**4. ID and epilepsy in autism**

*Autism Spectrum Disorder - Profile, Heterogeneity, Neurobiology and Intervention*

conditions [8].

without ID [9].

with ASD [8, 16].

**2. Age of onset of epilepsy**

in about 16% in ASD.

epilepsy.

(0.6–1%) [11–12]. This wide range is likely due to heterogeneity of groups being studied, particularly with regard to cognitive functioning of the participants, sample age range, sex and inclusion or exclusion of other co-occurring medical

In addition, methodological differences used for diagnosing ASD also lead to these differences in prevalence rate. In the earlier studies, only severe autism associated with a high rate of intellectual disability (ID) and a high rate of epilepsy were included, whereas more recent studies that have used the current broader "ASD" criteria (DSM-5) might lead to a lower rate of ID and a lower rate of epilepsy.

Several factors have been associated with a greater risk for developing epilepsy. Among them, ID is the single most common risk factor. Amiet et al., in a metaanalysis on epilepsy in autism encompassing articles from 1963–2006 demonstrated a relationship between epilepsy in autism with ID and gender. Here epilepsy was present in 21.5% of subjects with autism who also had ID and 8% of subjects

Previous studies in the ASD population have found that idiopathic ASD (i.e., no known cause) had a lower risk of developing epilepsy than those with syndromic autism (i.e., associated with underlying neural/genetic abnormalities) [13]. Pavone et al. found epilepsy in only 7.4% with idiopathic ASD compared to 55% of patients with syndromic ASD [14]. These findings match with the hypothesis that one abnormal neural dysfunction may make the brain more susceptible to another neurological dysfunction [15]. This also supports the hypothesis that epilepsy, ID and ASD may all be the result of a mutual underlying neurological condition. Equally, children with epilepsy also have an increased risk for being diagnosed

Besides, on average, autistic adults with epilepsy have, less cognitive ability and weaker daily living skills than their autistic peers who do not have seizures [17, 18]. There is also a strong influence on the quality of life and well-being in children with

Because of these facts, clinicians and researchers have worked to understand how epilepsy and ASD can relate to each other. Studying the two disorders in combination may help in understanding their genetic, molecular, and cellular mechanisms that are critical in the field of appropriate management of the both [19, 20].

Differing results have been found regarding the age of onset of epilepsy in ASD.

Reports have suggested that females with autism have higher rates of epilepsy than males [6, 8, 13, 16, 22, 25, 26]. Amiet's study reported prevalence of epilepsy, in autistic females 34.5% versus 18.5% in autistic males [9]. Studies have reported a more frequent association of epilepsy in persons with ID than without ID [6, 9]. Since females

Most of the researchers found seizure onset during early childhood [5, 21, 22]. However, Bolton et al. in a long-term follow-up study of 150 individuals with autism, found epilepsy onset in the majority of cases over 10 years and some in adulthood [7], this also agrees with few other studies [6, 23]. While others found, two peaks in the age distribution of seizure onset in autism, one in early childhood and a another in adolescence [13, 24]. Epilepsy persists in adulthood in up to 80%, with remission

**10**

**3. Sex**

Intellectual disability (ID), referring to general intelligence and adaptive functioning below −2 standard deviations for population norms, occurs in about 38% of children with ASD [29].

A key concept that has developed during the past 40 years is the strong association between intellectual disability and a higher prevalence of epilepsy in individuals with ASD [25]. Amiet et al. carried out a meta-analysis from published reports between 1963 and 2006 on autism and epilepsy to assess the relative risk of epilepsy in autism with respect to ID [9]. The pooled prevalence of epilepsy with and without ID was highly significant (21.5% versus 8% respectively). This study also highlighted on the association of increasing ID severity on the prevalence of epilepsy in autism [9, 30].

Other authors also have argued that intelligence mediates the relationship between autism and epilepsy [17, 26, 30–34], and lower the intellectual ability, the higher the prevalence of epilepsy and autism. According to Viscidi et al. al, low IQ is the best predictor of epilepsy in children and also commented that the presence of ID can guide prognosis and alert physicians regarding who are at increased risk for epilepsy [6]. A recent study on 6975 children by Jasua et al. with ASD found ID alone as an independent predictor for the increased prevalence of epilepsy [19, 20].

The high rate of co-occurrence of ID, epilepsy and ASD suggests potentially shared underlying mechanisms. All three could result from the same pathophysiologic mechanisms. Therefore, it may be more likely to occur in genetic conditions that lead to abnormal excitability and disrupted synaptic plasticity, such as fragile X syndrome, neuroligin 2 mutations, Rett syndrome, tuberous sclerosis complex, cyclin-dependent kinase-like 5 (CDKL5) mutations, and "interneuronopathies" resulting from aristaless-related homeobox, X-linked (ARX), all of which include ASDs, IDs, and epilepsy [35].
