**7. Regression in Autism**

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

seizures in ASD.

**sequelae**

Kleffner syndrome and ASD [82].

**6.2 Lennox–Gastaut syndrome (LGS)**

tions of maternal 15q11q13 [83].

**during slow sleep (CSWS)**

with epilepsy-aphasia phenotypes [85].

**6.1 West syndrome (WS)**

Immune dysfunction is found to be implicated in the development of epilepsy, and evidence of cellular and humoral immune dysfunction has also been implicated in ASD. Thus, studies suggest abnormalities in immune cell function result in

Another physiological abnormality that is becoming increasingly recognized in both ASD and epilepsy is the dysregulation of calcium [81]. On the other hand, epilepsy may be a common symptom of metabolic disorders and be a clue that a metabolic disorder may be the underlying etiology of the neurodevelopmental abnormalities in children with epilepsy and ASD. One advantage of investigating and diagnosing metabolic disorders is that treatments for many of these metabolic disorders are available.

**6. Epilepsy syndromes with ASD as frequent neurodevelopmental** 

Several specific epilepsy syndromes with early onset epilepsy show an autistic behavior, some also appear to be the risk factor for later diagnosis of ASD. If they are identified appropriately and treated, behavioral improvement which is radical in some of the cases can be seen. In these cases, epilepsy originates in the brain networks responsible for communication and interactions. These include infantile spasms and Lennox–Gastaut syndrome. More recently, clinical overlap has been observed in cases with continuous slow waves during sleep (CSWS) and Landau–

WS is an epileptic encephalopathy characterized by infantile spasm/epileptic spasms, an EEG pattern of hypsarrhythmia and cognitive stagnation or regression. They usually occur before 2 years of age. Genetic causes are present in many of them and abnormalities in several brain developmental pathways are noted.

ASD may develop in a few of them. However, an association between TSC and

LGS is a childhood-onset epilepsy, which is characterized by constellation of several distinct types of seizures and electroclinical features of diffuse slow spike waves and generalized paroxysmal fast activity in sleep. Prevalence of ASD in LGS is rare, although ASD has been reported in patient with LGS resulting from duplica-

**6.3 Landau–Kleffner syndrome (LKS)/continuous spikes and slow waves** 

LKS is an epilepsy-aphasia syndrome that is characterized by regression in language and characteristic CSWS on EEG-termed as electrical status epilepticus of slow sleep (ESES). Several children who had been diagnosed with ASD were noted to have a predominant language deficit. Stereotypies and withdrawal are also common in LKS, but whether these children also have deficits in social reciprocity is not clear. The association may be more related to severe receptive language deficit. Copy number variants have been detected in patients with LKS who also have associated ASD [84], and, most recently, GRIN2A mutation have been identified in patients

duplications of FOXG1 have been reported consistently.

**22**

Developmental regression is present in approximately one-third of children with ASD [86] and is believed to have an association with epilepsy. The relationship between regression and epilepsy in ASD has therefore long been of interest because of the hope that some developmental regression in idiopathic ASD could be caused by epilepsy and be reversible through using anti-seizure therapies [87].

The overlap of language and autistic regression to epilepsy, EEG epileptiform activity, sleep, and to epileptic encephalopathies such as LKS continue to be controversial areas of research and of clinical interest because of the close clinical resemblance to autism.

LKS or acquired epileptic aphasia may present as a developmental language regression followed by autistic-like social-communicative phenotype. LKS usually presents between 3 and 7 years of age with loss of language skill in children who were previously normal and most but not all affected children have convulsive seizures. In case on early LKS, it becomes difficult to differentiate it from ASD clinically and the diagnosis is done mainly on EEG finding and response to antiseizure treatment. The EEG in the awakened state often has a normal background with seizures of various types in LKS. During sleep, it is characterized by epileptic discharges throughout the sleep-electrical status epilepticus (ESES) on EEG that may affect cognitive processing. In children with autistic regression, both language and behavior in association with significant social deficits occur between 18 and 24 months compared to usually only language regression in LKS, which is more dramatic and the social deficits are less severe than those with autism [88]. McVicar et al. in their study reported that children with isolated language regression have a higher frequency of epileptiform discharges and seizures than children with both language and autistic (i.e., social and behavioral) regression [89].

An extensive review, in 2002 on epileptiform neurocognitive disorders linked with speech/language deterioration concluded that "acquired epileptiform aphasia (AEA) can be conceptualized on a spectrum with other epileptiform neurocognitive disorders that may share pathophysiological features". They also added that "without better documentation of potential factors around the time of the regression, it will be difficult to identify the fundamental factors that differentiate these conditions, their response to treatment and long-term prognosis" [90].

CSWS, an epileptic syndrome of that is associated with EEG pattern of ESES may present with regression in global skills that overlaps with autism [91]. However, the differences in age of regression, type of regression, frequency of epilepsy and EEG abnormalities suggest that these are distinct phenotypes.

Nonconvulsive status epilepticus (NCSE) may also have features that have a strong similarity to autism. The child may exhibit poor reciprocal social interaction, poor verbal and nonverbal communication. But with effective treatment, the features of autism disappear.

Magnetoencephalography has identified precise location of the source of these epileptic EEG discharges. The finding from this investigation shows that focal spike waves (FSW) in the perisylvian region and located in the superior temporal gyrus may cause auditory and verbal agnosia (LKS). When FSW predominate in the prefrontal regions, a cognitive regression with features of CSWS, when in cortical areas like the superior temporal sulcus or the fusiform gyrus involving the networks relating emotions to higher-level visual representations could interfere with the developing capacity to recognize the emotional signals of faces, that are typically deficient in autism.

Other epileptic disorders, like refractory partial epilepsies of frontal or temporal origin like the Benign epilepsy with centrotemporal spikes (BECTS)also interfere

#### **Figure 4.**

*Electroencephalogram finding of a (A) 4 years 6 months old boy with LKS, and regression of speech for one year showing spike and waves over frontal central and temporal regions (B) 7 year old girl with regression of speech and cognitive function in a case of CSWS showing ESES, generalized spike waves in all the channels.*

with developing language networks and/or other circuits involving the "social brain" such as the amygdala, cingulate and orbitofrontal cortex and account or contribute to language and autistic regression. Other examples are Focal dysplasias, hippocampal sclerosis, congenital tumors or tuberous sclerosis and hypothalamic hamartomas.

In addition, an increasing number of genetic and metabolic encephalopathies with severe developmental problems are now recognized with autistic regression where epilepsy may aggravate the regression.

It is also found that approximately 20% of children with autistic regression without epilepsy may have an abnormal EEG, the majority with spikes or spikeand-wave discharges [92]. Although this abnormal EEG is found usually after the regression, there is no evidence of a causal relationship between the epileptiform abnormalities and the regression [93].

**Figure 4** shows EEG of LKS in awake and CSWS in sleep with ESES.

#### **8. Autism in epilepsy**

A meta-analysis of 19 studies showed a pooled ASD prevalence of 6.3% in individuals with epilepsy, which is considerably higher than the reported prevalence of 0.75% to 1.1% in the general population [94]. Tuchman et al. reported approximately 30% of children with epilepsy have autism and/or intellectual or developmental disabilities [95]. Several studies have shown that children with epilepsy have an increased risk of being diagnosed with ASD [8, 16, 22]. A higher prevalence was found for studies with younger age groups, ID, and specific epilepsy syndromes (West syndrome, Dravet syndrome).

Epilepsy and autism both can arise from abnormal excitability and disrupted synaptic plasticity in the developing brain. This abnormal plasticity can also result from genetic conditions.

Early-life seizures can produce a variety of cellular and molecular changes in the hippocampus, including short-term enhancement of excitation and longterm enhancement of inhibitory neurotransmission and reductions in excitatory

**25**

*Epilepsy: A Common Co-Morbidity in ASD DOI: http://dx.doi.org/10.5772/intechopen.96484*

conditions in the general population.

**9. EEG abnormalities**

in most of the studies [101–105].

and cognitive problems [99].

problem [108, 109].

complex [37].

neurotransmission [35]. All these early seizures also have numerous disruptive effects on neural development, including abnormal synaptic reorganization, and cortical interneuron dysfunction [96, 97]. This in turn disrupts the construction of cortical networks necessary for acquiring certain skills during development, and may predispose an individual towards developing ASD [15]. Further, risk of both epilepsy and ASD is elevated in numerous genetic disorders as mentioned previously, such as Rett syndrome, fragile X syndrome, and tuberous sclerosis

Lukmaji et al. emphasized the importance of screening for autism in persons with epilepsy, and vice versa, to appropriately tailor treatment decisions and improve patient outcomes [28]. As in their systematic review revealed the occurrence of autism in persons with epilepsy and epilepsy in persons with autism to be higher than the previously reported independent occurrence of each of these

ASD are associated with increased incidence of EEG abnormalities. EEG epileptiform abnormalities were found at a range of 35% to 86% in ASD individuals with epilepsy [9, 21, 98] and up to 28.6% [21] to 60% [9] in individuals without epilepsy. These discharges are often more common when there is history of autistic regression, even if there is no history of seizures or epilepsy [99]. In addition to epileptiform discharges, non-epileptiform discharges were also found in ASD, these were- disorganized and slowing of background rhythm, asymmetry etc. [100]. But epileptiform EEGs seemed to be more common than nonepileptiform abnormalities

Abnormal EEG is considered as a biomarker of cortical dysfunction [8, 100] and

EEG should be considered in children with clinical or suspected seizures and, in all the children where autism is questionable and a clinical suspicion of LKS is present. Performing a sleep-EEG was highly recommended by Pacheva et al. in all patients to prevent underdiagnosis of ESES and LKS [21]. The authors also mentioned the need of timely treatment to get improved behavior and cognition in patients with ESES. Fernandez et al. also concluded in that a treatment trial with AED is justified in patients with epileptic encephalopathies and cognitive dysfunction/regression, that could be related to epileptiform discharges [107]. Children with LKS may also have an autistic-like regression that extends to behaviors beyond language [87]. Presence of epileptiform EEG abnormalities even in the absence of clinical seizure found in LKS and ESES is a controversial

provide evidence that autism is a neurobiological disorder [106]. Interictal discharges are thought to interfere with normal neural processing which may further impair cognitive function [17, 18, 100]. The clinical importance of epileptiform discharges without overt seizures are not clear, but they may also cause behavioral

**10. Management of individuals with both epilepsy and autism**

Both the conditions should be managed individually. This depends upon the causes if present, especially in case of epilepsy. First of all, the cause of epilepsy in autism should be investigated appropriately. It has to be ensured that the autistic features are not the result of ESES or frequent epileptiform discharges [110].

#### *Epilepsy: A Common Co-Morbidity in ASD DOI: http://dx.doi.org/10.5772/intechopen.96484*

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

with developing language networks and/or other circuits involving the "social brain" such as the amygdala, cingulate and orbitofrontal cortex and account or contribute to language and autistic regression. Other examples are Focal dysplasias, hippocampal sclerosis, congenital tumors or tuberous sclerosis and hypothalamic

*Electroencephalogram finding of a (A) 4 years 6 months old boy with LKS, and regression of speech for one year showing spike and waves over frontal central and temporal regions (B) 7 year old girl with regression of speech and cognitive function in a case of CSWS showing ESES, generalized spike waves in all the channels.*

In addition, an increasing number of genetic and metabolic encephalopathies with severe developmental problems are now recognized with autistic regression

It is also found that approximately 20% of children with autistic regression without epilepsy may have an abnormal EEG, the majority with spikes or spikeand-wave discharges [92]. Although this abnormal EEG is found usually after the regression, there is no evidence of a causal relationship between the epileptiform

A meta-analysis of 19 studies showed a pooled ASD prevalence of 6.3% in individuals with epilepsy, which is considerably higher than the reported prevalence of 0.75% to 1.1% in the general population [94]. Tuchman et al. reported approximately 30% of children with epilepsy have autism and/or intellectual or developmental disabilities [95]. Several studies have shown that children with epilepsy have an increased risk of being diagnosed with ASD [8, 16, 22]. A higher prevalence was found for studies with younger age groups, ID, and specific epilepsy syndromes

Epilepsy and autism both can arise from abnormal excitability and disrupted synaptic plasticity in the developing brain. This abnormal plasticity can also result

Early-life seizures can produce a variety of cellular and molecular changes in the hippocampus, including short-term enhancement of excitation and longterm enhancement of inhibitory neurotransmission and reductions in excitatory

**Figure 4** shows EEG of LKS in awake and CSWS in sleep with ESES.

**24**

hamartomas.

**Figure 4.**

where epilepsy may aggravate the regression.

abnormalities and the regression [93].

(West syndrome, Dravet syndrome).

**8. Autism in epilepsy**

from genetic conditions.

neurotransmission [35]. All these early seizures also have numerous disruptive effects on neural development, including abnormal synaptic reorganization, and cortical interneuron dysfunction [96, 97]. This in turn disrupts the construction of cortical networks necessary for acquiring certain skills during development, and may predispose an individual towards developing ASD [15]. Further, risk of both epilepsy and ASD is elevated in numerous genetic disorders as mentioned previously, such as Rett syndrome, fragile X syndrome, and tuberous sclerosis complex [37].

Lukmaji et al. emphasized the importance of screening for autism in persons with epilepsy, and vice versa, to appropriately tailor treatment decisions and improve patient outcomes [28]. As in their systematic review revealed the occurrence of autism in persons with epilepsy and epilepsy in persons with autism to be higher than the previously reported independent occurrence of each of these conditions in the general population.
