FULL-LENGTH ORIGINAL RESEARCH
Prevalence and etiology of epilepsy in a Norwegian county—A population based study *Marte Syvertsen, †Karl Otto Nakken, *Astrid Edland, *Gunnar Hansen, *Morten Kristoffer Hellum, and *Jeanette Koht Epilepsia, 56(5):699–706, 2015 doi: 10.1111/epi.12972
SUMMARY
Marte Syvertsen is a resident physician at the Department of Neurology, Drammen Hospital, Norway.
Objective: Epilepsy represents a substantial personal and social burden worldwide. When addressing the multifaceted issues of epilepsy care, updated epidemiologic studies using recent guidelines are essential. The aim of this study was to find the prevalence and causes of epilepsy in a representative Norwegian county, implementing the new guidelines and terminology suggested by the International League Against Epilepsy (ILAE). Methods: Included in the study were all patients from Buskerud County in Norway with a diagnosis of epilepsy at Drammen Hospital and the National Center for Epilepsy at Oslo University Hospital. The study period was 1999–2014. Patients with active epilepsy were identified through a systematic review of medical records, containing information about case history, electroencephalography (EEG), cerebral magnetic resonance imaging (MRI), genetic tests, blood samples, treatment, and other investigations. Epilepsies were classified according to the revised terminology suggested by the ILAE in 2010. Results: In a population of 272,228 inhabitants, 1,771 persons had active epilepsy. Point prevalence on January 1, 2014 was 0.65%. Of the subjects registered with a diagnostic code of epilepsy, 20% did not fulfill the ILAE criteria of the diagnosis. Epilepsy etiology was structural-metabolic in 43%, genetic/presumed genetic in 20%, and unknown in 32%. Due to lack of information, etiology could not be determined in 4%. Significance: Epilepsy is a common disorder, affecting 0.65% of the subjects in this cohort. Every fifth subject registered with a diagnosis of epilepsy was misdiagnosed. In those with a reliable epilepsy diagnosis, every third patient had an unknown etiology. Future advances in genetic research will probably lead to an increased identification of genetic and hopefully treatable causes of epilepsy. KEY WORDS: Epilepsy, Epidemiology, Prevalence, Classification, Norway.
Epilepsy is a complex neurologic condition comprising different syndromes and diseases characterized by recurrent unprovoked seizures. In Europe, approximately 3.4 million people have epilepsy,1 and the total cost of illness is believed to be about 15 billion Euro per year.2 The burden Accepted February 17, 2015; Early View publication March 25, 2015. *Department of Neurology, Drammen Hospital, Drammen, Norway; and †National Center for Epilepsy, Oslo University Hospital, Oslo, Norway Address correspondence to Marte Syvertsen, Department of Neurology, Drammen Hospital, 3004 Drammen, Norway. E-mail: marsyv@vestre viken.no Wiley Periodicals, Inc. © 2015 International League Against Epilepsy
of epilepsy is not connected only to recurrent seizures, but also to important aspects of life such as work and education, mental health, family, and social activities.3 Epidemiologic research is essential to plan and provide sufficient care for these patients. The epidemiology of epilepsy has been thoroughly investigated in different parts of the world,4,5 but different definitions of epilepsy and study designs make it difficult to compare the results. Several studies include adult or pediatric populations only, and case ascertainments vary from hospital-based to door-to-door surveys to studies based on antiepileptic drug prescription.1,4,5 Consequently, the International League Against Epilepsy (ILAE) recently
699
700 M. Syvertsen et al. published new standards for epidemiologic studies and surveillance of epilepsy, using the revised terminology and concepts for organization of seizures and epilepsies suggested by the ILAE in 2010.6,7 To the best of our knowledge, five European studies have determined prevalence of epilepsy, comprising all age groups based on a retrospective review of hospital records.8–12 They were all published prior to the updated ILAE criteria, and the methodologies are slightly incongruent. Through a record-based approach, including all age groups, our aim was to assess the prevalence of epilepsy in a representative Norwegian county, implementing the recently proposed guidelines and terminology of the ILAE.
Methods Study design The study was cross-sectional and population-based. We followed the strengthening the reporting of observational studies in epidemiology (STROBE) guidelines.13 Study area and population Drammen Hospital serves the patients from Buskerud County, which covers an area of 14,908 km2 and comprises 21 municipalities. The most recent national census of January 1, 2014, listed 272,228 inhabitants in Buskerud, or 5.3% of the Norwegian population. During the last 10 years, the number of inhabitants in Buskerud County increased with 12.3%.14 Due to a well-established welfare system, demographic data such as socioeconomic status, access to healthcare, and age-distribution are fairly equal and stable across our country. In Norway, it is a common practice to refer all patients with suspected epilepsy to a specialist for clinical evaluation and electroencephalography (EEG), as stated in the guidelines commonly used by neurologists and pediatricians across the country.15 Norway is well covered when it comes to specialists in neurology, currently with one registered specialist per 10,000 inhabitants.16 Buskerud County has only one neurologic ward and one pediatric ward, and one private neurologist and two private pediatricians. In addition, a private neurologic outpatient clinic and a tertiary referral center for epilepsy are located 15 and 17 km, respectively, from the county border. The referral center receives patients with difficult-to-treat epilepsy from all over Norway. The only EEG laboratory in Buskerud County is located at the Neurological Department of Drammen Hospital. Subject collection We performed a systematic search of the electronic coding system at the Department of Neurology, Pediatrics, Neurohabilitation and EEG laboratory at Drammen Hospital, using the International Classification System of Diseases (ICD).17 The search covered all subjects with a diagnostic Epilepsia, 56(5):699–706, 2015 doi: 10.1111/epi.12972
code of epilepsy, that is, ICD-10 codes G40.0-9, in the period from January 1, 1999 to January 1, 2014. We also identified subjects from Buskerud County at the tertiary referral center for epilepsy. An electronic search was performed at the center’s pediatric and adult outpatient clinic from January 1, 2010 to January 1, 2014. This search was not based on ICD-10 codes, but included the medical records of all subjects with a registered address in Buskerud County. The list of subjects seen at the referral center was not searchable prior to 2010. The medical records of each identified subject were thoroughly reviewed, and findings were recorded in a database by one researcher (MS). Diagnosis and classification was performed by a single reviewer (MS), based on conclusions from treating physicians and supervised by the coauthors with more than 20 years of experience in epileptology. Electroclinical epilepsy syndromes were diagnosed by the treating physicians. Inclusion and exclusion criteria All subjects with active epilepsy, who lived in Buskerud County and were alive on the prevalence day (January 1, 2014), were included (Fig. 1). Subjects with only febrile seizures, neonatal seizures, a solitary unprovoked seizure, or acute symptomatic seizures were excluded, as suggested by Thurman et al.6 Definitions and classification Epilepsy was defined as two unprovoked seizures occurring at least 24 h apart.6,18 Active epilepsy was defined as current treatment with antiepileptic medication or at least one seizure within the last 5 years.6,18 The group of subjects with misdiagnosed epilepsy was divided into six categories: (1) febrile seizures, (2) neonatal seizures, (3) solitary unprovoked seizures, (4) acute symptomatic seizures, (5) paroxysmal symptoms not consistent with epilepsy, and (6) others. Subjects with syncope or psychogenic seizures were included in the category of paroxysmal symptoms not consistent with epilepsy. The last category included subjects examined for concentration problems, subjects without seizures but with subclinical epileptiform activity in the EEG, and some with different conditions (for example migraine) who were mistakenly registered with epilepsy. Seizures were simply classified as focal or generalized. The etiology of epilepsy was classified as genetic/presumed genetic, structural-metabolic, or unknown, as suggested by the ILAE.6,7 The structural-metabolic epilepsies were grouped into 12 different categories as listed in the guidelines of the ILAE.6 Specific electroclinical syndromes were identified when possible.7 When prevalence was calculated for each municipality separately, those with an administrative center located more than 50 km from Drammen Hospital were considered rural. The remaining were considered central.
701 Epilepsy in a Norwegian County
Figure 1. Prevalence of epilepsy in Buskerud County. Epilepsia ILAE
Potential sources of bias Medical record information from only two main sources is a potential weakness of this study. However, there are just a few other specialists treating epilepsy in the area. For the private neurologist and pediatricians in the county, EEG equipment was not available. Thus, patients had to be referred to the hospital whenever an EEG was indicated. By selecting every eighth subject identified through our search at Drammen Hospital, we found that 193 of 200 were registered with at least one EEG recording during the last 15 years. Of the remaining seven, three had intellectual disability, making it difficult to conduct the test, three were diagnosed with epilepsy more than 15 years ago and remained stable on medication, and one had epilepsy secondary to glioblastoma. The National Center for Epilepsy has a large EEG laboratory. We suspected that a number of patients from Buskerud County were followed up there without being registered at Drammen Hospital. Thus, a separate electronic search was performed at the outpatient clinic of
the center, followed by a thorough review of medical records. Statistical methods Chi-square test was used for comparison of categorical variables, and p < 0.05 was considered statistically significant. Point prevalence was calculated based on the national census of January 1, 2014.14 A de facto power estimation was performed. Based on the present study, a point prevalence of epilepsy of 0.65% was estimated from a total population of 272,228 inhabitants in Buskerud County. On the condition of no misclassification of the disease, a source sample population of at least 72,721 subjects is needed to catch a prevalence of 0.65% with a precision interval from 0.60% to 0.70% and a probability of 95%. Ethics The study was approved by the Regional Committee for Medical Research Ethics, South East Norway (ethical agreement no. 2013/1027). Epilepsia, 56(5):699–706, 2015 doi: 10.1111/epi.12972
702 M. Syvertsen et al. Table 2. Nonepilepsy with a diagnostic code of epilepsy
Results Prevalence estimates At Drammen Hospital, we identified 1,717 subjects with active epilepsy. Through the additional search at the National Center for Epilepsy, we found 165 subjects from Buskerud County with active epilepsy, of which 111 were already in our database. Compared to the group followed at Drammen Hospital only, there were no differences in geographical or age distribution. However, there was a high percentage of refractory epilepsy at the referral center; 108 subjects (65%) had at least one seizure during the last year, and 134 (81%) had at least one seizure during the last 5 years. In the 54 patients followed at the epilepsy center only, mean age was significantly higher than in the 111 patients identified at both hospitals (44 14 and 34 17 years, respectively, p < 0.001). The total number of subjects with active epilepsy alive on the prevalence day (January 1, 2014) was 1,771 (Fig. 1). The prevalence of active epilepsy in Buskerud County was 6.5 per 1,000 inhabitants, with a 95% confidence interval of 6.2–6.8. There were 852 females and 919 males. There was no significant gender difference in prevalence; 6.3 per 1,000 females and 6.7 per 1,000 males (p = 0.15). Age-specific prevalence is shown in Table 1. When prevalence was calculated for each of the 21 municipalities separately, there was no significant difference between central and rural areas (p = 0.23) (Table S1). Excluded subjects Of the 2,662 subjects with a diagnostic code of epilepsy at Drammen Hospital, 538 (20%) did not fulfill the ILAE criteria of the diagnosis.6,18 The most common reason was paroxysmal symptoms not consistent with epilepsy (Table 2). Positive predictive value of the ICD-10 code G40 (epilepsy) at Drammen Hospital was 0.8. Of the 2,124 subjects with confirmed epilepsy at Drammen Hospital, 407 (19%) no longer had active epilepsy on the prevalence day. At the National Center for Epilepsy, 8
Table 1. Age-specific prevalence of epilepsy in Buskerud County Age 0–4 5–9 10–14 15–19 20–29 30–39 40–49 50–59 60–69 70–79 >80
Subjects with epilepsy
Population
Prevalence per 1,000
34 93 132 111 230 216 252 228 240 142 93
15,647 16,757 16,385 16,988 32,375 35,511 41,165 35,363 32,170 17,768 12,099
2.2 5.5 8.1 6.5 7.1 6.1 6.1 6.4 7.5 8.0 7.7
Epilepsia, 56(5):699–706, 2015 doi: 10.1111/epi.12972
Cause Paroxysmal symptoms not consistent with epilepsy Solitary unprovoked seizure Acute symptomatic seizures Febrile seizures Neonatal seizures Others
N = 538
Percent
239 124 87 15 6 67
44 23 16 3 1 12
(5%) of 173 no longer had active epilepsy. All in all, 415 (18%) of 2,297 subjects did no longer have active epilepsy (Fig. 1). Seizures In 1,127 subjects (64%) seizure-onset was focal only, whereas 538 (30%) had generalized-onset seizures only. Seventeen (1%) had both focal and generalized-onset seizures, of which 15 had rare genetic syndromes. The remaining two had intellectual disability of unknown cause, with developmental delay prior to onset of seizures. In 15 subjects (0.8%), the seizure type could not be classified as focal or generalized, including seven with West syndrome and epileptic spasms. Seizure type could not be determined in another 74 (4%) due to lack of information in the medical records. Etiology Etiology of epilepsy in Buskerud County is summarized in Figure 2. A genetic diagnosis was established in 49 (3%) of the included subjects (Table S2). In 37 of these, the mutation was not the direct cause of epilepsy, and the seizures were not the core symptom of the disorder. Consequently, they were allocated to the structural-metabolic epilepsy group. The remaining 12 (0.6%) were placed among the genetic epilepsies. Three had Dravet syndrome, two had febrile seizures plus (FS+), six had glucose transporter 1 (GLUT1) deficiency syndrome, and one had West syndrome, possibly caused by a chromosomal 1.2 Mb deletion (19p13.2-p13.13).19,20 In 347 subjects (20%), the etiology was presumed to be genetic, but no genetic diagnosis had yet been established. Of these, 27 had a history consistent with an epileptic encephalopathy, with seizures occurring prior to the developmental delay, but where no specific etiology had been identified. The remaining 320 subjects would formerly have been classified as having idiopathic generalized epilepsy (IGE), now named genetic generalized epilepsy (GGE). Structural-metabolic epilepsy was diagnosed in 767 subjects (43%). The most common cause was stroke. In 571 subjects (32%) the cause of epilepsy was unknown. This included subjects with benign epilepsy with centrotemporal spikes (BECTS) and a substantial group of subjects with focal seizures of unknown etiology. In 74 subjects (4%) the etiology could not be determined due to lack of information.
703 Epilepsy in a Norwegian County
Figure 2. Etiology of epilepsy in Buskerud County. Epilepsia ILAE
Electroclinical syndromes A specific electroclinical syndrome was diagnosed in 249 subjects (14%) (Table 3). Absence epilepsy (childhood absence epilepsy and juvenile absence epilepsy) was the most common, followed by juvenile myoclonic epilepsy (JME). Of the 320 subjects with GGE, 146 (46%) did not have a specific syndrome diagnosis (Fig. 2).
Discussion To the best of our knowledge, this is the first epidemiologic study that implements the recently revised terminology for organization of seizures and epilepsies.7 Through a thorough review of more than 2,500 medical records, we have mapped the different subgroups of epilepsy and identified a substantial group of subjects not fulfilling the diagnostic criteria. In the Norwegian county of Buskerud, we found the prevalence of epilepsy to be 0.65%. This is in accordance with five other European studies using a comparable method, but
Table 3. Electroclinical epilepsy syndromes N = 249
Electroclinical syndromes Epilepsy of infancy with migrating focal seizures West syndrome Myoclonic epilepsy in infancy (MEI) Dravet syndrome Febrile seizures plus (FS+) Panayiotopoulos syndrome Epilepsy with myoclonic atonic seizures (Doose syndrome) Benign epilepsy with centrotemporal spikes (BECTS) Lennox-Gastaut syndrome Epilepsy with continuous spike-and-wave during sleep (CSWS) Childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE) Juvenile myoclonic epilepsy (JME)
1 7 4 3 2 2 3 45 9 2 90 81
older classification systems.8–12 In two of the studies, the definition of active epilepsy was identical to ours. They were both Italian and found prevalences of 5.1/1,000 and 6.2/1,000, respectively.9,11 Epilepsia, 56(5):699–706, 2015 doi: 10.1111/epi.12972
704 M. Syvertsen et al. In rural Iceland, epilepsy prevalence was somewhat lower (4.8/1,000), but stricter inclusion criteria were employed. Active epilepsy was defined as at least one seizure within the last year or the use of antiepileptic medication for at least one year prior to the prevalence day.12 In a study from the Faroes, the definition of active epilepsy was also slightly stricter. Subjects taking antiepileptic medication, but who were seizure free for more than 5 years, were excluded. Surprisingly, the prevalence was quite high (7.6/1,000). The authors emphasized that the medical records of this study were usually written by physicians without special interest in epilepsy. Thus, some cases of nonepilepsy could have been misdiagnosed as epilepsy.10 The fifth study using a method comparable to ours, was from Northern Norway. Prevalence of epilepsy was rather low at 3.5/1,000. This study was conducted in a sparsely populated area >40 years ago, where main sources of income were related to fishing, farming, and transport. Thus, concealment caused by economic and social consequences could be substantial. Moreover, access to health care was limited because of geographical distance.8 Two recent Norwegian studies investigated the epidemiology of epilepsy in adults. They are not directly comparable to ours, because of different methods and smaller populations. In Oppland County, prevalence was calculated in five specific age groups. Mean prevalence of active epilepsy was 8.2/1,000.21 The other study from a small Norwegian municipality identified subjects by individual interview.22 Prevalence was high (11.7/1,000), even when the upper age limit for inclusion was 65 years and people with learning disabilities, mental disorders, or dementia were excluded. Response rate was 89%. Nevertheless, as the authors emphasize, a selection bias is possible. The original interview focused on headache, and an association between headache and seizures had been shown.23,24 Finally, estimating prevalence in small populations is difficult due to lack of statistical power. In the present study, case ascertainment may be incomplete, as the medical records of private neurologists and pediatricians were not searched. However, we believe this source of error to be minor, as most patients in Norway are examined with at least one EEG. During the last 15 years we found this to be the case for 97% of our 200 randomly selected patients. In addition, we believed that patients in central areas were more likely to be missed because of follow-up at a private facility. Thus, we compared prevalences in the central municipalities to those located >50 km away, but found no difference (Table S1). We expected to find several new subjects from Buskerud County through our search at the National Center for Epilepsy. The time period searched was shorter than that at Drammen Hospital. However, we think that most patients at the referral center were seen at least once during a 4-year period, as complex epilepsy requires close follow-up. More Epilepsia, 56(5):699–706, 2015 doi: 10.1111/epi.12972
than two thirds of the subjects identified at the referral center were already in our database, and final prevalence estimate rose by only 0.02%. Thus, we think additional searches at the few private clinics in the area would have had little impact on our results. As expected, we found a slightly higher prevalence of epilepsy in the elderly. We do, however, suspect an underreporting of cases in this age group. Compared to a door-to-door study of the elderly population in a suburb of Rotterdam, we found a considerably lower prevalence in the oldest age group. In the Rotterdam study, 1.2% of the population aged 85–94 had active epilepsy,25 compared to 0.77% (aged >80) in our material. Patients with significant comorbidities, for instance in nursing homes, may sometimes be diagnosed with epilepsy by telephone consultation only. Such consultations are not routinely registered with a diagnostic code at our hospital. Moreover, structural-metabolic epilepsy and focal seizures are more common in the elderly.26 It is not unlikely that, especially in this age group, nonconvulsive symptoms sometimes go unnoticed, leading to additional underestimation of hospital-based epilepsy prevalence in the elderly. We assume that the specificity of this study is high, as each case was verified through a thorough review of the medical record. Most of these records were written by neurologists or pediatricians with a special interest in epilepsy. Nevertheless, 538 subjects (20% of the original cohort) had been wrongly coded as epilepsy and were excluded. Because the ICD-10 code is needed mainly for administrative reasons, we think clinicians sometimes choose it swiftly, for example, based on preprinted lists available at the outpatient clinics. As a consequence, the code may sometimes differ from the doctor’s final conclusion and diagnosis, accessible through the detailed information of the medical record only. Epidemiologic studies of epilepsy based merely on existing coded data, may lead to a considerable overestimation of prevalence. A recent register-based study from Sweden found a noticeably higher prevalence of epilepsy (8.8/1,000) than the present study. However, lifetime prevalence was reported, as opposed to prevalence of active epilepsy.27 In regard to etiology, we have not been able to find other epidemiologic studies using the revised terminology proposed by the ILAE in 2010.7 Roughly, the new categories of genetic/presumed genetic, structural-metabolic and unknown correspond to the previous idiopathic, symptomatic, and cryptogenic. It is suggested that some syndromes formerly called idiopathic (namely myoclonic epilepsy in infancy, BECTS, Panayiotopoulos syndrome, and benign occipital epilepsy of Gastaut type) should now be placed under the category of unknown cause.7 Fifty-one of our subjects had one of these syndromes. We found no cases of genetic epilepsy with focal-onset seizures only (autosomal dominant nocturnal frontal lobe epilepsy [ADNFLE], autosomal dominant epilepsy with auditory features [ADEAF]).
705 Epilepsy in a Norwegian County These epilepsies have been categorized as cryptogenic, but would now be replaced to the genetic group. A potential weakness of the present study, is that classification was performed by one reviewer only, based on conclusions from treating physicians. Electroclinical syndromes were diagnosed by the treating physicians. It is a limitation to the study that diagnoses of electroclinical syndromes were not reevaluated by the authors, and that interrater reliability was not addressed. Our results are partly in agreement with Granieri et al. and Olafsson et al., who divided epilepsies into two broad etiologic categories: symptomatic and unknown. In the study by Granieri et al.,9 40% of epilepsies were symptomatic and 60% were of unknown etiology. Olafsson et al.12 found etiology to be symptomatic in 38% and unknown in 62%. In our material, 43% had structural-metabolic epilepsy, whereas a joint category of genetic and unknown etiology constituted 52%. Only 3% of our subjects had a verified genetic diagnosis, and
Prevalence and etiology of epilepsy in a Norwegian county—A population based study *Marte Syvertsen, †Karl Otto Nakken, *Astrid Edland, *Gunnar Hansen, *Morten Kristoffer Hellum, and *Jeanette Koht Epilepsia, 56(5):699–706, 2015 doi: 10.1111/epi.12972
SUMMARY
Marte Syvertsen is a resident physician at the Department of Neurology, Drammen Hospital, Norway.
Objective: Epilepsy represents a substantial personal and social burden worldwide. When addressing the multifaceted issues of epilepsy care, updated epidemiologic studies using recent guidelines are essential. The aim of this study was to find the prevalence and causes of epilepsy in a representative Norwegian county, implementing the new guidelines and terminology suggested by the International League Against Epilepsy (ILAE). Methods: Included in the study were all patients from Buskerud County in Norway with a diagnosis of epilepsy at Drammen Hospital and the National Center for Epilepsy at Oslo University Hospital. The study period was 1999–2014. Patients with active epilepsy were identified through a systematic review of medical records, containing information about case history, electroencephalography (EEG), cerebral magnetic resonance imaging (MRI), genetic tests, blood samples, treatment, and other investigations. Epilepsies were classified according to the revised terminology suggested by the ILAE in 2010. Results: In a population of 272,228 inhabitants, 1,771 persons had active epilepsy. Point prevalence on January 1, 2014 was 0.65%. Of the subjects registered with a diagnostic code of epilepsy, 20% did not fulfill the ILAE criteria of the diagnosis. Epilepsy etiology was structural-metabolic in 43%, genetic/presumed genetic in 20%, and unknown in 32%. Due to lack of information, etiology could not be determined in 4%. Significance: Epilepsy is a common disorder, affecting 0.65% of the subjects in this cohort. Every fifth subject registered with a diagnosis of epilepsy was misdiagnosed. In those with a reliable epilepsy diagnosis, every third patient had an unknown etiology. Future advances in genetic research will probably lead to an increased identification of genetic and hopefully treatable causes of epilepsy. KEY WORDS: Epilepsy, Epidemiology, Prevalence, Classification, Norway.
Epilepsy is a complex neurologic condition comprising different syndromes and diseases characterized by recurrent unprovoked seizures. In Europe, approximately 3.4 million people have epilepsy,1 and the total cost of illness is believed to be about 15 billion Euro per year.2 The burden Accepted February 17, 2015; Early View publication March 25, 2015. *Department of Neurology, Drammen Hospital, Drammen, Norway; and †National Center for Epilepsy, Oslo University Hospital, Oslo, Norway Address correspondence to Marte Syvertsen, Department of Neurology, Drammen Hospital, 3004 Drammen, Norway. E-mail: marsyv@vestre viken.no Wiley Periodicals, Inc. © 2015 International League Against Epilepsy
of epilepsy is not connected only to recurrent seizures, but also to important aspects of life such as work and education, mental health, family, and social activities.3 Epidemiologic research is essential to plan and provide sufficient care for these patients. The epidemiology of epilepsy has been thoroughly investigated in different parts of the world,4,5 but different definitions of epilepsy and study designs make it difficult to compare the results. Several studies include adult or pediatric populations only, and case ascertainments vary from hospital-based to door-to-door surveys to studies based on antiepileptic drug prescription.1,4,5 Consequently, the International League Against Epilepsy (ILAE) recently
699
700 M. Syvertsen et al. published new standards for epidemiologic studies and surveillance of epilepsy, using the revised terminology and concepts for organization of seizures and epilepsies suggested by the ILAE in 2010.6,7 To the best of our knowledge, five European studies have determined prevalence of epilepsy, comprising all age groups based on a retrospective review of hospital records.8–12 They were all published prior to the updated ILAE criteria, and the methodologies are slightly incongruent. Through a record-based approach, including all age groups, our aim was to assess the prevalence of epilepsy in a representative Norwegian county, implementing the recently proposed guidelines and terminology of the ILAE.
Methods Study design The study was cross-sectional and population-based. We followed the strengthening the reporting of observational studies in epidemiology (STROBE) guidelines.13 Study area and population Drammen Hospital serves the patients from Buskerud County, which covers an area of 14,908 km2 and comprises 21 municipalities. The most recent national census of January 1, 2014, listed 272,228 inhabitants in Buskerud, or 5.3% of the Norwegian population. During the last 10 years, the number of inhabitants in Buskerud County increased with 12.3%.14 Due to a well-established welfare system, demographic data such as socioeconomic status, access to healthcare, and age-distribution are fairly equal and stable across our country. In Norway, it is a common practice to refer all patients with suspected epilepsy to a specialist for clinical evaluation and electroencephalography (EEG), as stated in the guidelines commonly used by neurologists and pediatricians across the country.15 Norway is well covered when it comes to specialists in neurology, currently with one registered specialist per 10,000 inhabitants.16 Buskerud County has only one neurologic ward and one pediatric ward, and one private neurologist and two private pediatricians. In addition, a private neurologic outpatient clinic and a tertiary referral center for epilepsy are located 15 and 17 km, respectively, from the county border. The referral center receives patients with difficult-to-treat epilepsy from all over Norway. The only EEG laboratory in Buskerud County is located at the Neurological Department of Drammen Hospital. Subject collection We performed a systematic search of the electronic coding system at the Department of Neurology, Pediatrics, Neurohabilitation and EEG laboratory at Drammen Hospital, using the International Classification System of Diseases (ICD).17 The search covered all subjects with a diagnostic Epilepsia, 56(5):699–706, 2015 doi: 10.1111/epi.12972
code of epilepsy, that is, ICD-10 codes G40.0-9, in the period from January 1, 1999 to January 1, 2014. We also identified subjects from Buskerud County at the tertiary referral center for epilepsy. An electronic search was performed at the center’s pediatric and adult outpatient clinic from January 1, 2010 to January 1, 2014. This search was not based on ICD-10 codes, but included the medical records of all subjects with a registered address in Buskerud County. The list of subjects seen at the referral center was not searchable prior to 2010. The medical records of each identified subject were thoroughly reviewed, and findings were recorded in a database by one researcher (MS). Diagnosis and classification was performed by a single reviewer (MS), based on conclusions from treating physicians and supervised by the coauthors with more than 20 years of experience in epileptology. Electroclinical epilepsy syndromes were diagnosed by the treating physicians. Inclusion and exclusion criteria All subjects with active epilepsy, who lived in Buskerud County and were alive on the prevalence day (January 1, 2014), were included (Fig. 1). Subjects with only febrile seizures, neonatal seizures, a solitary unprovoked seizure, or acute symptomatic seizures were excluded, as suggested by Thurman et al.6 Definitions and classification Epilepsy was defined as two unprovoked seizures occurring at least 24 h apart.6,18 Active epilepsy was defined as current treatment with antiepileptic medication or at least one seizure within the last 5 years.6,18 The group of subjects with misdiagnosed epilepsy was divided into six categories: (1) febrile seizures, (2) neonatal seizures, (3) solitary unprovoked seizures, (4) acute symptomatic seizures, (5) paroxysmal symptoms not consistent with epilepsy, and (6) others. Subjects with syncope or psychogenic seizures were included in the category of paroxysmal symptoms not consistent with epilepsy. The last category included subjects examined for concentration problems, subjects without seizures but with subclinical epileptiform activity in the EEG, and some with different conditions (for example migraine) who were mistakenly registered with epilepsy. Seizures were simply classified as focal or generalized. The etiology of epilepsy was classified as genetic/presumed genetic, structural-metabolic, or unknown, as suggested by the ILAE.6,7 The structural-metabolic epilepsies were grouped into 12 different categories as listed in the guidelines of the ILAE.6 Specific electroclinical syndromes were identified when possible.7 When prevalence was calculated for each municipality separately, those with an administrative center located more than 50 km from Drammen Hospital were considered rural. The remaining were considered central.
701 Epilepsy in a Norwegian County
Figure 1. Prevalence of epilepsy in Buskerud County. Epilepsia ILAE
Potential sources of bias Medical record information from only two main sources is a potential weakness of this study. However, there are just a few other specialists treating epilepsy in the area. For the private neurologist and pediatricians in the county, EEG equipment was not available. Thus, patients had to be referred to the hospital whenever an EEG was indicated. By selecting every eighth subject identified through our search at Drammen Hospital, we found that 193 of 200 were registered with at least one EEG recording during the last 15 years. Of the remaining seven, three had intellectual disability, making it difficult to conduct the test, three were diagnosed with epilepsy more than 15 years ago and remained stable on medication, and one had epilepsy secondary to glioblastoma. The National Center for Epilepsy has a large EEG laboratory. We suspected that a number of patients from Buskerud County were followed up there without being registered at Drammen Hospital. Thus, a separate electronic search was performed at the outpatient clinic of
the center, followed by a thorough review of medical records. Statistical methods Chi-square test was used for comparison of categorical variables, and p < 0.05 was considered statistically significant. Point prevalence was calculated based on the national census of January 1, 2014.14 A de facto power estimation was performed. Based on the present study, a point prevalence of epilepsy of 0.65% was estimated from a total population of 272,228 inhabitants in Buskerud County. On the condition of no misclassification of the disease, a source sample population of at least 72,721 subjects is needed to catch a prevalence of 0.65% with a precision interval from 0.60% to 0.70% and a probability of 95%. Ethics The study was approved by the Regional Committee for Medical Research Ethics, South East Norway (ethical agreement no. 2013/1027). Epilepsia, 56(5):699–706, 2015 doi: 10.1111/epi.12972
702 M. Syvertsen et al. Table 2. Nonepilepsy with a diagnostic code of epilepsy
Results Prevalence estimates At Drammen Hospital, we identified 1,717 subjects with active epilepsy. Through the additional search at the National Center for Epilepsy, we found 165 subjects from Buskerud County with active epilepsy, of which 111 were already in our database. Compared to the group followed at Drammen Hospital only, there were no differences in geographical or age distribution. However, there was a high percentage of refractory epilepsy at the referral center; 108 subjects (65%) had at least one seizure during the last year, and 134 (81%) had at least one seizure during the last 5 years. In the 54 patients followed at the epilepsy center only, mean age was significantly higher than in the 111 patients identified at both hospitals (44 14 and 34 17 years, respectively, p < 0.001). The total number of subjects with active epilepsy alive on the prevalence day (January 1, 2014) was 1,771 (Fig. 1). The prevalence of active epilepsy in Buskerud County was 6.5 per 1,000 inhabitants, with a 95% confidence interval of 6.2–6.8. There were 852 females and 919 males. There was no significant gender difference in prevalence; 6.3 per 1,000 females and 6.7 per 1,000 males (p = 0.15). Age-specific prevalence is shown in Table 1. When prevalence was calculated for each of the 21 municipalities separately, there was no significant difference between central and rural areas (p = 0.23) (Table S1). Excluded subjects Of the 2,662 subjects with a diagnostic code of epilepsy at Drammen Hospital, 538 (20%) did not fulfill the ILAE criteria of the diagnosis.6,18 The most common reason was paroxysmal symptoms not consistent with epilepsy (Table 2). Positive predictive value of the ICD-10 code G40 (epilepsy) at Drammen Hospital was 0.8. Of the 2,124 subjects with confirmed epilepsy at Drammen Hospital, 407 (19%) no longer had active epilepsy on the prevalence day. At the National Center for Epilepsy, 8
Table 1. Age-specific prevalence of epilepsy in Buskerud County Age 0–4 5–9 10–14 15–19 20–29 30–39 40–49 50–59 60–69 70–79 >80
Subjects with epilepsy
Population
Prevalence per 1,000
34 93 132 111 230 216 252 228 240 142 93
15,647 16,757 16,385 16,988 32,375 35,511 41,165 35,363 32,170 17,768 12,099
2.2 5.5 8.1 6.5 7.1 6.1 6.1 6.4 7.5 8.0 7.7
Epilepsia, 56(5):699–706, 2015 doi: 10.1111/epi.12972
Cause Paroxysmal symptoms not consistent with epilepsy Solitary unprovoked seizure Acute symptomatic seizures Febrile seizures Neonatal seizures Others
N = 538
Percent
239 124 87 15 6 67
44 23 16 3 1 12
(5%) of 173 no longer had active epilepsy. All in all, 415 (18%) of 2,297 subjects did no longer have active epilepsy (Fig. 1). Seizures In 1,127 subjects (64%) seizure-onset was focal only, whereas 538 (30%) had generalized-onset seizures only. Seventeen (1%) had both focal and generalized-onset seizures, of which 15 had rare genetic syndromes. The remaining two had intellectual disability of unknown cause, with developmental delay prior to onset of seizures. In 15 subjects (0.8%), the seizure type could not be classified as focal or generalized, including seven with West syndrome and epileptic spasms. Seizure type could not be determined in another 74 (4%) due to lack of information in the medical records. Etiology Etiology of epilepsy in Buskerud County is summarized in Figure 2. A genetic diagnosis was established in 49 (3%) of the included subjects (Table S2). In 37 of these, the mutation was not the direct cause of epilepsy, and the seizures were not the core symptom of the disorder. Consequently, they were allocated to the structural-metabolic epilepsy group. The remaining 12 (0.6%) were placed among the genetic epilepsies. Three had Dravet syndrome, two had febrile seizures plus (FS+), six had glucose transporter 1 (GLUT1) deficiency syndrome, and one had West syndrome, possibly caused by a chromosomal 1.2 Mb deletion (19p13.2-p13.13).19,20 In 347 subjects (20%), the etiology was presumed to be genetic, but no genetic diagnosis had yet been established. Of these, 27 had a history consistent with an epileptic encephalopathy, with seizures occurring prior to the developmental delay, but where no specific etiology had been identified. The remaining 320 subjects would formerly have been classified as having idiopathic generalized epilepsy (IGE), now named genetic generalized epilepsy (GGE). Structural-metabolic epilepsy was diagnosed in 767 subjects (43%). The most common cause was stroke. In 571 subjects (32%) the cause of epilepsy was unknown. This included subjects with benign epilepsy with centrotemporal spikes (BECTS) and a substantial group of subjects with focal seizures of unknown etiology. In 74 subjects (4%) the etiology could not be determined due to lack of information.
703 Epilepsy in a Norwegian County
Figure 2. Etiology of epilepsy in Buskerud County. Epilepsia ILAE
Electroclinical syndromes A specific electroclinical syndrome was diagnosed in 249 subjects (14%) (Table 3). Absence epilepsy (childhood absence epilepsy and juvenile absence epilepsy) was the most common, followed by juvenile myoclonic epilepsy (JME). Of the 320 subjects with GGE, 146 (46%) did not have a specific syndrome diagnosis (Fig. 2).
Discussion To the best of our knowledge, this is the first epidemiologic study that implements the recently revised terminology for organization of seizures and epilepsies.7 Through a thorough review of more than 2,500 medical records, we have mapped the different subgroups of epilepsy and identified a substantial group of subjects not fulfilling the diagnostic criteria. In the Norwegian county of Buskerud, we found the prevalence of epilepsy to be 0.65%. This is in accordance with five other European studies using a comparable method, but
Table 3. Electroclinical epilepsy syndromes N = 249
Electroclinical syndromes Epilepsy of infancy with migrating focal seizures West syndrome Myoclonic epilepsy in infancy (MEI) Dravet syndrome Febrile seizures plus (FS+) Panayiotopoulos syndrome Epilepsy with myoclonic atonic seizures (Doose syndrome) Benign epilepsy with centrotemporal spikes (BECTS) Lennox-Gastaut syndrome Epilepsy with continuous spike-and-wave during sleep (CSWS) Childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE) Juvenile myoclonic epilepsy (JME)
1 7 4 3 2 2 3 45 9 2 90 81
older classification systems.8–12 In two of the studies, the definition of active epilepsy was identical to ours. They were both Italian and found prevalences of 5.1/1,000 and 6.2/1,000, respectively.9,11 Epilepsia, 56(5):699–706, 2015 doi: 10.1111/epi.12972
704 M. Syvertsen et al. In rural Iceland, epilepsy prevalence was somewhat lower (4.8/1,000), but stricter inclusion criteria were employed. Active epilepsy was defined as at least one seizure within the last year or the use of antiepileptic medication for at least one year prior to the prevalence day.12 In a study from the Faroes, the definition of active epilepsy was also slightly stricter. Subjects taking antiepileptic medication, but who were seizure free for more than 5 years, were excluded. Surprisingly, the prevalence was quite high (7.6/1,000). The authors emphasized that the medical records of this study were usually written by physicians without special interest in epilepsy. Thus, some cases of nonepilepsy could have been misdiagnosed as epilepsy.10 The fifth study using a method comparable to ours, was from Northern Norway. Prevalence of epilepsy was rather low at 3.5/1,000. This study was conducted in a sparsely populated area >40 years ago, where main sources of income were related to fishing, farming, and transport. Thus, concealment caused by economic and social consequences could be substantial. Moreover, access to health care was limited because of geographical distance.8 Two recent Norwegian studies investigated the epidemiology of epilepsy in adults. They are not directly comparable to ours, because of different methods and smaller populations. In Oppland County, prevalence was calculated in five specific age groups. Mean prevalence of active epilepsy was 8.2/1,000.21 The other study from a small Norwegian municipality identified subjects by individual interview.22 Prevalence was high (11.7/1,000), even when the upper age limit for inclusion was 65 years and people with learning disabilities, mental disorders, or dementia were excluded. Response rate was 89%. Nevertheless, as the authors emphasize, a selection bias is possible. The original interview focused on headache, and an association between headache and seizures had been shown.23,24 Finally, estimating prevalence in small populations is difficult due to lack of statistical power. In the present study, case ascertainment may be incomplete, as the medical records of private neurologists and pediatricians were not searched. However, we believe this source of error to be minor, as most patients in Norway are examined with at least one EEG. During the last 15 years we found this to be the case for 97% of our 200 randomly selected patients. In addition, we believed that patients in central areas were more likely to be missed because of follow-up at a private facility. Thus, we compared prevalences in the central municipalities to those located >50 km away, but found no difference (Table S1). We expected to find several new subjects from Buskerud County through our search at the National Center for Epilepsy. The time period searched was shorter than that at Drammen Hospital. However, we think that most patients at the referral center were seen at least once during a 4-year period, as complex epilepsy requires close follow-up. More Epilepsia, 56(5):699–706, 2015 doi: 10.1111/epi.12972
than two thirds of the subjects identified at the referral center were already in our database, and final prevalence estimate rose by only 0.02%. Thus, we think additional searches at the few private clinics in the area would have had little impact on our results. As expected, we found a slightly higher prevalence of epilepsy in the elderly. We do, however, suspect an underreporting of cases in this age group. Compared to a door-to-door study of the elderly population in a suburb of Rotterdam, we found a considerably lower prevalence in the oldest age group. In the Rotterdam study, 1.2% of the population aged 85–94 had active epilepsy,25 compared to 0.77% (aged >80) in our material. Patients with significant comorbidities, for instance in nursing homes, may sometimes be diagnosed with epilepsy by telephone consultation only. Such consultations are not routinely registered with a diagnostic code at our hospital. Moreover, structural-metabolic epilepsy and focal seizures are more common in the elderly.26 It is not unlikely that, especially in this age group, nonconvulsive symptoms sometimes go unnoticed, leading to additional underestimation of hospital-based epilepsy prevalence in the elderly. We assume that the specificity of this study is high, as each case was verified through a thorough review of the medical record. Most of these records were written by neurologists or pediatricians with a special interest in epilepsy. Nevertheless, 538 subjects (20% of the original cohort) had been wrongly coded as epilepsy and were excluded. Because the ICD-10 code is needed mainly for administrative reasons, we think clinicians sometimes choose it swiftly, for example, based on preprinted lists available at the outpatient clinics. As a consequence, the code may sometimes differ from the doctor’s final conclusion and diagnosis, accessible through the detailed information of the medical record only. Epidemiologic studies of epilepsy based merely on existing coded data, may lead to a considerable overestimation of prevalence. A recent register-based study from Sweden found a noticeably higher prevalence of epilepsy (8.8/1,000) than the present study. However, lifetime prevalence was reported, as opposed to prevalence of active epilepsy.27 In regard to etiology, we have not been able to find other epidemiologic studies using the revised terminology proposed by the ILAE in 2010.7 Roughly, the new categories of genetic/presumed genetic, structural-metabolic and unknown correspond to the previous idiopathic, symptomatic, and cryptogenic. It is suggested that some syndromes formerly called idiopathic (namely myoclonic epilepsy in infancy, BECTS, Panayiotopoulos syndrome, and benign occipital epilepsy of Gastaut type) should now be placed under the category of unknown cause.7 Fifty-one of our subjects had one of these syndromes. We found no cases of genetic epilepsy with focal-onset seizures only (autosomal dominant nocturnal frontal lobe epilepsy [ADNFLE], autosomal dominant epilepsy with auditory features [ADEAF]).
705 Epilepsy in a Norwegian County These epilepsies have been categorized as cryptogenic, but would now be replaced to the genetic group. A potential weakness of the present study, is that classification was performed by one reviewer only, based on conclusions from treating physicians. Electroclinical syndromes were diagnosed by the treating physicians. It is a limitation to the study that diagnoses of electroclinical syndromes were not reevaluated by the authors, and that interrater reliability was not addressed. Our results are partly in agreement with Granieri et al. and Olafsson et al., who divided epilepsies into two broad etiologic categories: symptomatic and unknown. In the study by Granieri et al.,9 40% of epilepsies were symptomatic and 60% were of unknown etiology. Olafsson et al.12 found etiology to be symptomatic in 38% and unknown in 62%. In our material, 43% had structural-metabolic epilepsy, whereas a joint category of genetic and unknown etiology constituted 52%. Only 3% of our subjects had a verified genetic diagnosis, and
