Seizure 44 (2017) 211–216

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Seizure
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Review

Long-term outcome of medically treated epilepsy

M. Sillanpää a,*, D. Schmidt b
a
Departments of Child Neurology and Public Health, University of Turku and Turku University Hospital, Turku, Finland
b
Epilepsy Research Group, Berlin, Germany

A R T I C L E I N F O A B S T R A C T

Article history: Purpose: To review the long-term outcome of epilepsy in[12_TD$IF] population-based studies.
Received 15 August 2016 Method: Analysis of population-based studies.
Received in revised form 1 September 2016 Results: About two of three patients with new-onset epilepsy will, in the long run, enter five-year
Accepted 4 September 2016
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,
Keywords: however, may have become better because of the improved level of knowledge on and public attitudes
Drug-treated epilepsy
toward people with epilepsy, and possibly fewer prejudices at home, daycare, school, military and labor
Long-term seizure prognosis
market.
Natural course
Population-based study Conclusion: While we still do not have a cure for epilepsy for all patients, relief of the medical and social
Long-term social outcome consequences is available for many and hope is on the horizon for people with epilepsy.
ß 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

1. Introduction [4–6,8,11–13]. The review and discussion of the present paper is

mainly, but not only, focused on the contribution of population-
The first attempts, in a modern sense, to explore the medical based reports.
and social outcome of patients with epilepsy were made in the
1950s [1] and 1960s [2] based on patients from hospitals and other
2. Prospective cohort studies
institutions. According to those studies and the previous literature
from 1901 to 1964 discussed by Rodin [2], the five-year terminal
2.1. Population-based long-term studies [11,12]
remission varied by etiology between 15 and 30%. Yet, studies
based on unselected population cohorts are needed to get unbiased
The recruitment of study subjects of Brorson [11] was from the
and valid data on this chronic disorder. The data are important for
Swedish province of Uppsala (total population of 0–19 years of age,
the treating doctor, but have usually have also many medical and
n = 54,000) including general and epilepsy hospital inpatients and
social implications for the patients and society. The first
outpatients and clients from provincial medico-social board and
population-based study, the Rochester Study [3], designed as a
special school registers, and the EEG laboratory of the university
record linkage system and linking on one record clinical data
hospital of Uppsala. Excluded were patients with neonatal seizures
derived 1935–1967 from inpatient, outpatient, emergency room
during the three first days of life; provoked seizures; unprovoked
contacts and home visits by health professionals at the Mayo
non-convulsive epileptic attacks; and potential study subjects not
Clinic. In long-term follow-up, 40% had entered terminal 5-year
medically treated for epilepsy. The baseline study sample included
remission [3]. In more recent population studies, about two thirds
195 children and adolescents aged 0–19 years who had had at least
were in 5-year terminal remission [4–7]. The improved prognosis
one provoked seizure in 1961–1964 and were thus considered as
can be ascribed, among other things, to advanced externally valid
having active epilepsy. The study is apparently population-based.
study populations, diagnostic methods and therapeutic armament
The baseline paper is a survey reported in Swedish by the national
[5,8–10]. Only a few long-term (more than 10 years), prospective
Social Board of Sweden in 1970 and not easily accessible. The
unselected population-based cohort studies have been reported
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.
* Corresponding author at: Department of Public Health, University of Turku, In the Turku study [12], recently re-named as the Turku Adult
Turku 20014, Finland. Childhood Onset Epilepsy (TACOE) study, the source population

http://dx.doi.org/10.1016/j.seizure.2016.09.002
1059-1311/ß 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
212 M. Sillanpää, D. Schmidt / Seizure 44 (2017) 211–216

consisted of children aged 15 years or less who were living in the However, institutions for patients who have epilepsy do exist in
catchment area of Turku University Hospital at the end of 1964 the UK [27,28], and it is well-known that institutionalized patients,
(n = 108,019), and had unprovoked seizures [14]. Epilepsy was and those with mental comorbidity in particular, are at markedly
defined as repeated, unprovoked seizures 24 h apart at the age of higher risk of epilepsy than those living in the community;
4 weeks to 15 years. Epileptic seizures and syndromes were later percentages between 25 and 40% [29–32] have been reported. The
re-classified [15] to be in line with the update ILAE definitions [16– enrolment method per se then excludes institutionalized patients,
18]. Active epilepsy was defined as onset of epilepsy in 1961–1964 because they are virtually invisible to GPs. An obvious weakness in
or one or more unprovoked seizures in a child with the diagnosis of GP-based inclusion method is external and internal validity [33],
epilepsy ascertained before 1961. Children with epilepsy were among other things, over-diagnoses and under-diagnoses
identified by reviewing the files from the following data sources: [34,35]. A study from Glasgow, UK, found that 799 (69%) of
inpatient and outpatient clinical and EEG records of hospitals and 1156 adults with a diagnosis of epilepsy had never attended local
institutions for mentally retarded or cerebral palsy in the epilepsy clinic and 55% of the population on antiepileptic
catchment area of Turku University Hospital and any hospitals medication had never received specialist advice [33]. The problem
or institutions the whole southern Finland potentially treating or concerns also children with epilepsy in the UK [36,37]. The study
having treated children with epilepsy; special schools in the area; comprised 302 patients with a single unprovoked seizure at
and community general practitioners’ offices and private offices’ presentation and 354 patients with epilepsy (two or more
records. Finally, the National Health Service Register data of unprovoked seizures) at presentation. In 318 patients, 73% were
refundable antiepileptic drugs for epilepsy (but not for other in 5-year terminal remission at the end of follow-up and 80% in
indications) could be reviewed by permission of the public those who could be followed up to the last contact. The 73% is
authorities. That method of approach detected five cases not probably calculated up to the last contact or death, whichever
earlier identified, but then proven to fulfill the inclusion criteria. came first, and the comparable with the previous studies.
Thus, the enrolment of the subjects was not only based on hospital Overall, approximately two thirds are in terminal remission
and institution records, but any public or private health units and, (Table 1).
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 2.3. Hospital-based studies
epilepsy. The special school and community and private office
records did not virtually contribute to the data collection, because Hospital-based studies are, mainly due to their easier feasibili-
all the relevant cases had been identified by the hospital records. ty, much more common than population studies. Typically, the
This was not unexpected, because there was and still is a rule in hospital studies rely on inpatient and outpatients of one tertiary
Finland that every child with an epileptic or suspected epileptic care hospital. Even in case of multi-institutional recruitment of
seizure should be referred to hospital with pediatric or child study subjects, they are approximations of the real prevalence and
neurological expertise [5,19]. Access to board-certified pediatri- incidence, because those studies are subject to selection bias and,
cian became possible all over the country since the 1950s to 1960s, subsequently, a weak external validity. The risk of a selection bias
when the countrywide network of tertiary care hospitals with is still higher, if the study population is based on one laboratory
pediatric departments was built and enabled specialist care for clients. In such a study, no more than 86% of regional physicians
children despite the place of residence in Finland [20]. The indicated they use to order an EEG after a first seizure [38]. A
registers of the national social security institution, based on the potential gap between intention and practice was not tested.
legislation largely copied form the British national health service, Among 127 children referred as patients of ‘‘first seizure’’ to a
effective since 1964, has been proved to be a reliable source of data tertiary care First Seizure Clinic, the diagnosis was epileptic in 74%,
for research purposes in many reports [21–24]. among patients referred by family physicians only 65% and an EEG
The review of all the above mentioned records including EEG done in all 127 children was abnormal in 41% [39]. Without
statements was made by one child neurologist (M.S.) who also
clinically examined all the 245 children who were ascertained as Table 1
children with epilepsy. One hundred and fifty children were Five-year terminal remission (5-YTR) reported from population-based and
institution-based long-term studies. I = incident cases; P = prevalent cases.
ascertained as incident cases, that is, they were first evaluated for
epilepsy in 1961–1964. The remaining 95 patients were diagnosed Study design Duration of 5-YTR (%) Author(s) and year
as prevalent cases, whose diagnosis of epilepsy was made before follow-up on or off
(years) medication
1961, but who had one or more unprovoked seizure during 1961–
1964 [5,12]. In addition to the reviewed records, EEG and clinical Population-based, prospective studies
neurological examination data, additional EEG and neuroimaging I&P (n = 227) 10 56 Sillanpää, 1983
I&P (n = 178) 20 58 Sillanpää, 1990
investigations were performed on clinical grounds, if needed.
I&P (n = 220) 30 64 Sillanpää et al., 1998
Ongoing surveillance after the baseline study detected only very I%P (n = 220) 40 61 Sillanpää et al., 1998
few children who fulfilled the inclusion criteria and should have I (n = 144) 40 67 Sillanpää et al., 2006
been considered in an epidemiological analysis. On 35-year follow- Surviving I&P (n = 133) 45 70 Sillanpää et al., 2015
Cases with one or 22 68 Cockerell et al., 1997
up, 67% were in five-year remission [5,25].
more, probably
unprovoked
2.2. Community based study [10] seizures (n = 228)

Population-based, retrospective studies

The British national general practice study of epilepsy (NGPSE), I (n = 475) 10 65 Annegers et al., 1979
with the study subjects followed for 25 years [26], was based on a I (n = 141) 20 70 Annegers et al., 1979
surveillance process with 275 general practitioners (GPs) recruit-
Hospital-based cohort studies
ing al patients of different ages who had any definite or possible I (n = 730) 10 79 Oka et al., 1989
new-onset epileptic seizures during 1984–1987. The method of I&P (n = 141) 10 52 Wakamoto et al., 2000
recruiting patients only covered those living in the community. I&P (n = 75) 20 56 Wakamoto et al., 2000
Subsequently, patients who resided in institutions (institutions for I (n = 413) 15 71 Geerts et al., 2010
I (n = 516) 21 60 Berg and Rychlik, 2015
mentally retarded, nursing homes or prisons) were excluded.
 M. Sillanpää, D. Schmidt / Seizure 44 (2017) 211–216
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 [40–42]. 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 30–4000 , ‘‘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
213
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 disor-
ders, 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]. Symp-
tomatic 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 [29–32]. 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 comor-
bidity 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
214 M. Sillanpää, D. Schmidt / Seizure 44 (2017) 211–216
(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
[9,83,84], 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]. Com-
pared 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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