J Autism Dev Disord DOI 10.1007/s10803-014-2126-6
ORIGINAL PAPER
Epilepsy Among Children and Adolescents with Autism Spectrum Disorders: A Population-Based Study Elina Jokiranta • Andre Sourander • Auli Suominen • Laura Timonen-Soivio Alan S. Brown • Matti Sillanpa¨a¨
•
Ó Springer Science+Business Media New York 2014
Abstract The present population-based study examines associations between epilepsy and autism spectrum disorders (ASD). The cohort includes register data of 4,705 children born between 1987 and 2005 and diagnosed as cases of childhood autism, Asperger’s syndrome or pervasive developmental disorders—not otherwise specified. Each case was matched to four controls by gender, date of birth, place of birth, and residence in Finland. Epilepsy was associated with ASD regardless of the subgroup after adjusting for covariates. The associations were stronger among cases with intellectual disability, especially among females. Epilepsy’s age at onset was similar between the cases and controls regardless of the ASD subgroup. These findings emphasize the importance to examine the neurodevelopmental pathways in ASD, epilepsy and intellectual disability.
Keywords Epilepsy Autism spectrum disorders Intellectual disability Gender Age at onset Population-based
E. Jokiranta (&) A. Sourander A. Suominen L. Timonen-Soivio Department of Child Psychiatry, University of Turku, Lemminka¨isenkatu 3/Teutori (3rd Floor), 20014 Turku, Finland e-mail: [email protected]
A. S. Brown Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
A. Sourander e-mail: [email protected] E. Jokiranta A. Sourander A. Suominen L. Timonen-Soivio Turku University Hospital, Turku, Finland
Abbreviations ASD Autism spectrum disorder CPR Finnish Central Population Register FIPS-A Finnish Prenatal Study of Autism and Autism Spectrum Disorders FHDR Finnish Hospital Discharge Register FMBR Finnish Medical Birth Register ICD International Classification of Diseases ID Intellectual disability PDD-NOS Pervasive developmental disorder—not otherwise specified SE Status epilepticus THL National Institute for Health and Welfare
M. Sillanpa¨a¨ Department of Child Neurology, University of Turku, Turku, Finland M. Sillanpa¨a¨ Department of Public Health, University of Turku, Turku, Finland
A. Sourander A. S. Brown Department of Psychiatry, New York State Psychiatric Institute, Columbia University College of Physicians and Surgeons, New York, NY, USA L. Timonen-Soivio Department of Child Neurology, Helsinki University Central Hospital, Helsinki, Finland
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J Autism Dev Disord
Introduction Autism spectrum disorders (ASD) are complex neurodevelopmental disorders characterized by qualitative abnormalities in language and communication patterns, in reciprocal social interactions, and a restrictive, stereotyped, repetitive repertoire of interests and activities (World Health Organization 1992). Epilepsy, a common comorbidity in ASD, is defined as a chronic neurologic condition characterized by recurrent spontaneous epileptic seizures (Engel 2001). Both ASD and epilepsy can be described as spectrum disorders which have diverse etiologies and pathologies and where the clinical manifestations as well as the severity of symptoms vary between the cases (Jensen 2011). Previous reviews have reported that the prevalence of epilepsy in ASD varies from 8 to 30 % (Spence and Schneider 2009; Tuchman et al. 2010). The variation is due to factors such as coexistent intellectual disability (ID) (Amiet et al. 2008; Mouridsen et al. 2011a, b; Woolfenden et al. 2012), female gender (Amiet et al. 2008; Danielsson et al. 2005), severe language dysfunction (Tuchman et al. 1991), and age (Giovanardi-Rossi et al. 2000; Hara 2007; Volkmar and Nelson 1990), which are all associated with the risk of epilepsy in ASD. Also, epilepsy is more common among subjects with childhood autism (Danielsson et al. 2005; Mouridsen et al. 2011a) or pervasive developmental disorder—not otherwise specified (PDD-NOS) (Challman et al. 2003; Mouridsen et al. 2011b; Parmeggiani et al. 2007) than subjects with Asperger’s syndrome (Cederlund and Gillberg 2004; Mouridsen et al. 2013). Both ASD and epilepsy by themselves have significant impacts on the child’s wellbeing and increase the stress and burden for the families. Moreover, ASD and epilepsy are often associated with comorbid conditions including ID, behavioural problems, mood disorders and attention problems (Austin and Caplan 2007; Hamiwka and Wirrell 2009; Simonoff et al. 2008). A child diagnosed with both ASD and epilepsy requires a comprehensive assessment and careful treatment including support for the families. Despite numerous clinical studies of the association between epilepsy and ASD, thus far there are only three population-based studies based on nationwide registries examining this association (Mouridsen et al. 2011a, b, 2013). In studies from Denmark, the prevalence of epilepsy in childhood autism was 24.6 % (Mouridsen et al. 2011a), in Asperger’s syndrome 3.9 % (Mouridsen et al. 2013) and in atypical autism/PDD-NOS 22.5 % (Mouridsen et al. 2011b). Epilepsy was more common among cases with ID (Mouridsen et al. 2011a, b) and females tended to have epilepsy more frequently than males (Mouridsen et al. 2011a, b, 2013). All epilepsy syndromes were observed
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among cases with ASD, but the most common were generalized and/or unspecified types. The limitations of the previous population-based studies include rather small sample sizes and the lack of covariates. The aim of the present study was to examine the associations between epilepsy and ASD with special reference to epilepsy syndromes, ID, gender and age at onset after adjusting for covariates. We hypothesized that epilepsy would be associated with ASD, but the magnitude of the associations would differ between childhood autism, Asperger’s syndrome and PDD-NOS.
Methods Data Sources ASD cases and their controls were identified through the Finnish Prenatal Study of Autism and Autism Spectrum Disorders (FIPS-A), a nested case–control study based on a national birth cohort including approx. 1.2 million births in Finland between 1987 and 2005. The FIPS-A has been described in detail previously (Lampi et al. 2011). Briefly, data in the FIPS-A were linked between several nationwide registries using unique personal identity code, given at birth to every Finnish resident and remaining the same throughout lifespan. The FIPS-A has been authorized by the Ministry of Social Affairs and Health of Finland (STM/2593/2008). The ethics committees of the hospital district of Southwest Finland and the Finnish National Institute for Health and Welfare and the Institutional Review Board of the New York State Psychiatric Institute have approved the study design. All the data used in this study were collected from three nationwide registries: the Finnish Hospital Discharge Register (FHDR), the Finnish Medical Birth Register (FMBR) and the Finnish Central Population Register (CPR). The FHDR is maintained by the National Institute for Health and Welfare (THL) including inpatient diagnoses since 1, January 1967 and outpatient diagnoses since 1, January 1998. The FHDR contains subject’s dates of admission and discharge, primary diagnosis of discharge and three possible subsidiary diagnoses. It covers all medical diagnoses, both somatic and psychiatric ones, made nationwide in hospitals or inpatient wards of local health centres, and in military wards, prison and private hospitals. The diagnostic classification is based on the International Classification of Diseases (ICD). The 8th revision (World Health Organization 1967) was used from 1969 to 1986, the 9th (World Health Organization 1977) from 1987 to 1995 and the 10th revision (World Health Organization 1992) has been used since January 1, 1996. The FHDR was used to identify subjects with ASD and/or
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epilepsy and also to obtain data on covariates as discussed below. The FMBR is also maintained by THL including a comprehensive data on every pregnancy, the prenatal period and the neonatal period up to 7 days of age on all births in Finland. The FMBR was established in 1987 including data on mothers and every live born child. The FMBR was used to identify controls and mothers and also to obtain the data on covariates. Information on the mothers was needed to obtain data on their psychiatric diagnoses and epilepsy diagnoses from the FHDR, used as covariates as discussed below. The CPR is a computerized nationwide register containing basic information (e.g. name, address, municipality of residence, citizenship, family relations) about Finnish residents and foreign citizens living permanently in Finland. The CPR was used to identify the fathers. Similarly to mothers, information on the fathers was needed to obtain data on their psychiatric diagnoses and epilepsy diagnoses, used as covariates. Paternity of newborn is based on an individual’s status as a husband of the mother at delivery. However, if the mother is unmarried, paternity is confirmed by acknowledgment of the father or by using DNA-testing if the father agrees with such testing. In this study paternity was established in 98.3 % of the subjects. Identification of Cases and Controls Cases with ASD were identified from the FHDR by codes from ICD-10 (F84x) and ICD-9 (299x). The most recent diagnosis was used and, based on the dates of birth and the dates during which each diagnostic system was used, the majority of cases were diagnosed by ICD-10 codes; only 19 cases were diagnosed based on ICD-9. We examined the association between epilepsy and ASD using the three main subgroups of ASD: childhood autism (F84.0) (n = 1,131), Asperger’s syndrome (F84.5) (n = 1,783), and other pervasive developmental disorders/pervasive developmental disorders—not otherwise specified (PDDNOS) (F84.8/F84.9) (n = 1,791). The combination of childhood autism, Asperger’s syndrome and PDD-NOS totalled 4,705 cases. Subjects diagnosed with epilepsy or status epilepticus (SE) were identified through the FHDR by using the ICD10 (G40, G41) and ICD-9 (345) codes. Diagnoses were classified into specific epilepsy syndrome categories according to the first diagnosis of epilepsy syndrome (see Table 6 in Appendix). However, if a subject was diagnosed at any time as a case of with petit mal/absentia (G40.7, G41.1, 3452A), that diagnosis was used in the classification. In Finland, an initial epilepsy diagnosis is made in specialized health services by a neurologist who also starts the treatment. If there is a suspicion of epilepsy, a subject
receives a referral to a neurologist from a primary health care; the neurologist conducts a comprehensive neurologic examination including electroencephalography (EEG) and magnetic resonance imaging (MRI). If needed, long-term video-EEG recordings can also be made. The goals of the comprehensive neurologic examination are first, to confirm that the symptoms are due to epilepsy and secondly, to determine the epilepsy syndrome as accurately as possible so that the most appropriate medication can be prescribed. Subjects diagnosed with ID were identified by the FHDR using the following ICD-10/9 codes: F70/317 (IQ B 70–50, i.e. mild ID), F71/318.0 (IQ B 49–35, i.e. moderate ID), F72/318.1 (IQ B 34–20, i.e. severe ID), F73/318.2 (IQ \ 20, i.e. profound ID), F78 (no ICD-9 code) (IQ unspecified), and F79/319 (IQ unspecified). In addition, cases with comorbid ID were grouped into those with mild ID (IQ B 70–50, ICD10/9 F70/317) and those with more severe ID (IQ B 49 or less, ICD10/9 F71/318.0; F72/318.1; F73/318.2). Each case was individually matched to four controls by date of birth (±30 days), gender, place of birth by hospital and residence in Finland. If a birth hospital control could not be found, the case was matched with a control born in the nearest regional hospital district. Controls were identified through the FMBR of subjects who did not meet the inclusion criteria for ASD or had severe or profound ID according to the FHDR. Overall 18,745 controls were matched from the FMBR. Covariates Prior to adjustment, bivariate analyses (Pearson’s v2-test, p \ 0.10) were conducted to test the significance of associations between covariates and epilepsy among controls as well as between covariates and ASD. The covariates included in the analysis were maternal socioeconomic status (upper white collar workers; lower white collar workers; blue collar workers; others); maternal age (\20, 20–24, 25–29, 30–34, 35–39, C40 years); paternal age (\20, 20–24, 25–29, 30–34, 35–39, 40–49; C50 years); smoking during pregnancy (yes/no); maternal psychiatric disorder (yes/no) (ICD-10 codes: F10–F99, excluding F70– F79; ICD-9 291–316 excluding 293–294; ICD-8 291–309 excluding 292–294; paternal psychiatric disorder (yes/no); maternal epilepsy (yes/no) (ICD-10 codes G40–G41; ICD9 and ICD-8 codes 345); paternal epilepsy (yes/no); birth weight (B1,500 g; 1,500–2,499 g; 2,500–3,999 g; 4,000–4,499 g; C4,500 g); gestational age (B31; 32–37; 38–41; C42 weeks) and 1 min Apgar scores (B6; 7–8; 9–10 scores). Based on the analysis, the following covariates were significantly associated both with epilepsy and ASD and were included in the statistical analyses: smoking during pregnancy, maternal psychiatric disorder, maternal
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J Autism Dev Disord Table 1 Covariates in relation to epilepsy in controls and in relation to risk of autism spectrum disorders Association between covariates and epilepsy No epilepsy, n (%) Gestational age
Epilepsy, n (%)
p
Association between covariates and autism spectrum disorders p
\.0001
\.0001
0.0584
0.0329
0.0209
\.0001
0.0055
\.0001
0.0542
0.0005
\.0001
\.0001
\.0001
\.0001
n = 18,410
n = 219
31 weeks or under
94 (0.5)
7 (3.2)
32–37 38–41
1,615 (8.8) 15,847 (86.1)
36 (16.4) 163 (74.4)
42 weeks or over
854 (4.6)
13 (5.9)
n = 18,076
n = 213
No
15,205 (84.1)
169 (79.3)
Yes
2,871 (15.9)
44 (20.7)
n = 18 524
n = 221
No
17,509 (94.5)
201 (91.0)
Yes
1,015 (5.5)
20 (9.1)
n = 18,524
n = 221
No
18,394 (99.3)
215 (97.3)
Yes
130 (0.7)
6 (2.7)
n = 18,307
n = 219
18,191 (99.4)
215 (98.2)
Smoking during pregnancy
Maternal psychiatric disorder
Maternal epilepsy diagnosis
Paternal epilepsy diagnosis No Yes
116 (0.6)
4 (1.8)
n = 18,447 68 (0.4)
n = 221 7 (3.2)
1,500–2,499 g
394 (2.1)
16 (7.2)
2,500–3,999 g
13,905 (75.4)
143 (64.7)
4,000–4,499 g
3,299 (17.9)
45 (20.4)
4,500 g or over
781 (4.2)
10 (4.5)
Birth weight \1,500 g
Apgar score at 1 min
n = 18,420
n = 220
9–10
14,064 (76.4)
162 (73.6)
7–8
3,661 (19.9)
37 (16.8)
0–6
695 (3.8)
21 (9.6)
epilepsy, paternal epilepsy, birth weight, gestational age and 1 min Apgar scores (Table 1). The data on these covariates were collected from the FMBR and the FHDR. Statistical Analysis Conditional logistic regression analysis of matched case– control strata was used to examine the associations between epilepsy and ASD. Associations between epilepsy and ASD were determined by using odds ratios (ORs) with 95 % confidence intervals (CIs). p Values were calculated using Pearson’s v2-test; statistical significance was defined as p \ 0.05. The model was adjusted for smoking during pregnancy, maternal psychiatric disorder, maternal epilepsy, paternal epilepsy, birth weight, gestational age and 1 min Apgar score. The analyses were also conducted for subjects with and without ID. Moreover, among those cases with comorbid ID, data were analyzed between cases with
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mild ID and more severe ID. In addition, data were analyzed separately for males and females with and without comorbid ID. Pearson’s v2-test or Fisher’s exact test were used to compare the age at onset distribution by year between cases and controls by the significance level of p \ 0.05. The statistical analyses were carried out using SAS statistical software (SAS Version 9.4; SAS Institute Inc., Cary, NC).
Results The mean ages for ASD diagnosis were as follows: 5.5 years (SD 3.6 years) for childhood autism, 9.6 years (SD 3.3 years) for Asperger’s syndrome and 7.2 years (SD 3.4 years) for PDD-NOS. ID was present in 12.7 % of all ASD cases, including 28.8 % of those with childhood autism, 1.3 % with Asperger’s syndrome and 13.8 % with PDD-NOS.
J Autism Dev Disord Table 2 Epilepsy, epilepsy syndromes and status epilepticus in cases with autism spectrum disorders and matched controls ASD totala
Childhood autism
Asperger’s syndrome
PDD-NOS
Case n (%)
Control n (%)
Case n (%)
Control n (%)
Case n (%)
Control n (%)
Case n (%)
Control n (%)
No
4,393 (93.4)
18,528 (98.8)
1,020 (90.2)
4,460 (98.9)
1,727 (96.9)
7,023 (98.8)
1,646 (91.9)
7,045 (98.8)
Yes
312 (6.6)
217 (1.2)
111 (9.8)
51 (1.1)
56 (3.1)
83 (1.2)
145 (8.1)
74 (1.6)
43 (0.2)
26 (2.6)
13 (0.3)
11 (0.6)
15 (0.2)
37 (2.1)
15 (0.2)
Idiopathic generalized
61 (1.3)
34 (0.2)
21 (1.9)
10 (0.2)
9 (0.5)
13 (0.2)
31 (1.7)
11 (0.2)
Symptomatic generalized
12 (0.3)
Epilepsy
Generalized
Focal
9 (0.05)
5 (0.4)
128 (2.7)
95 (0.5)
41 (3.6)
Idiopathic focal
30 (0.6)
23 (0.1)
7 (0.6)
70 (0.4)
33 (2.9)
Symptomatic focal
92 (2.0)
Epileptic syndromes
8 (0.2)
Other or unspecified
102 (2.2)
9 (0.05) 70 (0.4)
3 (0.07) 16 (0.4) 2 (0.04) 14 (0.3)
3 (0.3)
2 (0.04)
41 (3.6)
20 (0.4)
2 (0.1)
2 (0.03)
5 (0.3)
83 (1.2)
4 (0.06)
38 (1.7)
31 (0.5)
56 (3.1)
41 (0.6)
4 (0.2)
9 (0.1)
19 (1.1)
12 (0.2)
23 (1.3)
28 (0.4)
36 (2.0)
28 (0.4)
1 (0.06)
2 (0.03)
13 (0.7)
28 (0.4)
4 (0.2) 48 (2.7)
5 (0.07) 22 (0.3)
Status epilepticus No
4,675 (99.4)
Yes
30 (0.6)
Generalized status epilepticus
11 (0.2)
Psychomotor status epilepticus Partialis continua
18,731 (99.95) 14 (0.1)
1,119 (98.9)
4,508 (99.9)
1,781 (99.9)
7,097 (99.9)
1,775 (99.1)
7,126 (99.97)
12 (1.1)
3 (0.1)
2 (0.1)
9 (0.1)
16 (0.9)
2 (0.03)
6 (0.03)
4 (0.4)
0 (0.0)
0 (0.0)
5 (0.07)
7 (0.4)
1 (0.01)
6 (0.1)
2 (0.01)
2 (0.2)
1 (0.02)
0 (0.0)
1 (0.01)
4 (0.2)
0 (0.0)
0 (0.0)
1 (0.01)
0 (0.0)
0 (0.0)
0 (0.0)
1 (0.01)
0 (0.0)
0 (0.0)
ASD autism spectrum disorders, PDD-NOS pervasive developmental disorders—not otherwise specified a
Includes childhood autism, Asperger’s syndrome and PDD-NOS
Table 2 shows the frequencies of epilepsy, epilepsy syndrome categories and SE among cases and controls. 54.2 % had received an epilepsy diagnosis before an ASD diagnosis. 43.6 % received an ASD diagnosis before an epilepsy diagnosis. In addition, 2.2 % received both diagnoses at the same time. The associations between epilepsy and ASD subgroups were very similar in unadjusted and adjusted analyses and therefore only adjusted analyses are shown in Table 3. Epilepsy was associated with ASD regardless of the subgroup, but was most strongly associated with childhood autism and PDD-NOS. As shown in Table 3, childhood autism, Asperger’s syndrome and PDD-NOS were all associated with generalized, focal and unspecified epilepsies. Additionally, childhood autism was associated with epileptic syndromes. Childhood autism and PDD-NOS were associated with SE but Asperger’s syndrome was not (Table 3). Among cases with epilepsy and with comorbid ID, 46.3 % had first received an epilepsy diagnosis and later ASD and ID diagnosis. 45.4 % had first received an ASD diagnosis and later an epilepsy and ID diagnosis. A
minority, i.e. 8.3 % had first received an ID diagnosis and later an ASD and epilepsy diagnosis. Table 4 shows the frequencies and adjusted associations of epilepsy among ASD cases with and without comorbid ID. As shown in the table, the associations were present with and without comorbid ID. However, the magnitudes of the associations were stronger among ASD cases with comorbid ID. In addition, the risk for epilepsy was increased among cases with more severe ID than cases with mild ID (total ASD: OR 1.7, 95 % CI 1.005, 2.8, p = 0.04). In subgroups of ASD the corresponding figures were as follows: childhood autism: OR 1.1, 95 % CI 0.5, 2.3, p = 0.83, PDD-NOS: OR 2.6, 95 % CI 1.3, 5.5, p = 0.01. Table 5 shows the frequencies and adjusted associations of epilepsy among ASD males and females with and without comorbid ID. Among male cases with comorbid ID 22.4 % first received an ASD diagnosis followed by an epilepsy and ID diagnosis. Overall 55.2 % of these male cases received an epilepsy diagnosis before an ASD and ID diagnosis. Moreover, 22.4 % had received an ID diagnosis before and later ASD and epilepsy diagnosis. Among females with comorbid ID 26.8 % had first received an
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J Autism Dev Disord Table 3 Associations between autism spectrum disorders and epilepsy, epilepsy syndromes and status epilepticus
Epilepsy
ASD totala
Childhood autism
Asperger’s syndrome
PDD-NOS
Case n (%) Control n (%) OR (95 % CI)
Case n (%) Control n (%) OR (95 % CI)
Case n (%) Control n (%) OR (95 % CI)
Case n (%) Control n (%) OR (95 % CI)
6.0 (5.0, 7.3)***
9.9 (6.8, 14.3)***
3.0 (2.1, 4.4)***
6.8 (5.1, 9.2)***
Epilepsy syndromes Generalized
7.2 (4.8, 10.8)***
9.5 (4.5, 19.9)***
3.6 (1.6, 8.2)**
9.3 (4.9, 17.6)***
Idiopathic generalized
6.9 (4.4, 10.9)***
8.4 (3.8, 18.7)***
3.4 (1.4, 8.5)**
9.2 (4.5, 18.8)***
Symptomatic generalized
4.5 (1.7, 11.9)**
8.6 (1.6, 47.2)*
3.6 (0.5, 26.4)
3.6 (0.8, 16.5)
5.6 (4.2, 7.5)***
12.5 (6.6, 23.7)***
3.4 (2.0, 5.7)***
5.3 (3.4, 8.2)***
Idiopathic focal
4.8 (2.7, 8.4)***
13.8 (2.8, 67.0)**
1.6 (0.5, 5.4)
5.5 (2.6, 11.6)***
Symptomatic focal
5.3 (3.8, 7.5)***
10.9 (5.4, 21.8)***
3.5 (1.9, 6.4)***
4.7 (2.7, 8.0)***
Epileptic syndromes
3.9 (1.5, 10.6)**
10.4 (1.4, 77.6)*
2.3 (0.2, 26.1)
2.8 (0.7, 11.2)
Other or unspecified
6.2 (4.4, 8.6)***
8.2 (4.6, 14.4)***
2.2 (1.1, 4.5)*
9.2 (5.3, 15.8)***
Status epilepticus
Focal
8.5 (4.3, 16.8)***
20.5 (4.4, 94.5)***
0.9 (0.2, 4.5)
28.1 (6.4, 123.8)***
Generalized status epilepticus
6.7 (2.4, 18.2)***
N/A
N/A
23.4 (2.9, 191.4)**
Psychomotor status epilepticus
9.6 (1.9, 48.8)**
6.3 (0.5, 74.1)
N/A
N/A
Adjusted for smoking during pregnancy, maternal psychiatric disorder, maternal epilepsy, paternal epilepsy, gestational age, birth weight, 1 min Apgar scores ASD autism spectrum disorders, PDD-NOS pervasive developmental disorders—not otherwise specified, OR odds ratio, CI confidence interval, N/A not applicable * p \ 0.05, ** p \ 0.01, *** p \ 0.001 a
Includes childhood autism, Asperger’s syndrome and PDD-NOS
Table 4 Associations between autism spectrum disorders with and without intellectual disability and epilepsy ASD totala
Childhood autism
Asperger’s syndrome
PDD-NOS
Case n (%) Control n (%) OR (95 % CI)
Case n (%) Control n (%) OR (95 % CI)
Case n (%) Control n (%) OR (95 % CI)
Case n (%) Control n (%) OR (95 % CI)
No epilepsy, no ID
3,831 (95.4)
15,840 (99.0)
745 (94.9)
3,106 (99.2)
1,665 (96.9)
6,771 (98.9)
1,421 (94.0)
5,963 (99.0)
Epilepsy without ID
184 (4.6)
160 (1.0)
40 (5.1)
26 (0.8)
53 (3.1)
76 (1.1)
91 (6.0)
58 (1.0)
4.7 (3.7, 5.9)***
6.6 (3.9, 11.1)***
3.1 (2.1, 4.6)***
5.8 (4.1, 8.3)***
No epilepsy with ID
560 (81.2)
2,684 (97.8)
274 (79.2)
1,354 (98.2)
62 (95.4)
248 (95.6)
224 (80.3)
1,082 (97.7)
Epilepsy with ID
130 (18.8)
61 (2.2)
72 (20.8)
25 (1.8)
3 (4.6)
11 (4.3)
55 (19.7)
25 (2.3)
10.3 (7.2, 14.7)***
17.2 (9.6, 30.6)***
N/A
10.5 (6.0, 18.5)***
Adjusted for smoking during pregnancy, maternal psychiatric disorder, maternal epilepsy, paternal epilepsy, gestational age, birth weight, 1 min Apgar scores ASD autism spectrum disorders, PDD-NOS pervasive developmental disorders—not otherwise specified, ID intellectual disability, OR odds ratio, CI confidence interval, N/A not applicable * p \ 0.05, ** p \ 0.01, *** p \ 0.001 a
Includes childhood autism, Asperger’s syndrome and PDD-NOS
ASD diagnosis before an epilepsy and ID diagnosis. Overall 48.8 % of these female cases had received an epilepsy diagnosis before an ASD and ID diagnosis. In addition, 24.4 % had received an ID diagnosis before a diagnosis of ASD and epilepsy. As shown in the Table 5, the magnitude of the associations between epilepsy and ASD were stronger among males and females with
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comorbid ID than without ID. Moreover, the magnitudes of the associations were especially strong among ASD females with comorbid ID, particularly in PDD-NOS. Figure 1 shows the cumulative percentages of age at onset of epilepsy. The age at onset did not significantly differ between cases and controls for ASD total nor in the subgroups of ASD at any age.
J Autism Dev Disord Table 5 Associations between autism spectrum disorders with and without intellectual disability and epilepsy by sex ASD totala
Childhood autism
Asperger’s syndrome
PDD-NOS
Case n (%) Control n (%) OR (95 % CI)
Case n (%) Control n (%) OR (95 % CI)
Case n (%) Control n (%) OR (95 % CI)
Case n (%) Control n (%) OR (95 % CI)
No epilepsy, no ID
3,113 (95.9)
12,803 (99.0)
605 (95.7)
2,504 (99.3)
1,408 (97.0)
5,720 (98.9)
1,100 (94.6)
4,579 (99.0)
Epilepsy without ID
133 (4.1)
130 (1.0)
27 (4.3)
18 (0.7)
43 (3.0)
64 (1.1)
63 (5.4)
48 (1.0)
Male
4.1 (3.2, 5.4)***
6.0 (3.2, 11.3)***
3.2 (2.1, 4.9)***
4.7 (3.1, 7.1)***
No epilepsy with ID
414 (83.0)
1,940 (97.7)
208 (79.7)
1,021 (98.1)
50 (94.3)
204 (96.7)
156 (84.3)
715 (97.4)
Epilepsy with ID
85 (17.0)
46 (2.3)
53 (20.3)
20 (1.9)
3 (5.7)
7 (3.3)
29 (15.7)
19 (2.6)
9.3 (6.1, 14.2)***
17.4 (8.9, 34.1)***
N/A
7.2 (3.6, 14.3)***
Female No epilepsy, no ID
718 (93.4)
3,037 (99.0)
140 (91.5)
602 (98.7)
257 (96.3)
1,051 (98.9)
321 (92.0)
1,384 (99.3)
Epilepsy without ID
51 (6.6)
30 (1.0)
13 (8.5)
8 (1.3)
10 (3.8)
12 (1.1)
28 (8.0)
10 (0.7)
7.2 (4.4, 11.7)***
10.1 (3.7, 27.4)***
2.6 (1.04, 6.5)*
No epilepsy with ID
146 (76.4)
744 (98.0)
66 (77.7)
333 (98.5)
12 (100)
44 (91.7)
68 (72.3)
367 (98.4)
Epilepsy with ID
45 (23.6)
15 (2.0)
19 (22.4)
5 (1.5)
0 (0)
4 (8.3)
26 (27.7)
6 (1.6)
15.9 (7.7, 32.7)***
17.6 (5.5, 55.8)***
N/A
12.5 (5.6, 28.0)***
36.5 (10.0, 133.8)***
Adjusted for smoking during pregnancy, maternal psychiatric disorder, maternal epilepsy, paternal epilepsy, gestational age, birth weight, 1 min Apgar scores ASD autism spectrum disorders, PDD-NOS pervasive developmental disorders—not otherwise specified, ID intellectual disability, OR odds ratio, CI confidence interval, N/A not applicable * p \ 0.05, ** p \ 0.01, *** p \ 0.001 Includes childhood autism, Asperger’s syndrome and PDD-NOS
a
Discussion There are three main findings in the study. First, epilepsy was strongly associated with ASD after adjustment for covariates and in line with previous population-based studies (Mouridsen et al. 2011a, b, 2013). Childhood autism showed a nearly tenfold and PDD-NOS nearly a sevenfold increased odds for epilepsy compared with controls. Asperger’s syndrome showed a threefold increased odds for epilepsy. Our results are consistent with the previous studies showing that Asperger’s syndrome has a lower magnitude of association with epilepsy than childhood autism or PDD-NOS (Cederlund and Gillberg 2004; Mouridsen et al. 2013). The weaker association between epilepsy and Asperger’s syndrome might be due to absence of ID, because ID is a diagnostic exclusion criterion of Asperger’s syndrome. One substantial risk factor for epilepsy is ID and the prevalence increases with the severity of ID (van Blarikom et al. 2006). Consistent with that finding, the associations with ASD and its subgroups were stronger in the subgroups with comorbid ID. Second, all epilepsy syndromes had a rather similar strength of association with ASD. Our finding is in
agreement with previous studies showing that there is no specific epilepsy syndrome to be expected in ASD (Danielsson et al. 2005; Giovanardi-Rossi et al. 1995; Hara 2007; Mouridsen et al. 2011a, 2013; Steffenburg et al. 2003; Tuchman and Rapin 2002). Effective management of epilepsy requires the identification of the specific epilepsy syndrome, because information is often needed for antiepileptic medication, prognosis and interventional therapy (Peake et al. 2006). However, diagnosing an epilepsy syndrome among cases with ASD might be challenging because core symptoms of severe ASD; lack of or difficulties in communication limits the ability to report symptoms, and in some cases abnormal movements including the repetitive, stereotyped behaviors and/or ticlike movements might be difficult to distinguish from epileptic event (Peake et al. 2006). Third, age at onset of epilepsy did not differ between ASD cases and controls. The studies of Deykin and MacMahon (1979) and Volkmar and Nelson (1990) suggest that there is a bimodal age distribution of epilepsy in ASD, with the first peak occurring during the early years of childhood and the second peak in early puberty. Our data, however, indicate that the highest risk for epilepsy is in early
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J Autism Dev Disord Fig. 1 Age at onset of epilepsy among cases with autism spectrum disorders and controls
childhood, because nearly half of our study sample—both cases and controls—had received the epilepsy diagnosis before the age of 6. This finding is in line with a previous study (Danielsson et al. 2005), but is discrepant with studies showing increased risk in puberty (Deykin and MacMahon 1979; Giovanardi-Rossi et al. 2000; Hara 2007; Volkmar and Nelson 1990). This discrepancy might be explained at least partly by the use of different ASD criteria and varying study designs and sample sizes. Over half of the cases had first received the epilepsy diagnosis and were later diagnosed with ASD. The proportion of cases who had first received an ASD diagnosis prior to an epilepsy and ID diagnosis was approximately the same as for cases receiving first an epilepsy diagnosis and later an ASD and ID diagnosis. Even though there are numerous studies examining the prevalence of epilepsy in ASD, investigating ASD among subjects with epilepsy
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has only recently become an area of research interest. These studies show that the prevalence of ASD is substantially higher among subjects with epilepsy than the prevalence of ASD in the general population and the risk for ASD is increased especially among subjects with ID (Berg et al. 2011; Clarke et al. 2005; Matsuo et al. 2010). One possibility for the delayed ASD diagnosis among subjects with epilepsy might be the early onset of epilepsy, occurring prior to the time when ASD is typically diagnosed, i.e. prior to age three. Another hypothesis is that cases without comorbid ID together with less severe ASD symptoms (e.g. Asperger’s syndrome) are not detected as easily as are the more severely affected cases with comorbid ID (Matsuo et al. 2010). However, given that early onset of epilepsy is associated with an increased risk of ID (Berg et al. 2008; Cormack et al. 2007) and ASD is associated with ID, we suggest that clinicians
J Autism Dev Disord
need to pay particular attention to other possible diagnoses that are comorbid with epilepsy. ID and epilepsy by themselves are complex conditions with a heterogeneous etiology, caused by a range of pathological processes. It has been suggested that males are more often diagnosed with ID than are females (McLaren and Bryson 1987). However, some studies suggest that the male–female ratio becomes more equal when IQ decreases and that females are more often diagnosed with severe ID than males (Bradley et al. 2002; McLaren and Bryson 1987). Similarly, males are more often diagnosed with ASD than are females, but the sex ratio decreases significantly among cases with severe ID (Nicholas et al. 2008). Females with ASD have a higher risk of epilepsy than males, probably because females with ASD tend to have a higher rate of ID (Amiet et al. 2008). The present study provides some support to this, because the association with epilepsy was particularly high among ASD females with comorbid ID. In addition, this ID-epilepsy-female gender association has become a more significant research area after discovery of the causative gene for the condition known as ‘‘epilepsy and mental retardation limited to females’’ (EFMR) (Dibbens et al. 2008). This gender-specific disorder is characterized by seizure onset during early childhood and usually cognitive impairment, and interestingly, is associated with several psychiatric disorders including ASD (Scheffer et al. 2008). Understanding of this condition and its comorbidity with other psychiatric disorders is, however, limited, requiring further studies. Advances in genetic technology during the last decade are having a significant impact on our understanding of different disorders. Genetic studies show that disorders, which have formerly been defined as clinically distinct disorders (including schizophrenia, ASD, epilepsy, ID) share similarities in neurodevelopmental pathology (Friedman et al. 2008; Guilmatre et al. 2009; Mefford et al. 2008; Stoll et al. 2013). Moreover, epidemiological studies show that these disorders also cluster in families (Daniels et al. 2008; Jokiranta et al. 2013; Qin et al. 2005). Even though ASD and epilepsy are now defined as clinically distinct disorders, the strong association between them suggests that also they might share common underlying pathophysiological mechanisms. Our study is the first population-based one to examine the associations between epilepsy and ASD after adjusting for covariates. The following limitations must be considered. First, there may be some misclassification of diagnoses of ASD and epilepsy, typical of register studies. However, the Finnish hospital discharge registers have good validity for both childhood autism (Lampi et al. 2010) and epilepsy (Sillanpa¨a¨ et al. 2011). Second, the hospital discharge register includes inpatient diagnoses
since 1967, but outpatient diagnoses since 1998. Consequently, we were not able to include cases that were diagnosed and treated only in outpatient units prior to that year. It is to be noted, however, that since the most recent diagnosis was used for case identification, and ASD is generally a chronic condition, we expect that this would have captured many cases treated exclusively as outpatients with onset prior to 1998 in our study sample. Third, the ICD-10 classification is not equal to that of International League Against Epilepsy even though the differences are not insurmountable. Fourth, the cohort likely includes children who haven’t yet received the diagnosis (in this case ASD or epilepsy) due to the time window (e.g. children born in the end of 2005 and having Asperger’s syndrome probably will not have been given the diagnosis by the end of 2007, because typically highfunctioning cases receive the diagnosis after the toddler age) or because they haven’t received any treatments from the clinics. However, given that in Finland the treatment of ASD and epilepsy are free-of-charge, and, before the beginning of school (age 7), all children visit child health clinics at least once a year where the child’s health is assessed comprehensively, it is likely that children with symptoms of ASD or epilepsy will receive treatment and subsequently become registered in the FHDR. Finally, we are not able to show whether a subject’s epilepsy is active or not. In Finland, the initial epilepsy diagnosis is made by a neurologist in specialized health services who also starts the treatment. After achieving remission, among children and adolescents the treatment typically remains in specialized health services due to their young age. However, among adults the follow-up and treatment is typically transferred to the primary health care provider unless the condition requires specialized health services (i.e. epilepsy occurring during pregnancy or treatment refractory epilepsy).Thus, there is a lack of data among adults whose treatment has been transferred to primary health care, because we only have data from specialized health services. However, the majority of the subjects included in this study are children and adolescents, whose treatment remains in specialized health services. To conclude, epilepsy is associated with autism spectrum disorders and all the subgroups after adjustment for covariates. The strength of the association is influenced by comorbid intellectual disability. The intercorrelated occurrence of autism spectrum disorders, epilepsy and intellectual disability argues for shared underlying neurodevelopmental mechanisms and makes up a research challenge for the modern gene technology. Acknowledgments This study was funded by the Finnish Epilepsy Society, the Jane and Aatos Erkko Foundation, the Finnish Pediatric
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J Autism Dev Disord Research Foundation (E. Jokiranta), and the National Institute for Environmental Health Sciences (NIEHS) R01ES019004 (A. Brown, PI). Conflict of interest The authors have no financial relationships relevant to this article to disclose.
Appendix
Table 6 Specific diagnosis codes for epilepsy syndrome categories and status epilepticus Diagnostic group
Current classification ICD-10 (1996 to present)
Previous classification ICD-9 (1987–1995)
Epilepsy
G40
3450A–3451A, 3454A–3456B, 3458X, 3459X
Generalized
G40.3–G40.8 (excluding G40.5) G40.3 (generalized idiopathic epilepsy), G40.6 (grand mal seizures, unspecified, with or without petit mal), G40.7 (petit mal, unspecified, without grand mal seizures)
3450A–3453A
Symptomatic generalized
G40.4 (other generalized epilepsy and epileptic syndromes)
–
Focal
G40.0–G40.2
3454A–3454X, 3455A
Idiopathic focal
G40.0 (idiopathic focal epilepsy)
–
Symptomatic focal
G40.1 (focal epilepsy with simple partial seizures)– G40.2 (focal epilepsy with complex partial seizures)
–
Epileptic syndromes
G40.5 (special epileptic syndromes)
3456A, 3456B, 3457B
Other or unspecified
G40.8 (other epilepsy), G40.9 (unspecified epilepsy)
3458X 3459X
Status epilepticus
G41
3452A–3453A, 3457A–3457X
Generalized
G41.0 (grand mal status epilepticus), G41.1 (petit mal status epilepticus) G41.2 (complex partial status epilepticus)
3452A, 3453A
Idiopathic generalized
Psychomotor Partialis continua
–
3450A, 3451A
3457A 3457B
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among patients with epilepsy: Population based cohort study. British Medical Journal, 331, 23. SAS Institute Inc. (2010). SAS Version 9.4. Cary, NC. Scheffer, I. E., Turner, S. J., Dibbens, L. M., Bayly, M. A., Friend, K., Hodgson, B., et al. (2008). Epilepsy and mental retardation limited to females: An under-recognized disorder. Brain, 131, 918–927. Sillanpa¨a¨, M., Lastunen, S., Helenius, H., & Schmidt, D. (2011). Regional differences and secular trends in the incidence of epilepsy in Finland: A nationwide 23-year registry study. Epilepsia, 52, 1857–1867. Simonoff, E., Pickles, A., Charman, T., Chandler, S., Loucas, T., & Baird, G. (2008). Psychiatric disorders in children with autism spectrum disorders: Prevalence, comorbidity, and associated factors in a population-derived sample. Journal of the American Academy of Child and Adolescent Psychiatry, 47, 921–929. Spence, S. J., & Schneider, M. T. (2009). The role of epilepsy and epileptiform EEGs in autism spectrum disorders. Pediatric Research, 65, 599–606. Steffenburg, S., Steffenburg, U., & Gillberg, C. (2003). Autism spectrum disorders in children with active epilepsy and learning disability: Comorbidity, pre- and perinatal background, and seizure characteristics. Developmental Medicine and Child Neurology, 45, 724–730. Stoll, G., Pietila¨inen, O. P., Linder, B., Suvisaari, J., Brosi, C., Hennah, W., et al. (2013). Deletion of TOP3b, a component of FMRP-containing mRNPs, contributes to neurodevelopmental disorders. Nature Neuroscience, 16, 1228–1237. Tuchman, R., Cuccaro, M., & Alessandri, M. (2010). Autism and epilepsy: Historical perspective. Brain & Development, 32, 709–718. Tuchman, R., & Rapin, I. (2002). Epilepsy in autism. Lancet Neurology, 1, 352–358. Tuchman, R., Rapin, I., & Shinnar, S. (1991). Autistic and dysphasic children. II: Epilepsy. Pediatrics, 88, 1219–1225. van Blarikom, W., Tan, I. Y., Aldenkamp, A. P., & van Gennep, A. T. (2006). Epilepsy, intellectual disability, and living environment: A critical review. Epilepsy & Behaviour, 9, 14–18. Volkmar, F. R., & Nelson, D. S. (1990). Seizure disorders in autism. Journal of the American Academy of Child and Adolescent Psychiatry, 29, 127–129. Woolfenden, S., Sarkozy, V., Ridley, G., Coory, M., & Williams, K. (2012). A systematic review of two outcomes in autism spectrum disorder—Epilepsy and mortality. Developmental Medicine and Child Neurology, 54, 306–312. World Health Organization. (1967). International classification of diseases, eighth revision (ICD-8). Geneva: World Health Organization. World Health Organization. (1977). International classification of diseases, ninth revision (ICD-9). Geneva: World Health Organization. World Health Organization. (1992). International classification of diseases, tenth revision (ICD-10). Geneva: World Health Organization.
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ORIGINAL PAPER
Epilepsy Among Children and Adolescents with Autism Spectrum Disorders: A Population-Based Study Elina Jokiranta • Andre Sourander • Auli Suominen • Laura Timonen-Soivio Alan S. Brown • Matti Sillanpa¨a¨
•
Ó Springer Science+Business Media New York 2014
Abstract The present population-based study examines associations between epilepsy and autism spectrum disorders (ASD). The cohort includes register data of 4,705 children born between 1987 and 2005 and diagnosed as cases of childhood autism, Asperger’s syndrome or pervasive developmental disorders—not otherwise specified. Each case was matched to four controls by gender, date of birth, place of birth, and residence in Finland. Epilepsy was associated with ASD regardless of the subgroup after adjusting for covariates. The associations were stronger among cases with intellectual disability, especially among females. Epilepsy’s age at onset was similar between the cases and controls regardless of the ASD subgroup. These findings emphasize the importance to examine the neurodevelopmental pathways in ASD, epilepsy and intellectual disability.
Keywords Epilepsy Autism spectrum disorders Intellectual disability Gender Age at onset Population-based
E. Jokiranta (&) A. Sourander A. Suominen L. Timonen-Soivio Department of Child Psychiatry, University of Turku, Lemminka¨isenkatu 3/Teutori (3rd Floor), 20014 Turku, Finland e-mail: [email protected]
A. S. Brown Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
A. Sourander e-mail: [email protected] E. Jokiranta A. Sourander A. Suominen L. Timonen-Soivio Turku University Hospital, Turku, Finland
Abbreviations ASD Autism spectrum disorder CPR Finnish Central Population Register FIPS-A Finnish Prenatal Study of Autism and Autism Spectrum Disorders FHDR Finnish Hospital Discharge Register FMBR Finnish Medical Birth Register ICD International Classification of Diseases ID Intellectual disability PDD-NOS Pervasive developmental disorder—not otherwise specified SE Status epilepticus THL National Institute for Health and Welfare
M. Sillanpa¨a¨ Department of Child Neurology, University of Turku, Turku, Finland M. Sillanpa¨a¨ Department of Public Health, University of Turku, Turku, Finland
A. Sourander A. S. Brown Department of Psychiatry, New York State Psychiatric Institute, Columbia University College of Physicians and Surgeons, New York, NY, USA L. Timonen-Soivio Department of Child Neurology, Helsinki University Central Hospital, Helsinki, Finland
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J Autism Dev Disord
Introduction Autism spectrum disorders (ASD) are complex neurodevelopmental disorders characterized by qualitative abnormalities in language and communication patterns, in reciprocal social interactions, and a restrictive, stereotyped, repetitive repertoire of interests and activities (World Health Organization 1992). Epilepsy, a common comorbidity in ASD, is defined as a chronic neurologic condition characterized by recurrent spontaneous epileptic seizures (Engel 2001). Both ASD and epilepsy can be described as spectrum disorders which have diverse etiologies and pathologies and where the clinical manifestations as well as the severity of symptoms vary between the cases (Jensen 2011). Previous reviews have reported that the prevalence of epilepsy in ASD varies from 8 to 30 % (Spence and Schneider 2009; Tuchman et al. 2010). The variation is due to factors such as coexistent intellectual disability (ID) (Amiet et al. 2008; Mouridsen et al. 2011a, b; Woolfenden et al. 2012), female gender (Amiet et al. 2008; Danielsson et al. 2005), severe language dysfunction (Tuchman et al. 1991), and age (Giovanardi-Rossi et al. 2000; Hara 2007; Volkmar and Nelson 1990), which are all associated with the risk of epilepsy in ASD. Also, epilepsy is more common among subjects with childhood autism (Danielsson et al. 2005; Mouridsen et al. 2011a) or pervasive developmental disorder—not otherwise specified (PDD-NOS) (Challman et al. 2003; Mouridsen et al. 2011b; Parmeggiani et al. 2007) than subjects with Asperger’s syndrome (Cederlund and Gillberg 2004; Mouridsen et al. 2013). Both ASD and epilepsy by themselves have significant impacts on the child’s wellbeing and increase the stress and burden for the families. Moreover, ASD and epilepsy are often associated with comorbid conditions including ID, behavioural problems, mood disorders and attention problems (Austin and Caplan 2007; Hamiwka and Wirrell 2009; Simonoff et al. 2008). A child diagnosed with both ASD and epilepsy requires a comprehensive assessment and careful treatment including support for the families. Despite numerous clinical studies of the association between epilepsy and ASD, thus far there are only three population-based studies based on nationwide registries examining this association (Mouridsen et al. 2011a, b, 2013). In studies from Denmark, the prevalence of epilepsy in childhood autism was 24.6 % (Mouridsen et al. 2011a), in Asperger’s syndrome 3.9 % (Mouridsen et al. 2013) and in atypical autism/PDD-NOS 22.5 % (Mouridsen et al. 2011b). Epilepsy was more common among cases with ID (Mouridsen et al. 2011a, b) and females tended to have epilepsy more frequently than males (Mouridsen et al. 2011a, b, 2013). All epilepsy syndromes were observed
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among cases with ASD, but the most common were generalized and/or unspecified types. The limitations of the previous population-based studies include rather small sample sizes and the lack of covariates. The aim of the present study was to examine the associations between epilepsy and ASD with special reference to epilepsy syndromes, ID, gender and age at onset after adjusting for covariates. We hypothesized that epilepsy would be associated with ASD, but the magnitude of the associations would differ between childhood autism, Asperger’s syndrome and PDD-NOS.
Methods Data Sources ASD cases and their controls were identified through the Finnish Prenatal Study of Autism and Autism Spectrum Disorders (FIPS-A), a nested case–control study based on a national birth cohort including approx. 1.2 million births in Finland between 1987 and 2005. The FIPS-A has been described in detail previously (Lampi et al. 2011). Briefly, data in the FIPS-A were linked between several nationwide registries using unique personal identity code, given at birth to every Finnish resident and remaining the same throughout lifespan. The FIPS-A has been authorized by the Ministry of Social Affairs and Health of Finland (STM/2593/2008). The ethics committees of the hospital district of Southwest Finland and the Finnish National Institute for Health and Welfare and the Institutional Review Board of the New York State Psychiatric Institute have approved the study design. All the data used in this study were collected from three nationwide registries: the Finnish Hospital Discharge Register (FHDR), the Finnish Medical Birth Register (FMBR) and the Finnish Central Population Register (CPR). The FHDR is maintained by the National Institute for Health and Welfare (THL) including inpatient diagnoses since 1, January 1967 and outpatient diagnoses since 1, January 1998. The FHDR contains subject’s dates of admission and discharge, primary diagnosis of discharge and three possible subsidiary diagnoses. It covers all medical diagnoses, both somatic and psychiatric ones, made nationwide in hospitals or inpatient wards of local health centres, and in military wards, prison and private hospitals. The diagnostic classification is based on the International Classification of Diseases (ICD). The 8th revision (World Health Organization 1967) was used from 1969 to 1986, the 9th (World Health Organization 1977) from 1987 to 1995 and the 10th revision (World Health Organization 1992) has been used since January 1, 1996. The FHDR was used to identify subjects with ASD and/or
J Autism Dev Disord
epilepsy and also to obtain data on covariates as discussed below. The FMBR is also maintained by THL including a comprehensive data on every pregnancy, the prenatal period and the neonatal period up to 7 days of age on all births in Finland. The FMBR was established in 1987 including data on mothers and every live born child. The FMBR was used to identify controls and mothers and also to obtain the data on covariates. Information on the mothers was needed to obtain data on their psychiatric diagnoses and epilepsy diagnoses from the FHDR, used as covariates as discussed below. The CPR is a computerized nationwide register containing basic information (e.g. name, address, municipality of residence, citizenship, family relations) about Finnish residents and foreign citizens living permanently in Finland. The CPR was used to identify the fathers. Similarly to mothers, information on the fathers was needed to obtain data on their psychiatric diagnoses and epilepsy diagnoses, used as covariates. Paternity of newborn is based on an individual’s status as a husband of the mother at delivery. However, if the mother is unmarried, paternity is confirmed by acknowledgment of the father or by using DNA-testing if the father agrees with such testing. In this study paternity was established in 98.3 % of the subjects. Identification of Cases and Controls Cases with ASD were identified from the FHDR by codes from ICD-10 (F84x) and ICD-9 (299x). The most recent diagnosis was used and, based on the dates of birth and the dates during which each diagnostic system was used, the majority of cases were diagnosed by ICD-10 codes; only 19 cases were diagnosed based on ICD-9. We examined the association between epilepsy and ASD using the three main subgroups of ASD: childhood autism (F84.0) (n = 1,131), Asperger’s syndrome (F84.5) (n = 1,783), and other pervasive developmental disorders/pervasive developmental disorders—not otherwise specified (PDDNOS) (F84.8/F84.9) (n = 1,791). The combination of childhood autism, Asperger’s syndrome and PDD-NOS totalled 4,705 cases. Subjects diagnosed with epilepsy or status epilepticus (SE) were identified through the FHDR by using the ICD10 (G40, G41) and ICD-9 (345) codes. Diagnoses were classified into specific epilepsy syndrome categories according to the first diagnosis of epilepsy syndrome (see Table 6 in Appendix). However, if a subject was diagnosed at any time as a case of with petit mal/absentia (G40.7, G41.1, 3452A), that diagnosis was used in the classification. In Finland, an initial epilepsy diagnosis is made in specialized health services by a neurologist who also starts the treatment. If there is a suspicion of epilepsy, a subject
receives a referral to a neurologist from a primary health care; the neurologist conducts a comprehensive neurologic examination including electroencephalography (EEG) and magnetic resonance imaging (MRI). If needed, long-term video-EEG recordings can also be made. The goals of the comprehensive neurologic examination are first, to confirm that the symptoms are due to epilepsy and secondly, to determine the epilepsy syndrome as accurately as possible so that the most appropriate medication can be prescribed. Subjects diagnosed with ID were identified by the FHDR using the following ICD-10/9 codes: F70/317 (IQ B 70–50, i.e. mild ID), F71/318.0 (IQ B 49–35, i.e. moderate ID), F72/318.1 (IQ B 34–20, i.e. severe ID), F73/318.2 (IQ \ 20, i.e. profound ID), F78 (no ICD-9 code) (IQ unspecified), and F79/319 (IQ unspecified). In addition, cases with comorbid ID were grouped into those with mild ID (IQ B 70–50, ICD10/9 F70/317) and those with more severe ID (IQ B 49 or less, ICD10/9 F71/318.0; F72/318.1; F73/318.2). Each case was individually matched to four controls by date of birth (±30 days), gender, place of birth by hospital and residence in Finland. If a birth hospital control could not be found, the case was matched with a control born in the nearest regional hospital district. Controls were identified through the FMBR of subjects who did not meet the inclusion criteria for ASD or had severe or profound ID according to the FHDR. Overall 18,745 controls were matched from the FMBR. Covariates Prior to adjustment, bivariate analyses (Pearson’s v2-test, p \ 0.10) were conducted to test the significance of associations between covariates and epilepsy among controls as well as between covariates and ASD. The covariates included in the analysis were maternal socioeconomic status (upper white collar workers; lower white collar workers; blue collar workers; others); maternal age (\20, 20–24, 25–29, 30–34, 35–39, C40 years); paternal age (\20, 20–24, 25–29, 30–34, 35–39, 40–49; C50 years); smoking during pregnancy (yes/no); maternal psychiatric disorder (yes/no) (ICD-10 codes: F10–F99, excluding F70– F79; ICD-9 291–316 excluding 293–294; ICD-8 291–309 excluding 292–294; paternal psychiatric disorder (yes/no); maternal epilepsy (yes/no) (ICD-10 codes G40–G41; ICD9 and ICD-8 codes 345); paternal epilepsy (yes/no); birth weight (B1,500 g; 1,500–2,499 g; 2,500–3,999 g; 4,000–4,499 g; C4,500 g); gestational age (B31; 32–37; 38–41; C42 weeks) and 1 min Apgar scores (B6; 7–8; 9–10 scores). Based on the analysis, the following covariates were significantly associated both with epilepsy and ASD and were included in the statistical analyses: smoking during pregnancy, maternal psychiatric disorder, maternal
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J Autism Dev Disord Table 1 Covariates in relation to epilepsy in controls and in relation to risk of autism spectrum disorders Association between covariates and epilepsy No epilepsy, n (%) Gestational age
Epilepsy, n (%)
p
Association between covariates and autism spectrum disorders p
\.0001
\.0001
0.0584
0.0329
0.0209
\.0001
0.0055
\.0001
0.0542
0.0005
\.0001
\.0001
\.0001
\.0001
n = 18,410
n = 219
31 weeks or under
94 (0.5)
7 (3.2)
32–37 38–41
1,615 (8.8) 15,847 (86.1)
36 (16.4) 163 (74.4)
42 weeks or over
854 (4.6)
13 (5.9)
n = 18,076
n = 213
No
15,205 (84.1)
169 (79.3)
Yes
2,871 (15.9)
44 (20.7)
n = 18 524
n = 221
No
17,509 (94.5)
201 (91.0)
Yes
1,015 (5.5)
20 (9.1)
n = 18,524
n = 221
No
18,394 (99.3)
215 (97.3)
Yes
130 (0.7)
6 (2.7)
n = 18,307
n = 219
18,191 (99.4)
215 (98.2)
Smoking during pregnancy
Maternal psychiatric disorder
Maternal epilepsy diagnosis
Paternal epilepsy diagnosis No Yes
116 (0.6)
4 (1.8)
n = 18,447 68 (0.4)
n = 221 7 (3.2)
1,500–2,499 g
394 (2.1)
16 (7.2)
2,500–3,999 g
13,905 (75.4)
143 (64.7)
4,000–4,499 g
3,299 (17.9)
45 (20.4)
4,500 g or over
781 (4.2)
10 (4.5)
Birth weight \1,500 g
Apgar score at 1 min
n = 18,420
n = 220
9–10
14,064 (76.4)
162 (73.6)
7–8
3,661 (19.9)
37 (16.8)
0–6
695 (3.8)
21 (9.6)
epilepsy, paternal epilepsy, birth weight, gestational age and 1 min Apgar scores (Table 1). The data on these covariates were collected from the FMBR and the FHDR. Statistical Analysis Conditional logistic regression analysis of matched case– control strata was used to examine the associations between epilepsy and ASD. Associations between epilepsy and ASD were determined by using odds ratios (ORs) with 95 % confidence intervals (CIs). p Values were calculated using Pearson’s v2-test; statistical significance was defined as p \ 0.05. The model was adjusted for smoking during pregnancy, maternal psychiatric disorder, maternal epilepsy, paternal epilepsy, birth weight, gestational age and 1 min Apgar score. The analyses were also conducted for subjects with and without ID. Moreover, among those cases with comorbid ID, data were analyzed between cases with
123
mild ID and more severe ID. In addition, data were analyzed separately for males and females with and without comorbid ID. Pearson’s v2-test or Fisher’s exact test were used to compare the age at onset distribution by year between cases and controls by the significance level of p \ 0.05. The statistical analyses were carried out using SAS statistical software (SAS Version 9.4; SAS Institute Inc., Cary, NC).
Results The mean ages for ASD diagnosis were as follows: 5.5 years (SD 3.6 years) for childhood autism, 9.6 years (SD 3.3 years) for Asperger’s syndrome and 7.2 years (SD 3.4 years) for PDD-NOS. ID was present in 12.7 % of all ASD cases, including 28.8 % of those with childhood autism, 1.3 % with Asperger’s syndrome and 13.8 % with PDD-NOS.
J Autism Dev Disord Table 2 Epilepsy, epilepsy syndromes and status epilepticus in cases with autism spectrum disorders and matched controls ASD totala
Childhood autism
Asperger’s syndrome
PDD-NOS
Case n (%)
Control n (%)
Case n (%)
Control n (%)
Case n (%)
Control n (%)
Case n (%)
Control n (%)
No
4,393 (93.4)
18,528 (98.8)
1,020 (90.2)
4,460 (98.9)
1,727 (96.9)
7,023 (98.8)
1,646 (91.9)
7,045 (98.8)
Yes
312 (6.6)
217 (1.2)
111 (9.8)
51 (1.1)
56 (3.1)
83 (1.2)
145 (8.1)
74 (1.6)
43 (0.2)
26 (2.6)
13 (0.3)
11 (0.6)
15 (0.2)
37 (2.1)
15 (0.2)
Idiopathic generalized
61 (1.3)
34 (0.2)
21 (1.9)
10 (0.2)
9 (0.5)
13 (0.2)
31 (1.7)
11 (0.2)
Symptomatic generalized
12 (0.3)
Epilepsy
Generalized
Focal
9 (0.05)
5 (0.4)
128 (2.7)
95 (0.5)
41 (3.6)
Idiopathic focal
30 (0.6)
23 (0.1)
7 (0.6)
70 (0.4)
33 (2.9)
Symptomatic focal
92 (2.0)
Epileptic syndromes
8 (0.2)
Other or unspecified
102 (2.2)
9 (0.05) 70 (0.4)
3 (0.07) 16 (0.4) 2 (0.04) 14 (0.3)
3 (0.3)
2 (0.04)
41 (3.6)
20 (0.4)
2 (0.1)
2 (0.03)
5 (0.3)
83 (1.2)
4 (0.06)
38 (1.7)
31 (0.5)
56 (3.1)
41 (0.6)
4 (0.2)
9 (0.1)
19 (1.1)
12 (0.2)
23 (1.3)
28 (0.4)
36 (2.0)
28 (0.4)
1 (0.06)
2 (0.03)
13 (0.7)
28 (0.4)
4 (0.2) 48 (2.7)
5 (0.07) 22 (0.3)
Status epilepticus No
4,675 (99.4)
Yes
30 (0.6)
Generalized status epilepticus
11 (0.2)
Psychomotor status epilepticus Partialis continua
18,731 (99.95) 14 (0.1)
1,119 (98.9)
4,508 (99.9)
1,781 (99.9)
7,097 (99.9)
1,775 (99.1)
7,126 (99.97)
12 (1.1)
3 (0.1)
2 (0.1)
9 (0.1)
16 (0.9)
2 (0.03)
6 (0.03)
4 (0.4)
0 (0.0)
0 (0.0)
5 (0.07)
7 (0.4)
1 (0.01)
6 (0.1)
2 (0.01)
2 (0.2)
1 (0.02)
0 (0.0)
1 (0.01)
4 (0.2)
0 (0.0)
0 (0.0)
1 (0.01)
0 (0.0)
0 (0.0)
0 (0.0)
1 (0.01)
0 (0.0)
0 (0.0)
ASD autism spectrum disorders, PDD-NOS pervasive developmental disorders—not otherwise specified a
Includes childhood autism, Asperger’s syndrome and PDD-NOS
Table 2 shows the frequencies of epilepsy, epilepsy syndrome categories and SE among cases and controls. 54.2 % had received an epilepsy diagnosis before an ASD diagnosis. 43.6 % received an ASD diagnosis before an epilepsy diagnosis. In addition, 2.2 % received both diagnoses at the same time. The associations between epilepsy and ASD subgroups were very similar in unadjusted and adjusted analyses and therefore only adjusted analyses are shown in Table 3. Epilepsy was associated with ASD regardless of the subgroup, but was most strongly associated with childhood autism and PDD-NOS. As shown in Table 3, childhood autism, Asperger’s syndrome and PDD-NOS were all associated with generalized, focal and unspecified epilepsies. Additionally, childhood autism was associated with epileptic syndromes. Childhood autism and PDD-NOS were associated with SE but Asperger’s syndrome was not (Table 3). Among cases with epilepsy and with comorbid ID, 46.3 % had first received an epilepsy diagnosis and later ASD and ID diagnosis. 45.4 % had first received an ASD diagnosis and later an epilepsy and ID diagnosis. A
minority, i.e. 8.3 % had first received an ID diagnosis and later an ASD and epilepsy diagnosis. Table 4 shows the frequencies and adjusted associations of epilepsy among ASD cases with and without comorbid ID. As shown in the table, the associations were present with and without comorbid ID. However, the magnitudes of the associations were stronger among ASD cases with comorbid ID. In addition, the risk for epilepsy was increased among cases with more severe ID than cases with mild ID (total ASD: OR 1.7, 95 % CI 1.005, 2.8, p = 0.04). In subgroups of ASD the corresponding figures were as follows: childhood autism: OR 1.1, 95 % CI 0.5, 2.3, p = 0.83, PDD-NOS: OR 2.6, 95 % CI 1.3, 5.5, p = 0.01. Table 5 shows the frequencies and adjusted associations of epilepsy among ASD males and females with and without comorbid ID. Among male cases with comorbid ID 22.4 % first received an ASD diagnosis followed by an epilepsy and ID diagnosis. Overall 55.2 % of these male cases received an epilepsy diagnosis before an ASD and ID diagnosis. Moreover, 22.4 % had received an ID diagnosis before and later ASD and epilepsy diagnosis. Among females with comorbid ID 26.8 % had first received an
123
J Autism Dev Disord Table 3 Associations between autism spectrum disorders and epilepsy, epilepsy syndromes and status epilepticus
Epilepsy
ASD totala
Childhood autism
Asperger’s syndrome
PDD-NOS
Case n (%) Control n (%) OR (95 % CI)
Case n (%) Control n (%) OR (95 % CI)
Case n (%) Control n (%) OR (95 % CI)
Case n (%) Control n (%) OR (95 % CI)
6.0 (5.0, 7.3)***
9.9 (6.8, 14.3)***
3.0 (2.1, 4.4)***
6.8 (5.1, 9.2)***
Epilepsy syndromes Generalized
7.2 (4.8, 10.8)***
9.5 (4.5, 19.9)***
3.6 (1.6, 8.2)**
9.3 (4.9, 17.6)***
Idiopathic generalized
6.9 (4.4, 10.9)***
8.4 (3.8, 18.7)***
3.4 (1.4, 8.5)**
9.2 (4.5, 18.8)***
Symptomatic generalized
4.5 (1.7, 11.9)**
8.6 (1.6, 47.2)*
3.6 (0.5, 26.4)
3.6 (0.8, 16.5)
5.6 (4.2, 7.5)***
12.5 (6.6, 23.7)***
3.4 (2.0, 5.7)***
5.3 (3.4, 8.2)***
Idiopathic focal
4.8 (2.7, 8.4)***
13.8 (2.8, 67.0)**
1.6 (0.5, 5.4)
5.5 (2.6, 11.6)***
Symptomatic focal
5.3 (3.8, 7.5)***
10.9 (5.4, 21.8)***
3.5 (1.9, 6.4)***
4.7 (2.7, 8.0)***
Epileptic syndromes
3.9 (1.5, 10.6)**
10.4 (1.4, 77.6)*
2.3 (0.2, 26.1)
2.8 (0.7, 11.2)
Other or unspecified
6.2 (4.4, 8.6)***
8.2 (4.6, 14.4)***
2.2 (1.1, 4.5)*
9.2 (5.3, 15.8)***
Status epilepticus
Focal
8.5 (4.3, 16.8)***
20.5 (4.4, 94.5)***
0.9 (0.2, 4.5)
28.1 (6.4, 123.8)***
Generalized status epilepticus
6.7 (2.4, 18.2)***
N/A
N/A
23.4 (2.9, 191.4)**
Psychomotor status epilepticus
9.6 (1.9, 48.8)**
6.3 (0.5, 74.1)
N/A
N/A
Adjusted for smoking during pregnancy, maternal psychiatric disorder, maternal epilepsy, paternal epilepsy, gestational age, birth weight, 1 min Apgar scores ASD autism spectrum disorders, PDD-NOS pervasive developmental disorders—not otherwise specified, OR odds ratio, CI confidence interval, N/A not applicable * p \ 0.05, ** p \ 0.01, *** p \ 0.001 a
Includes childhood autism, Asperger’s syndrome and PDD-NOS
Table 4 Associations between autism spectrum disorders with and without intellectual disability and epilepsy ASD totala
Childhood autism
Asperger’s syndrome
PDD-NOS
Case n (%) Control n (%) OR (95 % CI)
Case n (%) Control n (%) OR (95 % CI)
Case n (%) Control n (%) OR (95 % CI)
Case n (%) Control n (%) OR (95 % CI)
No epilepsy, no ID
3,831 (95.4)
15,840 (99.0)
745 (94.9)
3,106 (99.2)
1,665 (96.9)
6,771 (98.9)
1,421 (94.0)
5,963 (99.0)
Epilepsy without ID
184 (4.6)
160 (1.0)
40 (5.1)
26 (0.8)
53 (3.1)
76 (1.1)
91 (6.0)
58 (1.0)
4.7 (3.7, 5.9)***
6.6 (3.9, 11.1)***
3.1 (2.1, 4.6)***
5.8 (4.1, 8.3)***
No epilepsy with ID
560 (81.2)
2,684 (97.8)
274 (79.2)
1,354 (98.2)
62 (95.4)
248 (95.6)
224 (80.3)
1,082 (97.7)
Epilepsy with ID
130 (18.8)
61 (2.2)
72 (20.8)
25 (1.8)
3 (4.6)
11 (4.3)
55 (19.7)
25 (2.3)
10.3 (7.2, 14.7)***
17.2 (9.6, 30.6)***
N/A
10.5 (6.0, 18.5)***
Adjusted for smoking during pregnancy, maternal psychiatric disorder, maternal epilepsy, paternal epilepsy, gestational age, birth weight, 1 min Apgar scores ASD autism spectrum disorders, PDD-NOS pervasive developmental disorders—not otherwise specified, ID intellectual disability, OR odds ratio, CI confidence interval, N/A not applicable * p \ 0.05, ** p \ 0.01, *** p \ 0.001 a
Includes childhood autism, Asperger’s syndrome and PDD-NOS
ASD diagnosis before an epilepsy and ID diagnosis. Overall 48.8 % of these female cases had received an epilepsy diagnosis before an ASD and ID diagnosis. In addition, 24.4 % had received an ID diagnosis before a diagnosis of ASD and epilepsy. As shown in the Table 5, the magnitude of the associations between epilepsy and ASD were stronger among males and females with
123
comorbid ID than without ID. Moreover, the magnitudes of the associations were especially strong among ASD females with comorbid ID, particularly in PDD-NOS. Figure 1 shows the cumulative percentages of age at onset of epilepsy. The age at onset did not significantly differ between cases and controls for ASD total nor in the subgroups of ASD at any age.
J Autism Dev Disord Table 5 Associations between autism spectrum disorders with and without intellectual disability and epilepsy by sex ASD totala
Childhood autism
Asperger’s syndrome
PDD-NOS
Case n (%) Control n (%) OR (95 % CI)
Case n (%) Control n (%) OR (95 % CI)
Case n (%) Control n (%) OR (95 % CI)
Case n (%) Control n (%) OR (95 % CI)
No epilepsy, no ID
3,113 (95.9)
12,803 (99.0)
605 (95.7)
2,504 (99.3)
1,408 (97.0)
5,720 (98.9)
1,100 (94.6)
4,579 (99.0)
Epilepsy without ID
133 (4.1)
130 (1.0)
27 (4.3)
18 (0.7)
43 (3.0)
64 (1.1)
63 (5.4)
48 (1.0)
Male
4.1 (3.2, 5.4)***
6.0 (3.2, 11.3)***
3.2 (2.1, 4.9)***
4.7 (3.1, 7.1)***
No epilepsy with ID
414 (83.0)
1,940 (97.7)
208 (79.7)
1,021 (98.1)
50 (94.3)
204 (96.7)
156 (84.3)
715 (97.4)
Epilepsy with ID
85 (17.0)
46 (2.3)
53 (20.3)
20 (1.9)
3 (5.7)
7 (3.3)
29 (15.7)
19 (2.6)
9.3 (6.1, 14.2)***
17.4 (8.9, 34.1)***
N/A
7.2 (3.6, 14.3)***
Female No epilepsy, no ID
718 (93.4)
3,037 (99.0)
140 (91.5)
602 (98.7)
257 (96.3)
1,051 (98.9)
321 (92.0)
1,384 (99.3)
Epilepsy without ID
51 (6.6)
30 (1.0)
13 (8.5)
8 (1.3)
10 (3.8)
12 (1.1)
28 (8.0)
10 (0.7)
7.2 (4.4, 11.7)***
10.1 (3.7, 27.4)***
2.6 (1.04, 6.5)*
No epilepsy with ID
146 (76.4)
744 (98.0)
66 (77.7)
333 (98.5)
12 (100)
44 (91.7)
68 (72.3)
367 (98.4)
Epilepsy with ID
45 (23.6)
15 (2.0)
19 (22.4)
5 (1.5)
0 (0)
4 (8.3)
26 (27.7)
6 (1.6)
15.9 (7.7, 32.7)***
17.6 (5.5, 55.8)***
N/A
12.5 (5.6, 28.0)***
36.5 (10.0, 133.8)***
Adjusted for smoking during pregnancy, maternal psychiatric disorder, maternal epilepsy, paternal epilepsy, gestational age, birth weight, 1 min Apgar scores ASD autism spectrum disorders, PDD-NOS pervasive developmental disorders—not otherwise specified, ID intellectual disability, OR odds ratio, CI confidence interval, N/A not applicable * p \ 0.05, ** p \ 0.01, *** p \ 0.001 Includes childhood autism, Asperger’s syndrome and PDD-NOS
a
Discussion There are three main findings in the study. First, epilepsy was strongly associated with ASD after adjustment for covariates and in line with previous population-based studies (Mouridsen et al. 2011a, b, 2013). Childhood autism showed a nearly tenfold and PDD-NOS nearly a sevenfold increased odds for epilepsy compared with controls. Asperger’s syndrome showed a threefold increased odds for epilepsy. Our results are consistent with the previous studies showing that Asperger’s syndrome has a lower magnitude of association with epilepsy than childhood autism or PDD-NOS (Cederlund and Gillberg 2004; Mouridsen et al. 2013). The weaker association between epilepsy and Asperger’s syndrome might be due to absence of ID, because ID is a diagnostic exclusion criterion of Asperger’s syndrome. One substantial risk factor for epilepsy is ID and the prevalence increases with the severity of ID (van Blarikom et al. 2006). Consistent with that finding, the associations with ASD and its subgroups were stronger in the subgroups with comorbid ID. Second, all epilepsy syndromes had a rather similar strength of association with ASD. Our finding is in
agreement with previous studies showing that there is no specific epilepsy syndrome to be expected in ASD (Danielsson et al. 2005; Giovanardi-Rossi et al. 1995; Hara 2007; Mouridsen et al. 2011a, 2013; Steffenburg et al. 2003; Tuchman and Rapin 2002). Effective management of epilepsy requires the identification of the specific epilepsy syndrome, because information is often needed for antiepileptic medication, prognosis and interventional therapy (Peake et al. 2006). However, diagnosing an epilepsy syndrome among cases with ASD might be challenging because core symptoms of severe ASD; lack of or difficulties in communication limits the ability to report symptoms, and in some cases abnormal movements including the repetitive, stereotyped behaviors and/or ticlike movements might be difficult to distinguish from epileptic event (Peake et al. 2006). Third, age at onset of epilepsy did not differ between ASD cases and controls. The studies of Deykin and MacMahon (1979) and Volkmar and Nelson (1990) suggest that there is a bimodal age distribution of epilepsy in ASD, with the first peak occurring during the early years of childhood and the second peak in early puberty. Our data, however, indicate that the highest risk for epilepsy is in early
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J Autism Dev Disord Fig. 1 Age at onset of epilepsy among cases with autism spectrum disorders and controls
childhood, because nearly half of our study sample—both cases and controls—had received the epilepsy diagnosis before the age of 6. This finding is in line with a previous study (Danielsson et al. 2005), but is discrepant with studies showing increased risk in puberty (Deykin and MacMahon 1979; Giovanardi-Rossi et al. 2000; Hara 2007; Volkmar and Nelson 1990). This discrepancy might be explained at least partly by the use of different ASD criteria and varying study designs and sample sizes. Over half of the cases had first received the epilepsy diagnosis and were later diagnosed with ASD. The proportion of cases who had first received an ASD diagnosis prior to an epilepsy and ID diagnosis was approximately the same as for cases receiving first an epilepsy diagnosis and later an ASD and ID diagnosis. Even though there are numerous studies examining the prevalence of epilepsy in ASD, investigating ASD among subjects with epilepsy
123
has only recently become an area of research interest. These studies show that the prevalence of ASD is substantially higher among subjects with epilepsy than the prevalence of ASD in the general population and the risk for ASD is increased especially among subjects with ID (Berg et al. 2011; Clarke et al. 2005; Matsuo et al. 2010). One possibility for the delayed ASD diagnosis among subjects with epilepsy might be the early onset of epilepsy, occurring prior to the time when ASD is typically diagnosed, i.e. prior to age three. Another hypothesis is that cases without comorbid ID together with less severe ASD symptoms (e.g. Asperger’s syndrome) are not detected as easily as are the more severely affected cases with comorbid ID (Matsuo et al. 2010). However, given that early onset of epilepsy is associated with an increased risk of ID (Berg et al. 2008; Cormack et al. 2007) and ASD is associated with ID, we suggest that clinicians
J Autism Dev Disord
need to pay particular attention to other possible diagnoses that are comorbid with epilepsy. ID and epilepsy by themselves are complex conditions with a heterogeneous etiology, caused by a range of pathological processes. It has been suggested that males are more often diagnosed with ID than are females (McLaren and Bryson 1987). However, some studies suggest that the male–female ratio becomes more equal when IQ decreases and that females are more often diagnosed with severe ID than males (Bradley et al. 2002; McLaren and Bryson 1987). Similarly, males are more often diagnosed with ASD than are females, but the sex ratio decreases significantly among cases with severe ID (Nicholas et al. 2008). Females with ASD have a higher risk of epilepsy than males, probably because females with ASD tend to have a higher rate of ID (Amiet et al. 2008). The present study provides some support to this, because the association with epilepsy was particularly high among ASD females with comorbid ID. In addition, this ID-epilepsy-female gender association has become a more significant research area after discovery of the causative gene for the condition known as ‘‘epilepsy and mental retardation limited to females’’ (EFMR) (Dibbens et al. 2008). This gender-specific disorder is characterized by seizure onset during early childhood and usually cognitive impairment, and interestingly, is associated with several psychiatric disorders including ASD (Scheffer et al. 2008). Understanding of this condition and its comorbidity with other psychiatric disorders is, however, limited, requiring further studies. Advances in genetic technology during the last decade are having a significant impact on our understanding of different disorders. Genetic studies show that disorders, which have formerly been defined as clinically distinct disorders (including schizophrenia, ASD, epilepsy, ID) share similarities in neurodevelopmental pathology (Friedman et al. 2008; Guilmatre et al. 2009; Mefford et al. 2008; Stoll et al. 2013). Moreover, epidemiological studies show that these disorders also cluster in families (Daniels et al. 2008; Jokiranta et al. 2013; Qin et al. 2005). Even though ASD and epilepsy are now defined as clinically distinct disorders, the strong association between them suggests that also they might share common underlying pathophysiological mechanisms. Our study is the first population-based one to examine the associations between epilepsy and ASD after adjusting for covariates. The following limitations must be considered. First, there may be some misclassification of diagnoses of ASD and epilepsy, typical of register studies. However, the Finnish hospital discharge registers have good validity for both childhood autism (Lampi et al. 2010) and epilepsy (Sillanpa¨a¨ et al. 2011). Second, the hospital discharge register includes inpatient diagnoses
since 1967, but outpatient diagnoses since 1998. Consequently, we were not able to include cases that were diagnosed and treated only in outpatient units prior to that year. It is to be noted, however, that since the most recent diagnosis was used for case identification, and ASD is generally a chronic condition, we expect that this would have captured many cases treated exclusively as outpatients with onset prior to 1998 in our study sample. Third, the ICD-10 classification is not equal to that of International League Against Epilepsy even though the differences are not insurmountable. Fourth, the cohort likely includes children who haven’t yet received the diagnosis (in this case ASD or epilepsy) due to the time window (e.g. children born in the end of 2005 and having Asperger’s syndrome probably will not have been given the diagnosis by the end of 2007, because typically highfunctioning cases receive the diagnosis after the toddler age) or because they haven’t received any treatments from the clinics. However, given that in Finland the treatment of ASD and epilepsy are free-of-charge, and, before the beginning of school (age 7), all children visit child health clinics at least once a year where the child’s health is assessed comprehensively, it is likely that children with symptoms of ASD or epilepsy will receive treatment and subsequently become registered in the FHDR. Finally, we are not able to show whether a subject’s epilepsy is active or not. In Finland, the initial epilepsy diagnosis is made by a neurologist in specialized health services who also starts the treatment. After achieving remission, among children and adolescents the treatment typically remains in specialized health services due to their young age. However, among adults the follow-up and treatment is typically transferred to the primary health care provider unless the condition requires specialized health services (i.e. epilepsy occurring during pregnancy or treatment refractory epilepsy).Thus, there is a lack of data among adults whose treatment has been transferred to primary health care, because we only have data from specialized health services. However, the majority of the subjects included in this study are children and adolescents, whose treatment remains in specialized health services. To conclude, epilepsy is associated with autism spectrum disorders and all the subgroups after adjustment for covariates. The strength of the association is influenced by comorbid intellectual disability. The intercorrelated occurrence of autism spectrum disorders, epilepsy and intellectual disability argues for shared underlying neurodevelopmental mechanisms and makes up a research challenge for the modern gene technology. Acknowledgments This study was funded by the Finnish Epilepsy Society, the Jane and Aatos Erkko Foundation, the Finnish Pediatric
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J Autism Dev Disord Research Foundation (E. Jokiranta), and the National Institute for Environmental Health Sciences (NIEHS) R01ES019004 (A. Brown, PI). Conflict of interest The authors have no financial relationships relevant to this article to disclose.
Appendix
Table 6 Specific diagnosis codes for epilepsy syndrome categories and status epilepticus Diagnostic group
Current classification ICD-10 (1996 to present)
Previous classification ICD-9 (1987–1995)
Epilepsy
G40
3450A–3451A, 3454A–3456B, 3458X, 3459X
Generalized
G40.3–G40.8 (excluding G40.5) G40.3 (generalized idiopathic epilepsy), G40.6 (grand mal seizures, unspecified, with or without petit mal), G40.7 (petit mal, unspecified, without grand mal seizures)
3450A–3453A
Symptomatic generalized
G40.4 (other generalized epilepsy and epileptic syndromes)
–
Focal
G40.0–G40.2
3454A–3454X, 3455A
Idiopathic focal
G40.0 (idiopathic focal epilepsy)
–
Symptomatic focal
G40.1 (focal epilepsy with simple partial seizures)– G40.2 (focal epilepsy with complex partial seizures)
–
Epileptic syndromes
G40.5 (special epileptic syndromes)
3456A, 3456B, 3457B
Other or unspecified
G40.8 (other epilepsy), G40.9 (unspecified epilepsy)
3458X 3459X
Status epilepticus
G41
3452A–3453A, 3457A–3457X
Generalized
G41.0 (grand mal status epilepticus), G41.1 (petit mal status epilepticus) G41.2 (complex partial status epilepticus)
3452A, 3453A
Idiopathic generalized
Psychomotor Partialis continua
–
3450A, 3451A
3457A 3457B
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