1045029

research-article2021
AUT0010.1177/13623613211045029AutismLiu et al.

Review

Autism

Prevalence of epilepsy in autism 2022, Vol. 26(1) 33­–50

© The Author(s) 2021
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DOI: 10.1177/13623613211045029
https://doi.org/10.1177/13623613211045029

review and meta-analysis journals.sagepub.com/home/aut

Xian Liu1,2, Xin Sun3, Caihong Sun2, Mingyang Zou2,

Yiru Chen1, Junping Huang4, Lijie Wu2 and Wen-Xiong Chen1

Abstract
The literature from inception to 2020 on the prevalence of epilepsy in autistic individuals was systematically reviewed
and further explored by subgroup analyses and meta-regression models. This systematic review is registered with
PROSPERO (CRD42020179725). A total of 66 studies from 53 articles were included. The updated pooled prevalence of
epilepsy in autistic individuals was 10% (95% CI: 6–14). The respective prevalence estimate of epilepsy was 19% (95% CI:
6–35) in the clinical sample-based cross-sectional study, 7% (95% CI: 3–11) in the cohort study, and 9% (95% CI: 5–15) in
the population-based cross-sectional study. The pooled prevalence of epilepsy was 7% (95% CI: 4–11) in autistic children
and 19% (95% CI: 14–24) in autistic adults. Compared to the school-aged group, the adolescence group (OR: 1.15, 95%
CI: 1.06–1.25) and the pre-school group (OR: 1.06, 95% CI: 0.94–1.19) were positively associated with the prevalence of
epilepsy. The moderators of age, human development index of the country, gender, and intellectual function accounted
for most of the heterogeneity. The prevalence estimates were associated with age, female gender, intellectual disability
rate, and the human development index of countries. About 1/10 autistic individuals co-occurred with epilepsy, which
was common in the clinical setting, adolescents, adults, females, or patients with intellectual disability, and less common
in the country with high human development index.

Lay abstract
Autistic individuals experience higher co-occurring medical conditions than the general population, and yet the estimates
of autistic individuals with epilepsy are not updated. Co-occurrence of epilepsy in autistic individuals often aggravated
cognitive impairment and increased the risk of poor long-term prognosis. Thus, an updated systematic review and
meta-analysis was conducted to study the relevant articles published from inception to 2020, evaluate the prevalence of
epilepsy in autistic individuals, and further explore the putative factors influencing the prevalence. A total of 66 studies
from 53 articles were included in this study. The results showed that epilepsy is more common in autistic individuals than
in the general population. The prevalence of epilepsy in autistic individuals in the clinical sample-based studies was higher
than that in the population-based based cross-sectional or cohort studies. The prevalence of epilepsy in autistic adults
was higher than that in autistic children. A significantly increased prevalence of epilepsy was detected in the autistic
adolescent group (11–17 years old), and a higher trend of prevalence of epilepsy was observed in the autistic pre-school
group (⩽ 6 -years-old) than that of the autistic school-aged group (7–10 years-old). The prevalence of epilepsy increased
with age, female rate, and low intellectual function rate of autistic individuals. However, the human development index
of countries was negatively associated with the pooled prevalence, which could be attributed to the different levels
of awareness, diagnostic technologies, and autism-service support worldwide. About 1/10 autistic individuals also had

1
Guangzhou Medical University, China Wen-Xiong Chen, The Assessment and Intervention Center for
2
Harbin Medical University, China Autistic Children, Department of Neurology, Guangzhou Women and
3
Shanghai Jiao Tong University, China Children’s Medical Center, Guangzhou Medical University, Guangzhou,
4
Tianjin Medical University, China 510623, China.
Email: gzchcwx@126.com
Corresponding authors:
Lijie Wu, Department of Children’s and Adolescent Health, College of
Public Health, Harbin Medical University, Harbin, 150081, China.
Email: wulijiehyd@126.com
34 Autism 26(1)
epilepsy, which was common in the clinical setting, adolescents, adults, females, or patients with intellectual disability and
less common in the country with high human development index. Thus, these findings provided critical and innovative
views on the prevalence of epilepsy in autistic individuals and contributed to the targeted clinical management and
preventive measures.
Keywords
adulthood, autism spectrum disorder (ASD), childhood, co-occurrence, epilepsy, meta-analyses
Introduction
Autism spectrum disorder (ASD) is a set of neurodevel-
opmental disorders characterized by early onset of
impaired social interaction, communication, stereotyped,
or repetitive behaviors, and restricted interests (Bailey
et al., 1996; Tărlungeanu et al., 2016). The increased
prevalence of ASD has been reported worldwide:
18.5/1000 children in the United States (Maenner et al.,
2020), 2.65 in China (Liu et al., 2018), and 43.6 in
Australia (May et al., 2020). Furthermore, the impair-
ment of ASD severely impacts the learning and social
functioning that may persist into adulthood (Wisner-
Carlson et al., 2020). Epilepsy is a neurological disorder
that is characterized by spontaneous and reoccurring sei-
zures (Profa & Franceschettia, 2003). The prevalence of
epilepsy in the general population was 4.6/1000 in
Northern Italy (Giussani et al., 2014) and 2.4/1000 in
China (Zhang et al., 2019), and that of epilepsy in indi-
viduals with autism ranges from 2.4% to 46% (Amiet
et al., 2013; Anukirthiga et al., 2019; Danielsson et al.,
2005; Neumeyer et al., 2019), which significantly
exceeded that of the general population. Similarly, ASDs
are prevalent in children with epilepsy. Previous studies
reported an increased risk of ASD in children with epi-
lepsy, with a prevalence of 7.5%–38% (Boel, 2004;
Clarke et al., 2005; Juneja et al., 2018; Matsuo et al.,
2010). The association of autism and epilepsy might be
mediated by the common pathophysiological mecha-
nisms (Tuchman & Rapin, 2002). In autistic children, the
co-occurrence with epilepsy often aggravated the impair-
ment of cognitive development and increased the possi-
bility of worse long-term outcomes (Aldinger et al.,
2015; Yeargin-Allsopp, 2008). Moreover, co-occurrence
with epilepsy in autistic individuals tends to persist from
childhood into adulthood, inevitably contributing to extra
challenges on the health and quality of life (Aldinger
et al., 2015; Pickett et al., 2011; Yeargin-Allsopp, 2008)
and increasing the considerable burden on public health
services (Kohane et al., 2012).
A systematic investigation of the prevalence of epilepsy
in autistic individuals provides an adequate evaluation and
intervention services. Such an investigation might also
shed light on the possible shared genetic mechanisms.
However, the reported prevalence might differ based on
various epidemiological methods (Kuhlthau et al., 2018;
Raznahan et al., 2010; L. Thompson et al., 2019). The
sociodemographic factors were related to healthcare acces-
sibility and socioeconomic status, which might influence
the understanding and diagnosis of the disease (Lai et al.,
2019). Furthermore, the intellectual function or gender
might affect the recognition and diagnosis of co-occurring
mental health conditions in autistic individuals (Danielsson
et al., 2005; Lai et al., 2019; Raznahan et al., 2010).
Previous studies pointed out an increased risk for seizures
in early childhood and adolescence (Volkmar & Nelson,
1990), while other studies reported that seizures might
begin in adolescence or adult (Bolton et al., 2011; Rossi
et al., 2000). However, whether there is an association
between the prevalence of epilepsy in autistic individuals
and age is yet controversial.
The prevalence estimates of epilepsy in autistic individu-
als reported in the literature are varied (Lauritsen et al., 2002;
Surén et al., 2012; Viscidi et al., 2014; Vohra et al., 2017;
Williams et al., 2008; Zhang et al., 2019). A previous meta-
analysis reported that the prevalence of epilepsy was 21.5%
in autistic subjects with intellectual disability (ID) versus 8%
in autistic subjects without ID based on the studies published
from 1963 through 2006 (Amiet et al., 2008). However, the
present meta-analysis did not report the pooled prevalence of
epilepsy among the autistic population, that is, children to
adults. Moreover, the meta-regression was not performed
further to analyze the heterogeneity of the study (Amiet
et al., 2008). Another recent systematic review also focused
on co-occurring epilepsy in autistic individuals (Lukmanji
et al., 2019). However, the study only reported the median
prevalence of epilepsy in autistic individuals (12.1%) rather
than presenting the pooled prevalence estimates by meta-
analysis (Lukmanji et al., 2019). Several other factors also
limit the interpretation of the review, such as including an
insufficient number of articles (only 20 articles) published
from inception to 2016 and several inappropriate studies
which did not provide the diagnostic criteria for ASD
(Lukmanji et al., 2019). Therefore, an updated systematic
review and meta-analysis on the prevalence of epilepsy in
autistic individuals is an urgent requirement.
The current review aimed to update literature system-
atically and analyze the appropriate estimates of the preva-
lence of epilepsy in autistic individuals, as well as identify
the aforementioned factors that may contribute to hetero-
geneity among the studies by meta-regression analysis.
Liu et al. 35
Methods
The protocol was registered with the International Prospective
Register of Systematic Reviews (PROSPERO) (registration
number: CRD42020179725). According to the Preferred
Reporting Items for Systematic reviews and Meta-analysis
(PRISMA) (Moher et al., 2009) and Meta-analysis of
Observational Studies in Epidemiology (MOOSE) guide-
lines (Stroup et al., 2000), we performed a systematic litera-
ture search in PubMed, EMBASE, and the Web of Science
from database inception through 13 April 2020.
Search strategy
We conducted the literature search for epilepsy, autism,
epidemiology, or comorbidity using “AND” as the com-
bining term. The search terms relating to autism, epilepsy,
epidemiology, and comorbidity were combined according
to the principles of Boolean logic (using AND, OR, or
NOT). The data were limited to human studies and publi-
cations written in English. No restrictions were defined on
the publication date or research location. The search terms
are presented in Supplemental Table 1.
Study selection
To ensure the validity of the search, two independent
reviewers conducted screening and selection by reading
the titles and abstracts of all studies. The full texts were
reviewed as required. The senior reviewer was consulted
when consensus on eligibility could not be achieved. The
inclusion criteria were as follows: (1) the observational
studies that estimated the prevalence of co-occurring epi-
lepsy in autistic individuals; (2) determination of ASD
diagnosis based on the clinical diagnosis (DSM-5)
(American Psychiatric Association, 2013) or structured
interviews (e.g. Autism Diagnostic Interview-Revised
(ADI-R) (Lord et al., 1994), Autism Diagnostic
Observation Schedule (ADOS) (Lord et al., 2000), or
equivalent); (3) diagnosis of epilepsy based on the defini-
tion of the International League Against Epilepsy (ILAE)
(Fisher et al., 2014). Reviews, experimental studies, and
studies without focusing on the prevalence of epilepsy in
autistic individuals were excluded.
The established search strategy retrieved 5650 publica-
tions. After duplicates were removed, 3863 were elimi-
nated by reviewing the titles and abstracts of 4133 articles.
The full-texts of 270 articles were reviewed, and 217 stud-
ies were excluded. Finally, 53 articles, including 66 stud-
ies, were analyzed in this meta-analysis (Figure 1).
Data extraction and quality review
The Strengthening the Reporting of Observational Studies
in Epidemiology (STROBE) (von Elm et al., 2007) was
used for data extraction. The extracted variables included
authors, country, study design, female rate, number of the
autistic individuals, comorbidity with epilepsy case,
comorbidity rate, the age range of autistic individuals, age
group, the proportion of ID, diagnostic criteria of ASD,
diagnostic criteria of epilepsy, and scores of the risk of
bias. Once the original study provided data on several pop-
ulations, the prevalence estimate of each population was
extracted separately. We retrieved data from the study with
the largest sample size among identical studies for further
prevalence estimates if duplicate data sources were identi-
fied. To ensure the validity of data extraction, the second
reviewer independently checked the data extracted. The
discrepancies were resolved by a senior reviewer.
Hoy risk of bias tool (Hoy et al., 2012) was used to
assess the risk of bias of studies measuring the prevalence
of epilepsy in ASDs. The tool consists of 10 items repre-
senting the risk of bias, each giving a score of 0 or 1 for the
absence or presence of bias. Items 1–4 assess the external
validity of the study (domains are selection and nonre-
sponse bias), and items 5–10 assess the internal validity
(items 5–9 assess the domain of measurement bias, and
item 10 assesses the bias related to the analysis) (Hoy
et al., 2012). This tool is appropriate for assessing the risk
of bias in population-based prevalence studies. The score
from 0 to 3 presented high quality, 4 to 6 a moderate qual-
ity, and 7 to 10 a low quality (Hoy et al., 2012; Lai et al.,
2019). Two independent reviewers undertook quality
assessments according to the Hoy risk of bias tool. If they
disagreed, the senior reviewer adjudicated the discrepan-
cies on quality assessment to reach a consensus.
Statistical analysis
The primary effect estimate of interest was the preva-
lence of epilepsy in autistic populations. The coverage of
the random effects (RE) confidence interval (CI) declines
below the nominal level (Brockwell & Gordon, 2001),
substantially underestimates the statistical error and pro-
duces overconfident conclusions (Noma, 2011; Poole &
Greenland, 1999) when the heterogeneity of included
studies is increased. The quality effects (QE) model could
use summary quality scores for bias adjustment in obser-
vational studies (Doi et al., 2013). The QE model of
meta-analysis is a clear improvement over the RE model
to handle heterogeneity when quality information is
available (Doi et al., 2015). Next, we performed a meta-
analysis based on the updated QE model (Doi et al., 2015;
Doi & Thalib, 2008) to determine the prevalence of het-
erogeneous studies. Also, 95% CIs for the pooled preva-
lence were determined. The heterogeneity should also be
considered carefully in the meta-analysis. Usually, a
large part of heterogeneity results from the factors gener-
ated in the process of study design and implementation,
such as study design, case definitions, and whether ran-
dom sampling is performed. The QE model was applied
for putative bias using the Q index (Doi et al., 2015; Doi
& Thalib, 2008), identified from the study’s quality
36 Autism 26(1)

Records identified through database searching

(n = 5650)

Idenficaon
Pubmed (n = 2225)
Embase (n =1180)
Cochrane library (n=2245)

Records aer duplicates removed

(n =1517)

Records screened
Screening

(n =4133)
Records removed after reviewing titles
and abstracts (n=3863)

Full-text articles assessed

for eligibility
(n =270)
Eligibility

Full-text articles excluded,

the following reasons (n =217)
Not interest of epilepsy in ASD (n=182)
Duplicates further identified (n=6)
Abstracts (n=22)
Duplicate data source (n=2)
No prevalence estimate information (n=1)
Not standard diagnostic strategies for ASD (n=2)
Review articles (n=2)
Included

Articles included in the meta-analysis

study(n=53)

Figure 1.  Flow diagram of studies selected for inclusion.

ratings (Hoy et al., 2012). The I2 statistic assessed the
heterogeneity for the pooled prevalence estimate. I2 val-
ues of 25%, 50%, and 75% were quantified as low, mod-
erate, and high heterogeneity, respectively (Higgins
et al., 2003). Compared to the RE model, the QE model
could use summary quality scores for bias adjustment of
observational studies (Doi et al., 2013). The pooled prev-
alence was also examined using RE models and com-
pared with that of the QE models.
Furthermore, subgroup analyses and meta-regression
analyses were conducted. Confounders, including study
design, age, human development index (HDI) of the coun-
try, female gender, and ID, were chosen based on theoreti-
cal, practical, and empirical association with comorbidity
prevalence (Loomes et al., 2017; McIntosh, 1996; S. G.
Thompson & Higgins, 2002; Wu et al., 2016). First, we
explored the difference in the prevalence estimates among
several studies based on design methods classified as a
cohort study, clinical sample-based cross-sectional study,
and population-based cross-sectional study. The cohort
study was defined based on that the autistic individuals
were continuously followed up for a period to observe the
targeted outcomes. Clinical sample-based cross-sectional
studies were defined as autistic individuals diagnosed and
recruited from hospitals and clinics without a follow-up. A
population-based cross-sectional study was defined as
autistic individuals diagnosed in the entire population or
random sampling population. The reported mean or
median age was input. The individuals < 18 years-old were
classified as childhood, while those ⩾ 18 years-old were
classified as adulthood. The countries were coded by the
UN’s 2018 HDI: higher scores represent better develop-
ment. Intelligence quotient (IQ) < 70 was defined as ID.
Next, we assessed the confounders’ effects, including the
study design, age, HDI of the country, female rate, and
proportion of ID. The current study further explored the
prevalence of epilepsy in autistic children by age using
subgroup analysis. Combined with childhood characteris-
tics and age prevalence distribution, age groups were
reclassified as follows: autistic children ⩽ 6 years-old were
classified as a pre-school group, autistic children between
7- and 10 -years-old were classified as school-aged chil-
dren group, and autistic children between the ages of 11
and 17 years were classified as adolescence group. In
Liu et al. 37
addition, univariable meta-regression was performed to
explore the association between the age groups and preva-
lence. In addition, linear regression models fitted scatter-
plots of the female rate and ID rate. For meta-regression
analysis, univariable and multivariate meta-regression
models were used to examine the independent effect of
confounders. Subsequently, we identified the combined
impact of confounders by multivariable meta-regression
models. Influence analyses (so-called leave-one-out sensi-
tivity analyses) were performed by sequential removal of
each study to confirm that the meta-analysis results were
not affected by any individual study (Liu et al., 2021). I2
and R2 statistics were used to quantify the heterogeneity
and the results of moderator analyses.
All statistical analyses were two-tailed, and p < 0.05
indicated statistical significance. Data analyses were con-
ducted by MetaXL version 5.3 (EpiGear, Queensland,
Australia).
Results
A total of 273,468 autistic individuals in the 66 studies from
53 articles were included in this meta-analysis. Of them,
11/53 articles (Aldinger et al., 2015; Eriksson et al., 2013;
Ewen et al., 2019; Houghton et al., 2017, 2018; Kohane
et al., 2012; Kuhlthau et al., 2018; Mannion & Leader, 2016;
Neumeyer et al., 2019; Soke et al., 2018; L. Thompson et al.,
2019) had conducted 24 studies, either focusing on the fol-
low-up points (Eriksson et al., 2013; Kuhlthau et al., 2018;
Mannion & Leader, 2016; L. Thompson et al., 2019), several
data collection sources (Aldinger et al., 2015; Ewen et al.,
2019; Kohane et al., 2012; L. Thompson et al., 2019), or sev-
eral age groups (Houghton et al., 2017, 2018; Neumeyer
et al., 2019; Soke et al., 2018). The remaining 42 articles had
only conducted one study in a separate article. Among 66
studies based on design, there were 18 clinical sample-based
studies, 20 cohort studies, and 28 population-based studies.
Of these, 55 studies reported the mean age or median age
ranging from 3 to 43 years-old. Regarding the age group, 46
studies focused on the co-occurrence rate of epilepsy in
autistic children, whereas 9 studies were focused on the co-
occurrence rate of epilepsy in autistic adults. The HDI of the
countries was 0.53–0.95. The proportion of female autistic
individuals was between 10.7% and 40.6%. The rate of ID in
autistic individuals was between 35% and 90% (Table 1).
The quality assessment of the included studies is demon-
strated in Table 1. According to the Hoy risk of bias tool, 66
studies were assessed for quality (Hoy et al., 2012). A total of
42 studies were classified as high quality and 24 as moderate
quality. The funnel plot is shown in the Supplemental
Figure S1.
The pooled estimate of the prevalence of epilepsy in
autistic individuals was 10% (95% CI: 6–14) using the QE
model. The meta-analyses showed high heterogeneity but
narrow 95% CIs (Figure 2). In the unadjusted RE model
meta-analysis, the pooled estimate of the prevalence of
epilepsy in autistic individuals was 13% (95% CI: 11–15)
(Supplemental Figure S2). The results of the RE model
were not conservative but positive when studies remained
heterogeneous because the inference was carried out,
ignoring the errors in the individual study variances for the
RE model (Brockwell & Gordon, 2001; Doi et al., 2013).
The QE model presented a conservative estimate than the
RE model.
The subgroup analyses by study design showed that the
clinical sample-based study’s prevalence estimate was
19% (95% CI: 6–35) with a wide 95% CI. The cohort
study’s prevalence estimate was 7% (95% CI: 3–11), while
that of the population-based cross-sectional studies was
10% (95% CI: 5–15) (Table 2).
The prevalence estimate of epilepsy in autistic adults
was 19% (95% CI: 14–24), whereas that in autistic chil-
dren was 7% (95% CI: 4–11) (Table 2). The current
study further explored the prevalence of epilepsy in
autistic children by age. While the school-aged children
group was defined as a reference, a significantly
increased prevalence estimate for co-occurring epilepsy
in autistic individuals within the adolescence group
(POR: 1.15, 95% CI: 1.06–1.25) and a high trend of
prevalence of epilepsy but without significance in the
pre-school group (POR: 1.06, 95% CI: 0.94–1.19) were
revealed by the meta-regression analysis (Supplemental
Figure S3).
Next, we performed the univariable meta-regression.
The cohort study was regarded as the reference, and the
population-based cross-sectional study and the clinical
sample-based cross-sectional study were positively associ-
ated with the prevalence estimates of epilepsy in autistic
individuals (POR: 1.12, 95% CI: 0.59–1.33 and POR:
1.47, 95% CI: 1.17–1.84, respectively). The childhood
period was regarded as the reference, and a high preva-
lence of epilepsy was estimated in adulthood (POR: 1.43,
95% CI: 1.28–1.59). A negative correlation was estab-
lished between the HDI of countries and the prevalence
estimates (POR: 0.05, 95% CI: 0.01–0.20). However, a
positive association was found between the female rate
and the prevalence estimates (POR: 1.04, 95% CI: 1.03–
1.06). Also, a significant proportion of ID was noted in
autistic individuals with high prevalence estimates co-
occurring with epilepsy (POR: 1.01, 95% CI: 1.01–1.01)
(Table 3). Considering there was a collinear correlation
between female and ID proportion in autistic individuals,
we included female rate or ID proportion and other covari-
ates in the multivariable meta-regression analysis, respec-
tively (Supplemental Table 3 and Table 4). The resulting
trend was similar, but the study design covariate was not
significant (Supplemental Table 3 and Table 4). Linear
plots for the association between female percentage and ID
 38

Table 1.  Summary of studies.

Authors Country Study design Female ASD Epilepsy Age (years), Age group Proportion Diagnostic Diagnostic Quality scores Comorbidity
rate M (SD) or of intellectual criteria of ASD criteria of from the Hoy rate
Range of ASD disability epilepsy Risk of Bias Tool
population

Akobirshoev (2020) The United Population-based 24.72 34,237 7311 ⩾ 18 Adulthood – ICD-9-CM ICD-9-CM 3 21.35
States study
Aldinger et al. (2015) The United Population-based 21.7 728 89 9.2 Childhood – ADI-R Clinical 2 12.23
(AGRE) States study diagnose
Aldinger et al. (2015) The United Population-based 13.3 2623 129 9 (3.6) Childhood – Clinic Clinical 2 4.92
(SSC) States study diagnosis, diagnose
ADI-R
Alfageh (2020) The United Population-based 21.15 20,194 909 0–65 Childhood & – Clinical Clinical 3 4.5
Kingdom study adulthood diagnosis diagnose
Anukirthiga et al. India Clinical sample- 23.4 90 41 7.7 (1.87) Childhood 75.5 DSM-5 Medical 4 45.56
(2019) based studies records
Brondino (2019) Italy Clinical sample- 24.6 191 29 24.04 (8.36) Adulthood – DSM 5 ICD-10 5 15.18
based studies
Danielsson et al. Sweden Cohort study 29 108 43 25.5 Adulthood – DSM-III-R Clinical 1 39.81
(2005) diagnose
Eriksson et al. (2013) Sweden Cohort study – 208 18 – Childhood 48 Clinical Clinical 4 8.65
(2-year follow-up) diagnosis diagnose
Eriksson et al. (2013) Sweden Clinical sample- – 208 13 – Childhood 48 Clinical Clinical 6 6.3
(cross-sectional) based studies diagnosis diagnose
Ewen et al. (2019) The United Cohort study – 2162 212 11.9 (3.21) Childhood – SCQ Clinical 2 9.8
(BDQ) States diagnose
Ewen et al. (2019) The United Cohort study – 5226 476 10.3 (3.14) Childhood – SCQ Clinical 2 9.1
(CAQ) States diagnose
Fombonne (1992) France Population-based 31.8 154 34 – Childhood 86.7 ICD-9 Clinical 4 22.08
study diagnose
Fombonne (2020) The United Cohort study 21.1 2917 452 23.2 (6.0) Adulthood 43.4 Clinical Clinical 2 15.5
States diagnosis diagnose
Fusar-Poli (2019) Italy Clinical sample- 24.1 195 33 26.5 Childhood & 44.1 DSM-5, Clinical 4 16.92
based studies adulthood ADOS-2, diagnose
ADI-R
Giovanardi Rossi Italy Clinical sample- 11.67 60 22.98 12–29 Childhood & DSM-III-R and Clinical 4 38.3
(2000) based studies adulthood DSM-IV diagnose
Hand (2019) The United Population-based 32.23 4685 1239 ⩾ 65 Adulthood – ICD-10 ICD-10 2 26.45
States study
Hara (2007) Japan Cohort study 20 130 33 18–35 Adulthood – DSM-IV Clinical 4 25.38
diagnose

(Continued)
Autism 26(1)
 Liu et al.

Table 1. (Continued)

Authors Country Study design Female ASD Epilepsy Age (years), Age group Proportion Diagnostic Diagnostic Quality scores Comorbidity
rate M (SD) or of intellectual criteria of ASD criteria of from the Hoy rate
Range of ASD disability epilepsy Risk of Bias Tool
population

Hisle-Gorman (2018) The United Cohort study 20.1 8760 251 10 Childhood – ICD-9 ICD-9 2 2.87
States
Houghton et al. (2017) The United Population-based – 71,386 5058 3–17 Childhood 17.3 ICD-9 Clinical 2 7.09
(childhood) States study diagnose
Houghton et al. (2017) The United Population-based – 22,303 3322 > 18 Adulthood 43.7 ICD-9 Clinical 2 14.9
(adulthood) States study diagnose
Houghton et al. (2018) The United Population-based – 6294 220 3–17 Childhood 0.35 Clinical Clinical 1 3.5
(childhood) Kingdom study diagnosis diagnose
Houghton et al. (2018) The United Population-based – 4562 493 > 18 Adulthood 8.46 Clinical Clinical 1 10.81
(adulthood) Kingdom study diagnosis diagnose
Icasiano (2004) Australia Population-based 10.7 177 10 9.5 Childhood 46.6 Clinical Clinical 1 6
study diagnosis, diagnose
DSM-IV
Jokiranta (2014) Finland Population-based 20.4 4705 312 5.5 Childhood 14.7 ICD-9/10 ICD-9/10 1 6.63
study
Kantzer (2013) Sweden Population-based 100 6 2.9 Childhood 36 DSM-IV-TR DSM-IV-TR 2 6
study ADOS-G
Kielinen (2004) Finland Population-based – 187 34 3–18 Childhood DSM-IV Clinical 2 18.18
study diagnose
Kohane et al. (2012) The United Clinical sample- – 9105 2235 < 35 Childhood & – ICD-9 ICD-9 1 24.55
(pediatric hospital) States based studies adulthood
Kohane et al. (2012) The United Clinical sample- – 5276 561 < 35 Childhood & – ICD-9 ICD-9 1 10.63
(general hospitals) States based studies adulthood
Kuhlthau et al. (2018) The United Population-based 16.2 4910 451 6.20 (3.50) Childhood – DSM-IV/V Clinical 2 9.19
(cross-sectional) States study ADOS diagnose
Kuhlthau et al. (2018) The United Cohort study 15.9 2722 239 – Childhood – DSM-IV/V Clinical 2 8.78
(longitudinal) States ADOS diagnose
Lagunju (2014) Nigeria Cohort study 16.7 54 13 > 6 Childhood – DSM-IV Clinical 2 24.07
diagnose
Lauritsen et al. (2002) Denmark Cohort study – 244 33 – – ICD-8 ICD-8 1 13.52
Mannion and Leader Ireland Cohort study 12.5 56 6 11 (3.58) Childhood 62 DSM-IV-TR Clinical 4 10.7
(2016) (follow-up) diagnose
Mannion and Leader Ireland Clinical sample- 12.5 56 5 11 (3.58) Childhood 62 DSM-IV-TR Clinical 4 8.9
(2016) (cross- based studies diagnose
sectional)

(Continued)
39
 40

Table 1. (Continued)

Authors Country Study design Female ASD Epilepsy Age (years), Age group Proportion Diagnostic Diagnostic Quality scores Comorbidity
rate M (SD) or of intellectual criteria of ASD criteria of from the Hoy rate
Range of ASD disability epilepsy Risk of Bias Tool
population

Mathu-Muju (2016) Canada Clinical sample- 23 303 61 9.46 Childhood 40 ICD-10 ICD-10 4 20.1
based studies
McCue (2016) The United Cohort study 21.9 610 50 10 Childhood – DSM-IV, Clinical 2 8.2
States ADOS/ADI-R diagnose
Memari (2012) Iran Population-based 20 91 17 9.40 (1.8) Childhood – Clinical Clinical 5 18.68
study diagnosis diagnose
Milovanovic (2019) Serbia Clinical sample- 19.64 112 17 6.58 (3.72) Childhood – ICD-10, ADI-R Clinical 4 15.18
based studies diagnose
Ming (2008) The United Clinical sample- 18.13 160 22 6 Childhood – ADOS, DSM- Clinical 4 13.75
States based studies IV diagnose
Mohammadi (2019) Iran Population-based 40.54 37 11 12 Childhood 70.3 Clinical Clinical 4 29.73
study diagnosis diagnose
Mouridsen (2011) Denmark Cohort study 27.97 118 29 27–57 Childhood & 71 ICD-8/9/10 ICD-8/9/10 4 24.58
adulthood
Mpaka (2016) Congo Clinical sample- 40 405 269 6.91 (4.3) Childhood 75.8 DSM-IV-R and DSM-IV-R 4 66.42
based studies the ADI-R criteria
Neumeyer et al. (2019) The United Population-based 18 2114 53 < 6 Childhood – ADOS/ADOS- Clinical 2 2.51
(< 6 years) States study 2, DSM IV diagnose
Neumeyer et al. (2019) The United Population-based 16.4 1221 42 ⩾ 6 Childhood – ADOS/ADOS- Clinical 2 3.44
(⩾ 6 years) States study 2, DSM IV diagnose
Pacheva (2019) Bulgaria Clinical sample- 33.9 59 26 5 Childhood 90 DSM-5 Clinical 5 44.07
based studies diagnose
Parmeggiani (2010) Italy Clinical sample- – 345 86 10.5 Childhood & – CARS, DSM-IV Clinical 5 24.93
based studies adulthood TR diagnose
Parmeggiani (2019) Italy Clinical sample- 21.9 105 11 12 Childhood 45.7 DSM-IV-TR Clinical 4 10.48
based studies diagnose
Peacock (2012) The United Population-based 19.58 8398 1063 9.50 Childhood 16 ICD-9-CM ICD-9 3 12.66
States study
Ramachandram (2019) Malaysia Clinical sample- 17.5 331 31 5.5 (2.64) Childhood – DSM 5 Clinical 4 9.37
based studies diagnose
Saemundsen (2013) Iceland Cohort study 26.32 267 19 11–15 Childhood 45.3 DSM-IV, Clinical 1 7
ICD-10 diagnose
Sathyabama (2019) Malaysia Clinical sample- 17.52 331 31 5.5 (2.64) Childhood – DSM-5 Clinical 4 9.4
based studies diagnose
Schendel (2016) Denmark Cohort study 22.4 20,492 1300 3–33 Childhood & – ICD-8 ICD-10. ICD-8; 1 6.34
adulthood ICD-10

(Continued)
Autism 26(1)
 Liu et al.

Table 1. (Continued)

Authors Country Study design Female ASD Epilepsy Age (years), Age group Proportion Diagnostic Diagnostic Quality scores Comorbidity
rate M (SD) or of intellectual criteria of ASD criteria of from the Hoy rate
Range of ASD disability epilepsy Risk of Bias Tool
population

Sharda (2012) India Clinical sample- 32.43 74 19 15 (6.64) Childhood & – DSM-IV Clinical 4 25.7
based studies adulthood diagnose
Soke et al. (2018) The United Population-based 22.09 783 22 4 Childhood – DSM-IV-TR, Clinical 3 2.81
(4 year-olds) States study ICD-10 diagnose
Soke et al. (2018) The United Population-based 18.97 1091 33 8 Childhood – DSM-IV-TR, Clinical 3 3.02
(8 year-olds) States study ICD-10 diagnose
Supekar (2017) The United Population-based – 4790 760.2 0–35 and > 35 Childhood & – ICD ICD-10 2 15.87
States study adulthood
Suren (2012) Norway Population-based 18.92 2352 263 0–11 Childhood – ICD-10 ICD-10 1 11.18
study
L. Thompson et al. Sweden Cohort study 15.5 207 13 – Childhood 37.7 DSM-IV, Clinical 2 6.28
(2019) (Stockholm ADOS diagnose
cohort T1)
L. Thompson et al. Sweden Cohort study 17.71 96 7 – Childhood 31.3 Clinic Clinical 2 7.29
(2019) (Gothenburg diagnosis, diagnose
cohort T1) DSM-IV
L. Thompson et al. Sweden Cohort study 17.71 96 5 – Childhood 26 Clinic Clinical 2 5.21
(2019) (Gothenburg diagnosis, diagnose
cohort T2) DSM-IV
L. Thompson et al. Sweden Cohort study 15.5 207 17 – Childhood 44.9 DSM-IV, Clinical 2 8.21
(2019) (Stockholm ADOS diagnose
cohort T2)
Viscidi et al. (2014) The United Population-based 13.19 2645 139 9 (3.6) Childhood 30 DSM-IV-TR, Clinical 4 5.26
States study ADI-R, ADOS diagnose
Vohra et al. (2017) The United Population-based 29 1772 403 22–64 Adulthood – ICD-9 Clinical 3 22.74
States study diagnose
Wu et al. (2016) The United Population-based 17.36 8564 434 8 Childhood – Clinical 2 5.07
States study diagnose
Yeargin-Allsopp (2008) The United Cohort study 12.79 86 7 11 Childhood – ICD-10 2 8.14
Kingdom
Zhang et al. (2019) China Population-based 23.96 192 22 7.59 (2.32) Childhood – SCQ, -V ICD-10 2 11.5
study

ASD: autism spectrum disorder; SD: standard deviation; ICD-8/9/9-CM/10: International Classification of Diseases 8th /9th/9th, Clinical Modification/10th Version; ADI-R: Autism Diagnostic Interview-Revised; DSM-II-TR/IV-TR/IV/5:
The Diagnostic and Statistical Manual of Mental Disorders III-TR /IV-TR/IV/5 Version; SCQ: Social Communication Questionnaire; ADOS: Autism Diagnostic Observation Schedule; CARS: Autism Rating Scale.
41
42 Autism 26(1)

MultipleCatQE
Study Prev (95% CI) % Weight
Akobirshoev,I 2020 0.21 ( 0.21, 0.22) 9.9
Aldinger, K.A 2015(AGRE) 0.12 ( 0.10, 0.15) 0.4
Aldinger,K.A 2015(SSC) 0.05 ( 0.04, 0.06) 1.1
Alfageh,B.H 2020 0.05 ( 0.04, 0.05) 5.9
Anukirthiga,B 2019 0.46 ( 0.35, 0.56) 0.2
Brondino,N 2019 0.15 ( 0.10, 0.21) 0.2
Danielsson,S 2005 0.40 ( 0.31, 0.49) 0.3
Eriksson,M.A 2013 (2-year follow-up) 0.09 ( 0.05, 0.13) 0.2
Eriksson, M.A2013 (Cross-sectional) 0.06 ( 0.03, 0.10) 0.1
Ewen, J.B 2019 (BDQ) 0.10 ( 0.09, 0.11) 0.9
Ewen, J.B 2019 (CAQ) 0.09 ( 0.08, 0.10) 1.9
Fombonne,E 1992 0.22 ( 0.16, 0.29) 0.2
Fombonne,E 2020 0.15 ( 0.14, 0.17) 1.2
Fusar-Poli,L 2019 0.17 ( 0.12, 0.23) 0.2
Giovanardi Rossi,P 2000 0.38 ( 0.26, 0.51) 0.2
Hand,B.N 2019 0.26 ( 0.25, 0.28) 1.7
Hara,H 2007 0.25 ( 0.18, 0.33) 0.2
Hisle-Gorman,E 2018 0.03 ( 0.03, 0.03) 3.1
Houghton,R 2017(adulthood) 0.07 ( 0.07, 0.07) 23.4
Houghton,R 2017(childhood) 0.15 ( 0.14, 0.15) 7.5
Houghton,R 2018(adulthood) 0.03 ( 0.03, 0.04) 2.5
Houghton,R 2018(childhood) 0.11 ( 0.10, 0.12) 1.9
Icasiano,F 2004 0.06 ( 0.03, 0.10) 0.3
Jokiranta,E 2014 0.07 ( 0.06, 0.07) 1.9
Kantzer, A.K 2013 0.06 ( 0.02, 0.12) 0.2
Kielinen,M 2004 0.18 ( 0.13, 0.24) 0.3
Kohane,I.S 2012 ( Pediatric Hospital) 0.25 ( 0.24, 0.25) 3.6
Kohane, I.S 2012(General Hospitals) 0.11 ( 0.10, 0.11) 2.2
Kuhlthau, K.A 2018(Cross-sectional) 0.09 ( 0.08, 0.10) 1.1
Kuhlthau, K.A 2018(Longitudinal ) 0.09 ( 0.08, 0.10) 1.8
Lagunju,I.A 2014 0.24 ( 0.13, 0.36) 0.2
Lauritsen, M.B 2002 0.14 ( 0.09, 0.18) 0.3
Mannion,A 2016( follow-up) 0.11 ( 0.04, 0.20) 0.2
Mannion,A 2016(Cross-sectional) 0.09 ( 0.03, 0.18) 0.2
Mathu-Muju,K.R2016 0.20 ( 0.16, 0.25) 0.2
McCue,L.M 2016 0.08 ( 0.06, 0.11) 0.4
Memari,A 2012 0.19 ( 0.11, 0.27) 0.1
Milovanovic, M 2019 0.15 ( 0.09, 0.22) 0.2
Ming,X 2008 0.14 ( 0.09, 0.20) 0.2
Mohammadi,M.R 2019 0.30 ( 0.16, 0.46) 0.2
Mouridsen,S.E 2011 0.25 ( 0.17, 0.33) 0.2
Mpaka,D.M 2016 0.66 ( 0.62, 0.71) 0.3
Neumeyer, A.M 2019(< 6 Years) 0.03 ( 0.02, 0.03) 0.9
Neumeyer,A.M 2019(e 6 Years) 0.03 ( 0.02, 0.05) 0.6
Pacheva,I 2019 0.44 ( 0.32, 0.57) 0.1
Parmeggiani, A 2010 0.25 ( 0.20, 0.30) 0.2
Parmeggiani, A 2019 0.10 ( 0.05, 0.17) 0.2
Peacock,G 2012 0.13 ( 0.12, 0.13) 2.6
Ramachandram,S 2019 0.09 ( 0.06, 0.13) 0.2
Saemundsen,E 2013 0.07 ( 0.04, 0.11) 0.3
Sathyabama,R 2019 0.09 ( 0.06, 0.13) 0.2
Schendel,D.E 2016 0.06 ( 0.06, 0.07) 7.7
Sharda,V 2012 0.26 ( 0.16, 0.36) 0.2
Soke, G.N 2018 (4-year-olds) 0.03 ( 0.02, 0.04) 0.4
Soke,G.N 2018(8-year-olds) 0.03 ( 0.02, 0.04) 0.5
Supekar, K 2017 0.16 ( 0.15, 0.17) 1.8
Suren,P 2012 0.11 ( 0.10, 0.12) 1.1
Thompson,L 2019( Stockholm cohortT1) 0.08 ( 0.05, 0.12) 0.3
Thompson,L 2019(Gothenburg cohortT1) 0.07 ( 0.03, 0.13) 0.2
Thompson,L 2019(Gothenburg cohortT2) 0.06 ( 0.03, 0.10) 0.3
Thompson,L 2019(Stockholm cohortT2) 0.05 ( 0.01, 0.11) 0.2
Viscidi,E.W 2014 0.05 ( 0.04, 0.06) 0.8
Vohra,R 2017 0.23 ( 0.21, 0.25) 0.7
Wu,Y,T 2016 0.05 ( 0.05, 0.06) 3.0
Yeargin-Allsopp,M 2008 0.08 ( 0.03, 0.15) 0.2
Zhang,A 2019 0.11 ( 0.07, 0.16) 0.3

Overall 0.10 ( 0.06, 0.14) 100.0

Q=12226.96, p=0.00, I2=99%

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7

Prevalence

Figure 2.  Forest plot depicting the prevalence of epilepsy in autistic population by QE model of meta-analysis.
*QE model, quality effects model.
Liu et al. 43

Table 2.  Pooled estimates of the prevalence of epilepsy in autistic individuals stratified by study design and age group.

Subgroup analysis Numbers in Autism population Prevalence 95% CI Weight I2 P

meta-analysis sample size (n) (%) (%) (%)
Study design
  Cohort study 20 44,767 7.06 3.30–11.35 19.3  
  Population-based cross-sectional study 28 211,295 9.90 5.40–14.91 71.92  
  Clinical sample-based cross-sectional study 18 17,406 19.44 5.91–35.13 8.73 99 < 0.001
*Age group
 Childhood 46 141,670 7.27 3.90–11.04 54.20 99 < 0.001
 Adulthood 9 60,649 18.78 13.65–24.18 23.45 99 < 0.001

*One study missing the specific age information, and 10 studies including children and adults were excluded.

Table 3.  Univariable meta-regression analyses for moderators on prevalence estimates of epilepsy in in autistic individuals.

POR 95% CI P R2
Study design
  Cohort study ref 15.16
  Population-based cross-sectional study 1.12 0.59–1.33 0.175  
  Clinical sample-based cross-sectional study 1.47 1.17–1.84 0.001  
Age
 Childhood ref  
 Adulthood 1.43 1.28–1.59 < 0.001 65.52
  HDI of countries 0.05 0.01–0.20 < 0.001 6.10
  Female rate 1.04 1.03–1.06 < 0.001 49.94
  Intellectual disability proportion 1.01 1.01–1.01 < 0.001 63.26

POR: prevalence odds ratio; CI: confidence interval; HDI: Human Development Index.
R2 is the proportion of true heterogeneity that can be explained by the moderator. P-values show whether the moderator is statistically significant
in explaining heterogeneity.

proportion showed that female autistic individuals have a
higher proportion of ID. (Supplemental Figure S4).
Influence analyses indicated that the results were consist-
ent and did not alter following the iterative removal of one
study (Supplemental Table 5).
Discussion
In the current meta-analysis, we first presented the pooled
prevalence of epilepsy in the whole autistic population
(from children to adults). To the best of our knowledge,
this is the most comprehensive and updated systematic
review and meta-analysis, extending the findings from
previous systematic reviews (Amiet et al., 2008; Lukmanji
et al., 2019). The current study reported that the updated
pooled prevalence estimates indicated that epilepsy is
common in autistic individuals. We also showed that the
moderators of study design, age, HDI of the country, gen-
der, and intellectual function accounted for most of the
heterogeneity. First, we observed that (1) the prevalence
reported from the clinical sample-based cross-sectional
study was higher than that from cohort study or popula-
tion-based cross-sectional study; (2) HDI of countries was
negatively associated with the prevalence; (3) a higher
prevalence of epilepsy was observed in autistic adults than
in autistic children; (4) Compared to the autistic school-
aged group, autistic adolescence faced a significantly
increased risk of co-occurring epilepsy. The current study
also confirmed that the female rate or ID rate was posi-
tively associated with the prevalence estimates, which was
in line with the previous study (Amiet et al., 2008). These
findings could help clinicians strengthen awareness of the
high rate of epilepsy in autistic individuals and effectively
manage autistic individuals with epilepsy.
Studies from clinical samples reported a higher preva-
lence than population-based cross-sectional or cohort stud-
ies. Several reasons may explain this finding. First,
individuals with severe autism who might have a severe ID
were more likely to seek medical services so that the clin-
ical-based studies might contain severe autistic individu-
als. The prevalence of epilepsy in individuals with ID was
increased compared to those without ID (Van Blarikom
et al., 2006). Second, the sample sizes from clinical-based
studies were smaller than those of population-based cross-
sectional or cohort studies, which might limit the repre-
sentativeness. However, the high prevalence from clinical
samples implied the greater demands for medical care for
epilepsy in autistic individuals in a clinical setting.
44 Autism 26(1)
The co-occurrence of epilepsy among autistic individu-
als could onset at any age. The current study found that the
prevalence of epilepsy in autistic adults was higher than
that in autistic children. This sustained state of comorbid-
ity with epilepsy provides adequate assessment, treatment,
and management. Interestingly, several previous studies
pointed out that there may be a bimodal age distribution of
onset of epilepsy in autistic individuals, with the first age
peak occurring at the early age of childhood and the sec-
ond at puberty (Deykin & MacMahon, 1979; Volkmar &
Nelson, 1990). Bolton et al. reported that seizures began
after the age of 10 years in most autistic people and did not
start until adulthood in some (Bolton et al., 2011). Our
results were partially in line with the previous studies
(Bolton et al., 2011; Deykin & MacMahon, 1979; Volkmar
& Nelson, 1990) but discrepant with the study’s outcome
showing reduced puberty risk (Danielsson et al., 2005).
The current study indicated that epilepsy occurs in child-
hood or adulthood, and the prevalence of epilepsy in autis-
tic adults was higher than that in autistic children. Several
reasons could be ascribed to these findings. First, because
the mean age rather than the onset age of epilepsy of the
study population was collected in the current meta-analy-
sis, and the correlation between the mean age and cumula-
tive prevalence was only explored accordingly. Epilepsy
occurs not only in childhood but also in adulthood, and a
cumulative incidence rate could be recorded during the
adult period. Second, autistic individuals show significant
age-related differences in cortical anatomy, especially in
cortical thickness and cortical dysmaturation (Raznahan
et al., 2010). The specific neurobiological processes of
autistic individuals are not fixed but continue to change
from childhood to adulthood (Raznahan et al., 2010).
Usually, autistic adults with a combination of epilepsy are
accompanied by significant brain dysfunction (Danielsson
et al., 2005), which might exacerbate and induce epileptic
seizures. Our finding raises the possibility that the neuro-
biological processes, which are mediated by restructuring
the brain and trimming the synapses, may be relevant to
the increased prevalence of epilepsy with age (Bolton
et al., 2011).
We also found that the adolescent group had an
increased risk of co-occurring epilepsy than the school-
aged group. A previous study speculated that puberty
might be the age peak for the prevalence of epilepsy in
autistic children, which was in line with our finding
(Bolton et al., 2011). Puberty is a period of most signifi-
cant hormonal and endocrine changes, which might raise
the occurrence rate of epilepsy and deteriorate the preex-
isting seizure (Morrell, 1992; Niijima & Wallace, 1989;
Rosciszewska, 1987). In addition, steroid hormones are
correlated to the neurons of the central nervous system,
subsequently changing neuronal excitability, synaptic con-
nections, and protein synthesis (Logsdon-Pokorny, 2000;
Morrell, 1992). The influence of specific hormones is
modulated by the entire endocrine milieu (Morrell, 1992).
During adolescence, hormonal changes, particularly for
girls, can profoundly affect seizure activity (Logsdon-
Pokorny, 2000; Zupanc & Haut, 2008). Previous studies
reported a bimodal distribution regarding age at the preva-
lence of epilepsy in autistic children, with the first peak in
early childhood and the second peak in adolescence
(Deykin & MacMahon, 1979; Volkmar & Nelson, 1990).
Clinically, in addition to the adolescence group, the autis-
tic children in the pre-school period might also face the
possibility of co-occurring epilepsy, although our study
observed the increased risk of prevalence during pre-
school but not significantly. The current study urged that
clinicians need to raise awareness to identify the possibil-
ity of comorbidity with epilepsy in autistic individuals
during the possible risky age peak. Our findings also
implied that the burden of epilepsy in the autistic popula-
tion increases gradually with age. The change in comor-
bidity with epilepsy during transition stages (from
childhood to adulthood), sensitive to temporal relation-
ships, needs further investigations.
The HDI published by the United Nations Development
Program is a measure of achievement in life expectancy,
education, and per-capita income (Mylevaganam, 2017).
Higher scores reflect high development. Therefore, HDI is
widely accepted to reflect the countries’ development (Lai
et al., 2019; Mylevaganam, 2017). However, previous
studies did not assess the effects of moderators of HDI of
countries on the prevalence of epilepsy in autistic individ-
uals (Amiet et al., 2008; Lukmanji et al., 2019). In this
study, the countries where the studies were conducted
were coded using the HDI. First, we unveiled that the HDI
of the country of origin was one of the sources of hetero-
geneity. The HDI of the country had a negative correlation
with epilepsy co-occurrence in autistic individuals. A pre-
vious meta-analysis study also found that the studies from
countries with higher HDI reported a lower prevalence of
comorbidity with obsessive-compulsive and related disor-
ders than those with lower HDI (Lai et al., 2019). This
phenomenon could be attributed to different levels of
awareness, diagnostic technologies, and autism-specific
clinical support among different countries (Lai et al., 2019;
Olusanya et al., 2018).
The more significant the proportion of ID in autistic
individuals, the higher the prevalence of comorbid epi-
lepsy. Our results were consistent with previous studies,
wherein the prevalence of comorbid epilepsy in autistic
individuals was more significant in people with ID (Berg
& Plioplys, 2012; Rossi et al., 2000; Van Blarikom et al.,
2006). The comorbidity with epilepsy might aggravate the
brain region (Zhang et al., 2019) and cause a greater pos-
sibility of developing an ID (Van Blarikom et al., 2006).
Other studies also observed that the correlation between
ASD and comorbid epilepsy might be driven by ID (Berg
& Plioplys, 2012; Ellenberg et al., 1986). Nonetheless, the
Liu et al. 45
causal correlation between comorbid epilepsy and ID
needs to be explored further.
Studies with a high female rate reported a higher preva-
lence of epilepsy than those with a lower female rate.
Previous studies indicated that female autistic individuals
were more vulnerable than males and had comorbidity
with neurological diseases, including epilepsy (Amiet
et al., 2008; Danielsson et al., 2005; Gillberg et al., 1991;
Houghton et al., 2018; Lai et al., 2019), which was in line
with our findings. Epilepsy is always correlated with ID
(Ewen et al., 2019). Female autistic individuals have a
higher risk of comorbidity with epilepsy than males, prob-
ably because female autistic individuals tend to have a
higher proportion of ID (Amiet et al., 2008; Nicholas et al.,
2008), which partially explains a higher incidence of epi-
lepsy in females. The present meta-analysis demonstrated
that the female rate in autistic individuals was positively
associated with ID. Therefore, clinicians should focus on
identifying the possibility of epilepsy in female autistic
individuals, especially those with ID (Chen, 2019).
Clinical and research implications
Co-occurrence with epilepsy is common among autistic
individuals. The recognition of this phenomenon would
help in identifying phenotypic differences in the autistic
population, contributing to prognosis, and choosing inter-
ventions. Thus, it is imperative to improve clinical attention
for the diagnosis of comorbid epilepsy, especially during
the transition age when the possibility of developing
comorbid conditions increases obviously. Comprehensive
and systematic clinical care for autistic individuals should
be warranted. For female autistic individuals and autistic
individuals with intellectual disabilities, it is essential to be
cautious about the possibility of comorbidity with epilepsy
(Chen, 2019). Treatment and rehabilitation support strate-
gies should be closely related to the ongoing diagnoses
(Hyman et al., 2020). Discovering the co-occurrence with
epilepsy in autistic individuals is crucial for etiological
mechanisms. The co-occurrence with epilepsy in autistic
individuals might be partially accounted for by the interac-
tions between shared underlying genetic pathways (Ben-
Shalom et al., 2017; Salpietro et al., 2019; Tu et al., 2017)
and environmental risk factors (Kim et al., 2019; P.
Thompson et al., 2020). Thus, exploring the possible co-
occurring mechanisms with epilepsy in autistic individuals
may be useful for preventive measures and treatment
strategies.
Strengths and limitations
First, this is the most comprehensive systematic review
and meta-analysis for the prevalence of epilepsy in autistic
individuals. The inclusion criteria for epilepsy and ASD
were carefully defined, providing valid prevalence
estimates for the current study. Second, confounders, such
as study design, age, HDI of the country, gender, and intel-
lectual function, were comprehensive and accounted for
the heterogeneity by meta-regression analyses. Third, our
study’s QE model of meta-analysis is more efficient than
the RE model to handle heterogeneity. The estimates from
the QE model of meta-analysis have more conservative
CIs that retain the nominal coverage probability than those
from the RE model (Doi et al., 2015).
Nevertheless, the present study has several limitations.
First, there was a high level of heterogeneity. However,
subgroup analyses and meta-regression were performed to
explore the possible sources of heterogeneity. The compre-
hensive confounders that we considered in this study could
account for most of the heterogeneity. Future research
focused on the co-occurrence with other conditions of
autistic individuals, which might consider the following
factors, such as study design, study country, age, ID pro-
portion, and female rate. Second, because there were miss-
ing data regarding the ID proportion and female rate, the
power of meta-regression analysis might be lower. Third,
uncovering whether epilepsy is secondary to the core
symptoms of ASD or core symptoms of ASD that occur
after epilepsy is challenging in our study due to the lack of
diagnostic time of epilepsy and ASD. Therefore, future
studies would address these limitations by designing a lon-
gitudinal population-based birth cohort study.
Conclusion
Co-occurrence with epilepsy is common in autistic indi-
viduals with an overall pooled prevalence of 10%. In addi-
tion, the prevalence of epilepsy in autistic adults was
higher than that in autistic children, and there might be a
peak prevalence of epilepsy toward adolescence or pre-
school period in autistic individuals. Our findings also pro-
vided critical and innovative views on the prevalence of
epilepsy in autistic individuals modified by the study
design, HID of the country, age, the female rate, and the
proportion of ID.
Availability of data and materials
All data relevant to this study are presented in the manuscript.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Funding
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article:
This study was supported by the grants of Science and Technology
Department of Guangdong Province of China (2016A020215019),
46 Autism 26(1)
the fund from Guangzhou Institute of Pediatrics, Guangzhou
Women and Children’s Medical Center (YIP-2018-049), partly
supported major Scientific and Technological Projects of Brain
Science and Brain-like Research of Guangzhou (202007030002),
Science and Technology Project of Guangzhou Municipal Health
Commission (2019A011028).
ORCID iD
Wen-Xiong Chen https://orcid.org/0000-0001-9076-2006
Supplemental material
Supplemental material for this article is available online.
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