disease in register-based follow-up studies: experience from the Helsinki heart study.
      ,
      • Pajunen P.
      • Paakkonen R.
      • Hämäläinen H.
      • et al.
      Trends in fatal and nonfatal strokes among persons aged 35 to >or =85 years during 1991–2002 in Finland.
      ].
      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 [
      • Sillanpää M.
      • Jalava M.
      • Kaleva O.
      • Shinnar S.
      Long-term prognosis of seizures with onset in childhood.
      ,
      • Sillanpää M.
      Medico-social prognosis of children with epilepsy. Epidemiological study and analysis of 245 patients.
      ]. 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 [
      • Sillanpää M.
      • Jalava M.
      • Kaleva O.
      • Shinnar S.
      Long-term prognosis of seizures with onset in childhood.
      ,
      • Sillanpää M.
      • Schmidt D.
      Natural history of treated childhood-onset epilepsy: prospective, long-term population-based study.
      ].

      2.2 Community based study [
      • Hart Y.M.
      • Sander J.W.A.S.
      • Shorvon S.D.
      National general practice study on epileptic seizures: objectives and study methodology of the largest reported prospective cohort study of epilepsy.
      ]

      The British national general practice study of epilepsy (NGPSE), with the study subjects followed for 25 years [
      • Bell G.S.
      • Neligan A.
      • Giavasi C.
      • et al.
      Outcome of seizures in the general population after 25 years: a prospective follow-up, observational cohort study.
      ], 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 [
      • Klenerman P.
      • Sander J.W.A.S.
      • Shorvon S.
      Mortality in patients with epilepsy: a study of patients in long term residential care.
      ,
      • Novy J.
      • Belluzzo M.
      • Caboclo L.O.
      • et al.
      The lifelong course of chronic epilepsy: the Chalfont experience.
      ], 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% [
      • Gustavson K.H.
      • Holmgren G.
      • Jonsell R.
      • Son Blomquist H.K.
      Severe mental retardation in children in a northern Swedish county.
      ,
      • Forsgren L.
      Prevalence of epilepsy in adults in northern Sweden.
      ,
      • Jalava M.
      • Sillanpää M.
      Concurrent illnesses in adults with childhood-onset epilepsy: a population-based 35-year follow-up study.
      ,
      • Sidenvall R.
      • Forsgren L.
      • Heijbel J.
      Prevalence and characteristics of epilepsy in children in northern Sweden.
      ] 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 [
      • Leach J.P.
      • Lauder R.
      • Nicolson A.
      • Smith D.F.
      Epilepsy in the UK: misdiagnosis, mistreatment, and undertreatment? The Wrexham area epilepsy project.
      ], among other things, over-diagnoses and under-diagnoses [
      • Goodridge D.M.
      • Shorvon S.D.
      Epileptic seizures in a population of 6000. I: Demography, diagnosis and classification, and role of the hospital services.
      ,
      • Scheepers B.
      • Clough P.
      • Pickles C.
      The misdiagnosis of epilepsy: findings of a population study.
      ]. 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 [
      • Leach J.P.
      • Lauder R.
      • Nicolson A.
      • Smith D.F.
      Epilepsy in the UK: misdiagnosis, mistreatment, and undertreatment? The Wrexham area epilepsy project.
      ]. The problem concerns also children with epilepsy in the UK [
      • Jeavons P.M.
      The practical management of epilepsy.
      ,
      • Cross J.H.
      Pitfalls in the diagnosis and differential diagnosis of epilepsy.
      ]. 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 designDuration of follow-up (years)5-YTR (%) on or off medicationAuthor(s) and year
      Population-based, prospective studies
      I&P (n = 227)1056Sillanpää, 1983
      I&P (n = 178)2058Sillanpää, 1990
      I&P (n = 220)3064Sillanpää et al., 1998
      I%P (n = 220)4061Sillanpää et al., 1998
      I (n = 144)4067Sillanpää et al., 2006
      Surviving I&P (n = 133)4570Sillanpää et al., 2015
      Cases with one or more, probably unprovoked seizures (n = 228)2268Cockerell et al., 1997
      Population-based, retrospective studies
      I (n = 475)1065Annegers et al., 1979
      I (n = 141)2070Annegers et al., 1979
      Hospital-based cohort studies
      I (n = 730)1079Oka et al., 1989
      I&P (n = 141)1052Wakamoto et al., 2000
      I&P (n = 75)2056Wakamoto et al., 2000
      I (n = 413)1571Geerts et al., 2010
      I (n = 516)2160Berg 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 [
      • Camfield P.R.
      • Camfield C.S.
      • Dooley J.M.
      • Tibbles J.A.
      • Fung T.
      • Garner B.
      Epilepsy after a first unprovoked seizure in childhood.
      ]. 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% [
      • Hamiwka L.D.
      • Singh N.
      • Niosi J.
      • Wirrell E.C.
      Diagnostic inaccuracy in children with “first seizure”: role for a first seizure clinic.
      ]. 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 [
      • Hauser W.
      • Annegers J.F.
      • Elveback L.R.
      Mortality in patients with epilepsy.
      ,
      • Olafsson E.
      • Hauser W.A.
      • Gudmundsson G.
      Long-term survival of people with unprovoked seizures.
      ,
      • Forsgren L.
      • Sillanpää M.
      Natural course of epilepsies.
      ]. A more than 10-fold excess mortality is associated with a symptomatic etiology of seizures and neurodeficits [
      • Sillanpää M.
      • Shinnar S.
      Long-term mortality in childhood-onset epilepsy.
      ]. The SMRs are higher than in the general population in all etiological categories, even in subjects with idiopathic or cryptogenic etiology [
      • Hauser W.
      • Annegers J.F.
      • Elveback L.R.
      Mortality in patients with epilepsy.
      ,
      • Sillanpää M.
      • Shinnar S.
      Long-term mortality in childhood-onset epilepsy.
      ], and higher in children than adults [
      • Forsgren L.
      • Hauser A.W.
      • Olafsson E.
      • Sander J.W.A.S.
      • Sillanpää M.
      • Tomson T.
      Mortality of epilepsy in developed countries: a review.
      ]. More than half the fatalities are seizure-related [
      • Sillanpää M.
      • Shinnar S.
      Long-term mortality in childhood-onset epilepsy.
      ] including SUDEP as the most common single seizure-related cause [
      • Sillanpää M.
      • Shinnar S.
      SUDEP and other causes of mortality in childhood onset epilepsy.
      ]. 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 [
      • Hauser W.
      • Annegers J.F.
      • Elveback L.R.
      Mortality in patients with epilepsy.
      ]. 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 [
      • Gaitatzis A.
      • Johnson A.L.
      • Chadwick D.W.
      • Shorvon S.D.
      • Sander J.W.
      Life expectancy in people with newly diagnosed epilepsy.
      ].

      4. Long-term medical outcome

      4.1 Natural course

      Based on the literature review, Sander [
      • Sander J.W.A.S.
      • Sillanpää M.
      Natural history prognosis.
      ] 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) [
      • Sillanpää M.
      • Schmidt D.
      Natural history of treated childhood-onset epilepsy: prospective, long-term population-based study.
      ]. The fluctuating course of epilepsies is so far unexplained [
      • Schmidt D.
      • Sillanpää M.
      Evidence-based review on the natural history of the epilepsies.
      ].

      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 [
      • Sillanpää M.
      • Jalava M.
      • Kaleva O.
      • Shinnar S.
      Long-term prognosis of seizures with onset in childhood.
      ,
      • Wakamoto H.
      • Nagao H.
      • Hayashi M.
      • Morimoto T.
      Long-term medical, educational, and social prognoses of childhood-onset epilepsy: a population-based study in a rural district of Japan.
      ], 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 [
      • Sillanpää M.
      • Jalava M.
      • Kaleva O.
      • Shinnar S.
      Long-term prognosis of seizures with onset in childhood.
      ,
      • Oka E.
      • Yamatogi Y.
      • Ohtsuka Y.
      • Ohtahara S.
      Clinical course and prognosis of childhood epilepsy.
      ,
      • Geerts A.
      • Arts W.F.
      • Stroink H.
      • et al.
      Course and outcome of childhood epilepsy: a 15-year follow-up of the Dutch study of epilepsy in childhood.
      ] vs. all-age epilepsy [
      • Annegers J.F.
      • Hauser W.A.
      • Elveback L.R.
      Remission of seizures and relapse in patients with epilepsy.
      ]. The prognosis tends to become better, the longer the follow-up period is [
      • Sillanpää M.
      • Jalava M.
      • Kaleva O.
      • Shinnar S.
      Long-term prognosis of seizures with onset in childhood.
      ,
      • Annegers J.F.
      • Hauser W.A.
      • Elveback L.R.
      Remission of seizures and relapse in patients with epilepsy.
      ]. Outcome is better in cohorts with incident cases [
      • Sillanpää M.
      • Jalava M.
      • Kaleva O.
      • Shinnar S.
      Long-term prognosis of seizures with onset in childhood.
      ,
      • Oka E.
      • Yamatogi Y.
      • Ohtsuka Y.
      • Ohtahara S.
      Clinical course and prognosis of childhood epilepsy.
      ,
      • Geerts A.
      • Arts W.F.
      • Stroink H.
      • et al.
      Course and outcome of childhood epilepsy: a 15-year follow-up of the Dutch study of epilepsy in childhood.
      ] than in those with combined incident and prevalent cases [
      • Sillanpää M.
      • Jalava M.
      • Kaleva O.
      • Shinnar S.
      Long-term prognosis of seizures with onset in childhood.
      ,
      • Wakamoto H.
      • Nagao H.
      • Hayashi M.
      • Morimoto T.
      Long-term medical, educational, and social prognoses of childhood-onset epilepsy: a population-based study in a rural district of Japan.
      ].
      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 [
      • Fisher R.A.
      • Acevado C.
      • Arzimanoglou A.
      • et al.
      ILAE official report: a practical clinical definition of epilepsy.
      ], was found in 61% of 133 patients with newly diagnosed childhood onset epilepsy followed for 45 years [
      • Sillanpää M.
      • Saarinen M.
      • Schmidt D.
      Clinical conditions of long-term cure in childhood-onset epilepsy: a 45-year follow-up study.
      ]. 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 [
      • Sillanpää M.
      • Saarinen M.
      • Schmidt D.
      Clinical conditions of long-term cure in childhood-onset epilepsy: a 45-year follow-up study.
      ]. A number of additional independent predictors of 5YTR have been presented including pre-seizure factors; seizure-related factors; and treatment-related factors [
      • Sillanpää M.
      Natural course of treated epilepsy and medico-social outcomes, Turku studies. Part II.
      ].
      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 [
      • Sillanpää M.
      • Schmidt D.
      Natural history of treated childhood-onset epilepsy: prospective, long-term population-based study.
      ]. Significant and independent predictors in the phenomenology of the natural course of treated epilepsy include high pre-treatment and early-treatment seizure frequency [
      • Sillanpää M.
      • Saarinen M.
      • Schmidt D.
      Clinical conditions of long-term cure in childhood-onset epilepsy: a 45-year follow-up study.
      ,
      • Sillanpää M.
      Remission of seizures and predictors of intractability in long-term follow-up.
      ,
      • Sillanpää M.
      • Schmidt D.
      Early seizure frequency and aetiology predict long-term medical outcome in childhood-onset epilepsy.
      ]; delayed time to first remission [
      • Sillanpää M.
      • Schmidt D.
      Delayed time to first remission identifies poor long-term drug response of childhood-onset epilepsy: a prospective population-based study.
      ]; and clustering of seizures during treatment [
      • Sillanpää M.
      • Schmidt D.
      Seizure clustering during drug treatment affects seizure outcome and mortality of childhood-onset epilepsy.
      ]. Episodes of status epilepticus have an effect on seizure outcome [
      • Sillanpää M.
      • Shinnar S.
      Status epilepticus in a population-based cohort with childhood-onset epilepsy in Finland.
      ] and are significantly more common in drug-resistant than in drug-responsive epilepsy [
      • Sillanpää M.
      Remission of seizures and predictors of intractability in long-term follow-up.
      ].

      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 [
      • Keränen T.
      • Riekkinen P.
      Remission of seizures in untreated epilepsy.
      ]. 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 [
      • Sillanpää M.
      • Schmidt D.
      Prognosis of seizure recurrence after stopping antiepileptic drugs in seizure-free patients. A long-term population-based study of childhood-onset epilepsy.
      ]. Modern antiepileptic drug development has not improved the outcome [
      • Löscher W.
      • Schmidt D.
      Modern antiepileptic drug development has failed to deliver: ways out of the current dilemma.
      ]. Incident drug-resistance need not, however, be irreversible [
      • Sillanpää M.
      • Schmidt D.
      Is incident drug-resistance of childhood-onset epilepsy reversible? A long-term follow-up study.
      ], but up to 20% will never enter 5-year remission [
      • Sillanpää M.
      • Schmidt D.
      Natural history of treated childhood-onset epilepsy: prospective, long-term population-based study.
      ].

      4.4 Comorbidities and neurodeficits

      According to a recent comprehensive report [
      • Besag F.
      • Aldenkamp A.
      • Caplan R.
      • Dunn D.W.
      • Gobbi G.
      • Sillanpää M.
      Psychiatric and behavioural disorders in children with epilepsy. Report of the child neuropsychiatry taskforce, neurobiology commission, international league against epilepsy.
      ], 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 [
      • Sillanpää M.
      Remission of seizures and predictors of intractability in long-term follow-up.
      ,
      • Berg A.T.
      • Shinnar S.
      • Levy S.R.
      • Testa F.M.
      • Smith-Rapaport S.
      • Beckerman B.
      • et al.
      Early development of intractable epilepsy in children: a prospective study.
      ,
      • Spooner C.G.
      • Berkovic S.F.
      • Mitchell L.A.
      • Wrennall J.A.
      • Harvey A.S.
      New-onset temporal lobe epilepsy in children: lesion on MRI predicts poor seizure outcome.
      ]. 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 [
      • Sillanpää M.
      • Schmidt D.
      Predicting antiepileptic drug response in children with epilepsy.
      ]. Symptomatic etiology is closely related to an abnormal neurological status and major neurodeficits [
      • Brorson L.
      Socialstyrelsen redovisar: Epileptikervården, Epilepsi hos barn och ungdom.
      ,
      • Sillanpää M.
      Remission of seizures and predictors of intractability in long-term follow-up.
      ,
      • Sillanpää M.
      Epilepsy in children: prevalence, disability, and handicap.
      ], as defined by Annegers et al. [
      • Annegers J.F.
      • Hauser W.A.
      • Elveback L.R.
      Remission of seizures and relapse in patients with epilepsy.
      ]. Epilepsy is diagnosed in 25–40% of patients with mental impairments [
      • Gustavson K.H.
      • Holmgren G.
      • Jonsell R.
      • Son Blomquist H.K.
      Severe mental retardation in children in a northern Swedish county.
      ,
      • Forsgren L.
      Prevalence of epilepsy in adults in northern Sweden.
      ,
      • Jalava M.
      • Sillanpää M.
      Concurrent illnesses in adults with childhood-onset epilepsy: a population-based 35-year follow-up study.
      ,
      • Sidenvall R.
      • Forsgren L.
      • Heijbel J.
      Prevalence and characteristics of epilepsy in children in northern Sweden.
      ]. Patients with mental, motor or both impairments enter remission significantly less often than those without any such impairment (35–38%) vs. (72–77%) [
      • Brorson L.O.
      • Wranne L.
      Long-term prognosis in childhood epilepsy: survival and seizure prognosis.
      ]. Risk for refractory seizures was 4.1-fold in patients with mental comorbidity and 5.6-fold in those with gross motor comorbidity [
      • Sillanpää M.
      Remission of seizures and predictors of intractability in long-term follow-up.
      ].

      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% [
      • Annegers J.F.
      • Hauser W.A.
      • Elveback L.R.
      Remission of seizures and relapse in patients with epilepsy.
      ]. 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% [
      • Sillanpää M.
      • Schmidt D.
      Prognosis of seizure recurrence after stopping antiepileptic drugs in seizure-free patients. A long-term population-based study of childhood-onset epilepsy.
      ].

      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%[
      • Yamatogi Y.
      • Ohtahara S.
      Age-dependent encephalopathy: a longitudinal study.
      ] and 89%[
      • Jeavons P.M.
      • Bower B.D.
      • Dimitrakoudi M.
      Long-term prognosis of 150 cases of “West syndrome”.
      ] 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 [
      • Riikonen R.
      Long-term outcome of west syndrome: a study of adults with a history of infantile spasm.
      ]. Patients with Lennox–Gastaut syndrome have a still more gloomy prognosis; only few per cent are in complete remission [
      • Beaumanoir A.
      • Foletti G.
      • Volanschi D.
      Status epilepticus in Lennox-Gastaut syndrome.
      ], except for one study that reported 23% of 26 patients to have maintained seizure freedom at 18–35 years of follow-up [
      • Kim H.J.
      • Kim H.D.
      • Lee J.S.
      • Heo K.
      • Kim D.S.
      • Kang H.C.
      Long-term prognosis of patients with Lennox-Gastaut syndrome in recent decades.
      ].
      Among children with childhood absence epilepsy (CAS) (onset at age 4–10), in the long run, typical absence seizures disappear in more than 90% [
      • Hedström A.
      • Olsson I.
      Epidemiology of absence epilepsy.
      ]. Early good effect of therapy is a favorable prognostic sign [
      • Currier R.D.
      • Kooi K.A.
      • Saidman L.J.
      Prognosis of pure petit mal.
      ]. 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 [
      • Wolf P.
      • Inoue Y.
      Therapeutic response of absence seizures in patients with of an epilepsy clinic for adolescents and adults.
      ].
      Benign epilepsy of childhood with centrotemporal spikes (BECTS) denotes an excellent outcome with 95% in complete remission [
      • Astradsson A.
      • Olafsson E.
      • Ludvigsson P.
      • Björgvinsson H.
      • Hauser W.A.
      Rolandic epilepsy: an incidence study in Iceland.
      ,
      • Sillanpää M.
      Long-term prognosis of adults with benign epilepsy of childhood.
      ]. 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 [
      • Sillanpää M.
      • Jalava M.
      • Kaleva O.
      • Shinnar S.
      Long-term prognosis of seizures with onset in childhood.
      ,
      • Kokkonen J.
      • Kokkonen E.R.
      • Saukkonen A.L.
      • Pennanen P.
      Psychosocial outcome of young adults with epilepsy in childhood.
      ]. 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) [
      • Sillanpää M.
      • Jalava M.
      • Kaleva O.
      • Shinnar S.
      Long-term prognosis of seizures with onset in childhood.
      ]. 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 [
      • Sillanpää M.
      • Jalava M.
      • Kaleva O.
      • Shinnar S.
      Long-term prognosis of seizures with onset in childhood.
      ,
      • Koponen A.
      • Seppälä U.
      • Eriksson K.
      • et al.
      Social functioning and psychological well-being of 347 young adults with epilepsy only – population-based, controlled study from Finland.
      ]. Subjects with epilepsy lacked significantly more often vocational education than controls, even though the difference was modest [
      • Sillanpää M.
      • Jalava M.
      • Kaleva O.
      • Shinnar S.
      Long-term prognosis of seizures with onset in childhood.
      ]. Adults with epilepsy showed no significant differences by type of education in a case control study derived from seven European countries [
      • RESt-1Group T.
      Social aspects of epilepsy in the adult in seven European countries.
      ].

      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 [
      • Sillanpää M.
      Long-term outcome of epilepsy.
      ,
      • Zielinski J.J.
      Epidemiology and medico-social problems of epilepsy in Warsaw.
      ,
      • Collins J.
      Psychosocial well-being and epilepsy: an empirical study.
      ], the employment rate is usually reported to be about 60%. However, in more recent reports, the employability rate is given as be about 70% [
      • Wakamoto H.
      • Nagao H.
      • Hayashi M.
      • Morimoto T.
      Long-term medical, educational, and social prognoses of childhood-onset epilepsy: a population-based study in a rural district of Japan.
      ,
      • Sillanpää M.
      • Schmidt D.
      Long-term employment of adults with childhood-onset epilepsy: a prospective population-based study.
      ]. In the population study by Sillanpää et al. [
      • Sillanpää M.
      • Jalava M.
      • Kaleva O.
      • Shinnar S.
      Long-term prognosis of seizures with onset in childhood.
      ], 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 [
      • Kniess T.
      • Stefan H.
      • Brodisch P.
      Diagnosis of epilepsy – consequences for work and a professional activities.
      ]. While the employability rate was significantly lower among subjects than in controls in the study by Sillanpää et al. [
      • Sillanpää M.
      • Jalava M.
      • Kaleva O.
      • Shinnar S.
      Long-term prognosis of seizures with onset in childhood.
      ], Kokkonen et al. [
      • Kokkonen J.
      • Kokkonen E.R.
      • Saukkonen A.L.
      • Pennanen P.
      Psychosocial outcome of young adults with epilepsy in childhood.
      ] 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 [
      • Dansky L.V.
      • Andermann E.
      • Andermann F.
      Marriage and fertility in epileptic patients.
      ,
      • Artama M.
      • Isojärvi J.I.
      • Raitanen J.
      • Auvinen A.
      Birth rate among patients with epilepsy: a nationwide population-based cohort study in Finland.
      ]. The birth rate was significantly lower among patients off medications during the study period than those on oxcarbazepine (but not on other antiepileptic drugs) [
      • Artama M.
      • Isojärvi J.I.T.
      • Auvinen A.
      Antiepileptic drug use and birth rate in patients with epilepsy – a population-based cohort study in Finland.
      ]. 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) [
      • Sillanpää M.
      • Jalava M.
      • Kaleva O.
      • Shinnar S.
      Long-term prognosis of seizures with onset in childhood.
      ]. The socioeconomic status was not significantly lower in subjects than controls (52% vs. 65%, p = 0.08) [
      • Sillanpää M.
      • Jalava M.
      • Kaleva O.
      • Shinnar S.
      Long-term prognosis of seizures with onset in childhood.
      ]. Epilepsy has a long-term and significant impact on the quality of life [
      • Räty L.
      • Hamrin E.
      • Söderfält B.
      Quality of life in newly-debuted epilepsy. An empirical study.
      ]. 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 [
      • Lindsten H.
      • Stenlund H.
      • Forsgren L.
      Leisure time and social activity after a newly diagnosed unprovoked epileptic seizure in adult age. A population-based case-referent study.
      ].

      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.

      References

        • Alström C.H.
        A study of epilepsy in its clinical, social and genetic aspects.
        Acta Psychiatr Neurol. 1950; 57: 1-296
        • Rodin E.A.
        The prognosis of patients with epilepsy.
        1968
        • Hauser W.A.
        • Kurland L.T.
        The epidemiology of epilepsy in Rochester, Minnesota, 1935 through 1967.
        Epilepsia. 1975; 16: 1-66
        • Sillanpää M.
        Social functioning and seizure status of young adults with onset of epilepsy in childhood. An epidemiological 20-year follow-up study.
        Acta Neurol Scand. 1983; 68: 1-81
        • Sillanpää M.
        • Jalava M.
        • Kaleva O.
        • Shinnar S.
        Long-term prognosis of seizures with onset in childhood.
        N Engl J Med. 1998; 338: 1715-1722
        • Brorson L.O.
        • Wranne L.
        Long-term prognosis in childhood epilepsy: survival and seizure prognosis.
        Epilepsia. 1987; 28: 324-330
        • MacDonald B.K.
        • Johnson A.L.
        • Goodridge D.M.
        • Cockerell O.C.
        • Sander J.W.
        • Shorvon S.D.
        Factors predicting prognosis of epilepsy after presentation with seizures.
        Ann Neurol. 2000; 48: 833-841
        • Sillanpää M.
        Children with epilepsy as adults: outcome after 30 years of follow-up.
        Acta Paediatr Scand Suppl. 1990; 79: 1-78
        • Sillanpää M.
        Long-term outcome of epilepsy.
        Epileptic Disord. 2000; 2: 79-88
        • Hart Y.M.
        • Sander J.W.A.S.
        • Shorvon S.D.
        National general practice study on epileptic seizures: objectives and study methodology of the largest reported prospective cohort study of epilepsy.
        NGPSE. Neuroepidemiology. 1989; 8: 221-227
        • Brorson L.
        Socialstyrelsen redovisar: Epileptikervården, Epilepsi hos barn och ungdom.
        En klinisk, psykometrisk och social undersökning inom Uppsala län. Socialstyrels, Epileptikervården, Stockholm1970 (in Swedish, with English summary)
        • Sillanpää M.
        Medico-social prognosis of children with epilepsy. Epidemiological study and analysis of 245 patients.
        Acta Paediatr Scand. 1973; 237: 1-104
        • Sillanpää M.
        • Anttinen A.
        • Rinne J.O.
        • Joutsa J.
        • Sonninen P.
        • Erkinjuntti M.
        • et al.
        Childhood-onset epilepsy five decades later. A prospective population-based cohort study.
        Epilepsia. 2015; 56: 1774-1783
        • Gastaut H.
        Clinical and electroencephalographical classification of epileptic seizures.
        Epilepsia. 1970; 11: 102-113
        • Sillanpää M.
        • Jalava M.
        • Shinnar S.
        Epilepsy syndromes in patients with childhood-onset seizures in Finland.
        Pediatr Neurol. 1999; 21: 533-537
        • Commission on revised classification of seizures
        Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Commission on classification and terminology of the international league against epilepsy.
        Epilepsia. 1981; 22: 489-501
        • Commission on revised classification of epilepsy 1989
        Proposal for revised classification of epilepsies and epileptic syndromes. Commission on classification and terminology of the international league against epilepsy.
        Epilepsia. 1989; 30: 389-399
        • Commission on epidemiology prognosis
        Guidelines for epidemiologic studies on epilepsy.
        Epilepsia. 1993; 34: 592-596
        • Rantala H.
        • Ingalsuo H.
        Occurrence and outcome of epilepsy in children younger than 2 years.
        J Pediatr. 1999; 135: 761-764
        • Sillanpää M.
        Suomen lastenneurologian historia.
        Painola, OY, Kaarina2013: 1-280 (in Finnish)
        • Gissler M.
        • Teperi J.
        • Hemminki E.
        • Meriläinen J.
        Data quality after restructuring a national medical registry.
        Scand J Soc Med. 1995; 23: 75-80
        • Heinonen R.
        Finns accept the registration of their own data (in Finnish).
        N Engl J Med. 1997; 4: 25-28
        • Pietilä K.
        • Tenkanen L.
        • Mänttäri M.
        • Manninen V.
        How to define coronary heart disease in register-based follow-up studies: experience from the Helsinki heart study.
        Ann Med. 1997; 29: 253-259
        • Pajunen P.
        • Paakkonen R.
        • Hämäläinen H.
        • et al.
        Trends in fatal and nonfatal strokes among persons aged 35 to >or =85 years during 1991–2002 in Finland.
        Stroke. 2005; 36: 244-248
        • Sillanpää M.
        • Schmidt D.
        Natural history of treated childhood-onset epilepsy: prospective, long-term population-based study.
        Brain. 2006; 129: 617-624
        • Bell G.S.
        • Neligan A.
        • Giavasi C.
        • et al.
        Outcome of seizures in the general population after 25 years: a prospective follow-up, observational cohort study.
        J Neurol Neurosurg Psychiatry. 2016; 87: 843-850
        • Klenerman P.
        • Sander J.W.A.S.
        • Shorvon S.
        Mortality in patients with epilepsy: a study of patients in long term residential care.
        J Neurol Neurosurg Psychiatry. 1993; 56: 149-152
        • Novy J.
        • Belluzzo M.
        • Caboclo L.O.
        • et al.
        The lifelong course of chronic epilepsy: the Chalfont experience.
        Brain. 2013; 136: 3187-3199
        • Gustavson K.H.
        • Holmgren G.
        • Jonsell R.
        • Son Blomquist H.K.
        Severe mental retardation in children in a northern Swedish county.
        J Ment Defic Res. 1977; 21: 161-180
        • Forsgren L.
        Prevalence of epilepsy in adults in northern Sweden.
        Epilepsia. 1992; 33: 450-458
        • Jalava M.
        • Sillanpää M.
        Concurrent illnesses in adults with childhood-onset epilepsy: a population-based 35-year follow-up study.
        Epilepsia. 1996; 37: 1155-1163
        • Sidenvall R.
        • Forsgren L.
        • Heijbel J.
        Prevalence and characteristics of epilepsy in children in northern Sweden.
        Seizure. 1996; 5: 139-146
        • Leach J.P.
        • Lauder R.
        • Nicolson A.
        • Smith D.F.
        Epilepsy in the UK: misdiagnosis, mistreatment, and undertreatment? The Wrexham area epilepsy project.
        Seizure. 2005; 14: 514-520
        • Goodridge D.M.
        • Shorvon S.D.
        Epileptic seizures in a population of 6000. I: Demography, diagnosis and classification, and role of the hospital services.
        Br Med J (Clin Res Ed). 1983; 287: 641-644
        • Scheepers B.
        • Clough P.
        • Pickles C.
        The misdiagnosis of epilepsy: findings of a population study.
        Seizure. 1998; 7: 403-406
        • Jeavons P.M.
        The practical management of epilepsy.
        Update. 1975; 1: 11-15
        • Cross J.H.
        Pitfalls in the diagnosis and differential diagnosis of epilepsy.
        Paediatrics Child Health. 2009; 19: 199-202
        • Camfield P.R.
        • Camfield C.S.
        • Dooley J.M.
        • Tibbles J.A.
        • Fung T.
        • Garner B.
        Epilepsy after a first unprovoked seizure in childhood.
        Neurology. 1985; 35: 1657-1660
        • Hamiwka L.D.
        • Singh N.
        • Niosi J.
        • Wirrell E.C.
        Diagnostic inaccuracy in children with “first seizure”: role for a first seizure clinic.
        Epilepsia. 2007; 48: 1062-1066
        • Hauser W.
        • Annegers J.F.
        • Elveback L.R.
        Mortality in patients with epilepsy.
        Epilepsia. 1980; 21: 399-412
        • Olafsson E.
        • Hauser W.A.
        • Gudmundsson G.
        Long-term survival of people with unprovoked seizures.
        Epilepsia. 1998; 39: 89-92
        • Forsgren L.
        • Sillanpää M.
        Natural course of epilepsies.
        in: Handbook of neurology. vol. 108. Elsevier, Amsterdam2012: 643-661
        • Sillanpää M.
        • Shinnar S.
        Long-term mortality in childhood-onset epilepsy.
        N Engl J Med. 2010; 363: 2522-2529
        • Forsgren L.
        • Hauser A.W.
        • Olafsson E.
        • Sander J.W.A.S.
        • Sillanpää M.
        • Tomson T.
        Mortality of epilepsy in developed countries: a review.
        Epilepsia. 2005; 46: 18-25
        • Sillanpää M.
        • Shinnar S.
        SUDEP and other causes of mortality in childhood onset epilepsy.
        Epilepsy Behav. 2013; 28: 249-255
        • Gaitatzis A.
        • Johnson A.L.
        • Chadwick D.W.
        • Shorvon S.D.
        • Sander J.W.
        Life expectancy in people with newly diagnosed epilepsy.
        Brain. 2004; 127: 2427-2432
        • Sander J.W.A.S.
        • Sillanpää M.
        Natural history prognosis.
        in: Epilepsy. A comprehensive textbook. vol. I/III. Raven Press, New York1997: 69-86
        • Schmidt D.
        • Sillanpää M.
        Evidence-based review on the natural history of the epilepsies.
        Curr Opin Neurol. 2012; 25: 159-163
        • Wakamoto H.
        • Nagao H.
        • Hayashi M.
        • Morimoto T.
        Long-term medical, educational, and social prognoses of childhood-onset epilepsy: a population-based study in a rural district of Japan.
        Brain Dev. 2000; 22: 246-255
        • Oka E.
        • Yamatogi Y.
        • Ohtsuka Y.
        • Ohtahara S.
        Clinical course and prognosis of childhood epilepsy.
        Acta Paediatr Jpn. 1989; 31: 259-266
        • Geerts A.
        • Arts W.F.
        • Stroink H.
        • et al.
        Course and outcome of childhood epilepsy: a 15-year follow-up of the Dutch study of epilepsy in childhood.
        Epilepsia. 2010; 51: 1189-1197
        • Fisher R.A.
        • Acevado C.
        • Arzimanoglou A.
        • et al.
        ILAE official report: a practical clinical definition of epilepsy.
        Epilepsia. 2014; 55: 475-482
        • Sillanpää M.
        • Saarinen M.
        • Schmidt D.
        Clinical conditions of long-term cure in childhood-onset epilepsy: a 45-year follow-up study.
        Epilepsy Behav. 2014; 37: 49-53
        • Sillanpää M.
        Natural course of treated epilepsy and medico-social outcomes, Turku studies. Part II.
        J Epileptol. 2016; 24: 25-39
        • Sillanpää M.
        Remission of seizures and predictors of intractability in long-term follow-up.
        Epilepsia. 1993; 34: 930-936
        • Sillanpää M.
        • Schmidt D.
        Early seizure frequency and aetiology predict long-term medical outcome in childhood-onset epilepsy.
        Brain. 2009; 132: 989-998
        • Sillanpää M.
        • Schmidt D.
        Delayed time to first remission identifies poor long-term drug response of childhood-onset epilepsy: a prospective population-based study.
        Epilepsy Behav. 2009; 16: 507-511
        • Sillanpää M.
        • Schmidt D.
        Seizure clustering during drug treatment affects seizure outcome and mortality of childhood-onset epilepsy.
        Brain. 2008; 131: 938-944
        • Sillanpää M.
        • Shinnar S.
        Status epilepticus in a population-based cohort with childhood-onset epilepsy in Finland.
        Ann Neurol. 2002; 52: 303-310
        • Keränen T.
        • Riekkinen P.
        Remission of seizures in untreated epilepsy.
        BMJ. 1993; 307: 307
        • Sillanpää M.
        • Schmidt D.
        Prognosis of seizure recurrence after stopping antiepileptic drugs in seizure-free patients. A long-term population-based study of childhood-onset epilepsy.
        Epilepsy Behav. 2006; 8: 713-719
        • Löscher W.
        • Schmidt D.
        Modern antiepileptic drug development has failed to deliver: ways out of the current dilemma.
        Epilepsia. 2011; 52: 657-678
        • Sillanpää M.
        • Schmidt D.
        Is incident drug-resistance of childhood-onset epilepsy reversible? A long-term follow-up study.
        Brain. 2012; 135: 2256-2262
        • Besag F.
        • Aldenkamp A.
        • Caplan R.
        • Dunn D.W.
        • Gobbi G.
        • Sillanpää M.
        Psychiatric and behavioural disorders in children with epilepsy. Report of the child neuropsychiatry taskforce, neurobiology commission, international league against epilepsy.
        Epileptic Disord. 2016; 18: 1-114
        • Berg A.T.
        • Shinnar S.
        • Levy S.R.
        • Testa F.M.
        • Smith-Rapaport S.
        • Beckerman B.
        • et al.
        Early development of intractable epilepsy in children: a prospective study.
        Neurology. 2001; 56: 1445-1452
        • Spooner C.G.
        • Berkovic S.F.
        • Mitchell L.A.
        • Wrennall J.A.
        • Harvey A.S.
        New-onset temporal lobe epilepsy in children: lesion on MRI predicts poor seizure outcome.
        Neurology. 2006; 67: 2117-2118
        • Sillanpää M.
        • Schmidt D.
        Predicting antiepileptic drug response in children with epilepsy.
        Expert Rev Neurother. 2011; 1: 877-885
        • Sillanpää M.
        Epilepsy in children: prevalence, disability, and handicap.
        Epilepsia. 1992; 33: 444-449
        • Annegers J.F.
        • Hauser W.A.
        • Elveback L.R.
        Remission of seizures and relapse in patients with epilepsy.
        Epilepsia. 1979; 20: 729-737
        • Yamatogi Y.
        • Ohtahara S.
        Age-dependent encephalopathy: a longitudinal study.
        Folia Psychiatr Neurol Jpn. 1981; 35: 321-332
        • Jeavons P.M.
        • Bower B.D.
        • Dimitrakoudi M.
        Long-term prognosis of 150 cases of “West syndrome”.
        Epilepsia. 1973; 14: 153-164
        • Riikonen R.
        Long-term outcome of west syndrome: a study of adults with a history of infantile spasm.
        Epilepsia. 1996; 37: 367-372
        • Beaumanoir A.
        • Foletti G.
        • Volanschi D.
        Status epilepticus in Lennox-Gastaut syndrome.
        in: Niedermeyer E. Degen R. The Lennox-Gastaut syndrome. AR Liss, New York1988: 283-299
        • Kim H.J.
        • Kim H.D.
        • Lee J.S.
        • Heo K.
        • Kim D.S.
        • Kang H.C.
        Long-term prognosis of patients with Lennox-Gastaut syndrome in recent decades.
        Epilepsy Res. 2015; 110: 10-19
        • Hedström A.
        • Olsson I.
        Epidemiology of absence epilepsy.
        Pediatr Neurol. 1991; 7: 100-104
        • Currier R.D.
        • Kooi K.A.
        • Saidman L.J.
        Prognosis of pure petit mal.
        Neurology. 1963; 13: 959-967
        • Wolf P.
        • Inoue Y.
        Therapeutic response of absence seizures in patients with of an epilepsy clinic for adolescents and adults.
        J Neurol. 1984; 231: 225-229
        • Astradsson A.
        • Olafsson E.
        • Ludvigsson P.
        • Björgvinsson H.
        • Hauser W.A.
        Rolandic epilepsy: an incidence study in Iceland.
        Epilepsia. 1998; 39: 884-886
        • Sillanpää M.
        Long-term prognosis of adults with benign epilepsy of childhood.
        Epileptologia. 2010; 18: 117-123
        • Kokkonen J.
        • Kokkonen E.R.
        • Saukkonen A.L.
        • Pennanen P.
        Psychosocial outcome of young adults with epilepsy in childhood.
        J Neurol Neurosurg Psychiatry. 1997; 62: 265-268
        • Koponen A.
        • Seppälä U.
        • Eriksson K.
        • et al.
        Social functioning and psychological well-being of 347 young adults with epilepsy only – population-based, controlled study from Finland.
        Epilepsia. 2007; 48: 907-912
        • RESt-1Group T.
        Social aspects of epilepsy in the adult in seven European countries.
        Epilepsia. 2000; 41: 998-1004
        • Zielinski J.J.
        Epidemiology and medico-social problems of epilepsy in Warsaw.
        1974
        • Collins J.
        Psychosocial well-being and epilepsy: an empirical study.
        Epilepsia. 1990; 31: 418-426
        • Sillanpää M.
        • Schmidt D.
        Long-term employment of adults with childhood-onset epilepsy: a prospective population-based study.
        Epilepsia. 2010; 51: 1053-1060
        • Kniess T.
        • Stefan H.
        • Brodisch P.
        Diagnosis of epilepsy – consequences for work and a professional activities.
        J Epileptol. 2015; 23: 103-112
        • Dansky L.V.
        • Andermann E.
        • Andermann F.
        Marriage and fertility in epileptic patients.
        Epilepsia. 1980; 21: 261-271
        • Artama M.
        • Isojärvi J.I.
        • Raitanen J.
        • Auvinen A.
        Birth rate among patients with epilepsy: a nationwide population-based cohort study in Finland.
        Am J Epidemiol. 2004; 159: 1057-1063
        • Artama M.
        • Isojärvi J.I.T.
        • Auvinen A.
        Antiepileptic drug use and birth rate in patients with epilepsy – a population-based cohort study in Finland.
        Hum Reprod. 2006; 21: 2290-2295
        • Räty L.
        • Hamrin E.
        • Söderfält B.
        Quality of life in newly-debuted epilepsy. An empirical study.
        Acta Neurol Scand. 1999; 100: 221-226
        • Lindsten H.
        • Stenlund H.
        • Forsgren L.
        Leisure time and social activity after a newly diagnosed unprovoked epileptic seizure in adult age. A population-based case-referent study.
        Acta Neurol Scand. 2003; 107: 125-133