**9. EEG abnormalities**

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 in most of the studies [101–105].

Abnormal EEG is considered as a biomarker of cortical dysfunction [8, 100] and 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 and cognitive problems [99].

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 problem [108, 109].

## **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].

The diagnosis of epilepsy become more difficult in autism, especially if there is accompanying intellectual disability because history taking in these cases becomes more difficult.

The treatment of epilepsy in ASD is based on the general principles of treatment of epileptic seizures with traditional antiepileptic drugs (AEDs). Usually, valproate, lamotrigine and levetiracetam are used as the most effective and tolerable AEDs for individuals with ASD [74]. But levetiracetam can have negative effects on mood and behavior and be associated with deterioration in children, whereas lamotrigine tends to be a mood-leveling antiepileptic drug and Topiramate can be associated with word-finding difficulties [110].

The discovery of the role of neuronal autoantibodies has been one of the most exciting developments in the recent years. These antibodies can result in seizures, loss of skills, (sometimes a dramatic loss), behavioral changes and even psychosis. Effective immunotherapy can, in at least some cases, reverse all these changes [111, 112]. This is an area which requires further consideration.

New therapeutic options were suggested for ASD and epilepsy, based on the opinion that gene defects could determine all the symptoms of these disorders. This also includes modulators of GABA A receptors, GABA agonists, modulators of GABA metabolism, glutamate receptor antagonists, insulin-like growth factor 1 and m-TOR inhibitors for ASD-epilepsy comorbidity [113]. M-TOR inhibitors like Everolimus (Rapamycin) and Sirolimus have positive results in patients with TSC, ASD and PTEN-related disorders. After treatment with conventional GABAnergic agonists, a paradoxical result was reported in ASD [101]. In addition, ASD with epilepsy having 15q11.2 duplication, effectiveness of benzodiazepines was reported to be lowered [114].

In addition to the treatment, the usual management of autism should be continued.

#### **10.1 Management of additional comorbidities in the presence of both epilepsy and autism**

#### *10.1.1 Attention deficit hyperactivity disorder*

ADHD is common in children with autism and in children and adolescent with epilepsy. Diagnosing ADHD in epilepsy sometimes becomes difficult, because some of the children with epilepsy present with features of ADHD. This is due to frequent epileptiform discharge. In those cases, treating these epileptic discharges with AEDs will alleviate these symptoms. Few children with epilepsy may have inattention, hyperactivity and distractibility as a result of antiepileptic medication, as for example, treatment with phenobarbitone, benzodiazepine or vigabatrin [110]. So, review of antiepilepetic medication is very important before diagnosing the child as having ADHD.

Epilepsy is a highly variable condition and after treatment with AED, there might be is no change in seizure or even there is high frequency of seizure and since ADHD medication is started, it may be incorrectly concluded that this increase in seizures is because of the ADHD treatment.

There are two groups of medication currently used to treat ADHD: stimulants (methylphenidate, amphetamine) and non-stimulants (Atomoxetine, alpha-2 agonists). When children with symptoms of ADHD require medication, current guidelines recommend starting with a trial of a stimulant like methylphenidate. If this first stimulant does not prove to be effective, the alternative stimulant is then used [115]. If stimulants are not effective or cause intolerable adverse effects, then nonstimulants like atomoxetine, alpha-2 agonists, and antidepressants are used.

**27**

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

drug in epilepsy.

be monitored carefully.

*10.1.2 Anxiety*

behavioral problems.

Cochrane review.

Methylphenidate is the most commonly used medicine for ADHD. Large observational studies conducted in children and adolescents with epilepsy have found that ADHD medications in general and stimulants like methylphenidate are not associated with increased risk of seizures [116]. Use of low and moderate doses of methylphenidate has been observed in reduction of seizure frequency and severity along with improved quality of life in a Brazilian study done in 2015 [117]. However, it is important to monitor seizure frequency in the first few weeks and months after prescribing methylphenidate [116] as there are still questions regarding use of this

Guidance for identification and treatment of individuals with attention deficit/hyperactivity disorder and ASD based upon expert consensus in the UK in 2020 [118] emphasized on non-pharmacological interventions and care management, including psychoeducation, carer interventions, behavioral/environmental and Cognitive Behavioral Therapy (CBT) approaches and educational interventions, followed by pharmacological treatments. They have commented that in children, pharmacological intervention should be preceded by behavioral observation and psychological intervention as the first-line treatment. And if psychological/environmental interventions fail in children, then ADHD medication may be helpful for treating symptoms of inattention. Medication should be used in a 'low and slow' approach as people with both ADHD with epilepsy may be more treatment resistant and more prone to develop side effects to medication. Medication should be given for the shortest time possible and side effects should

Researchers also mentioned about the relative little evidence, on using other ADHD treatments, such as atomoxetine, guanfacine and clonidine in children with autism, having both epilepsy and ADHD [110]. However, several research papers and reviews found no clear evidence about exacerbation of seizures with these medications. Besag et al., in their paper summarized, about 30% of children with epilepsy had ADHD and about 70% among those with epilepsy and ADHD benefited from treatment of their ADHD symptoms with methylphenidate [119].

Anxiety is commonly found in young people with autism and epilepsy. Children with epilepsy with co-morbid psychiatric disorders like — ADHD, depression, and anxiety disorders, end up with significant compromise in academic performance

Risperidone and Aripiprazole in low dose can improve the behavior in children with autism. The mechanism is probably through decreasing anxiety. But the dose used should be very low because of the risk of seizure exacerbation with high doses of these antipsychotic drugs. On the other hand, the antiepileptic drugs like carbamazepine, phenobarbital and phenytoin may decrease the blood levels of antipsychotic drugs and a larger dose of antipsychotics may be required who are taking these AEDs. The management goals in pediatric epilepsy with anxiety disorders are — adequate seizure control, optimization of the functioning of the child and keeping the patient in best and simple pharmaco-therapeutic regimen [121].

The clinician should avoid an antiepileptic drug which is having side effects like

Behavioral therapy should be the first-line approach to managing anxiety. Despite the effectiveness of selective serotonin reuptake inhibitors in decreasing anxiety in adults and teenagers there is a lack of evidence for a beneficial role of these drugs in treating anxiety in children with autism, according to a

and social skills, leading to deterioration in the Quality of life [120].

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

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

[111, 112]. This is an area which requires further consideration.

more difficult.

to be lowered [114].

**and autism**

having ADHD.

*10.1.1 Attention deficit hyperactivity disorder*

seizures is because of the ADHD treatment.

continued.

with word-finding difficulties [110].

The diagnosis of epilepsy become more difficult in autism, especially if there is accompanying intellectual disability because history taking in these cases becomes

The treatment of epilepsy in ASD is based on the general principles of treatment of epileptic seizures with traditional antiepileptic drugs (AEDs). Usually, valproate, lamotrigine and levetiracetam are used as the most effective and tolerable AEDs for individuals with ASD [74]. But levetiracetam can have negative effects on mood and behavior and be associated with deterioration in children, whereas lamotrigine tends to be a mood-leveling antiepileptic drug and Topiramate can be associated

The discovery of the role of neuronal autoantibodies has been one of the most exciting developments in the recent years. These antibodies can result in seizures, loss of skills, (sometimes a dramatic loss), behavioral changes and even psychosis. Effective immunotherapy can, in at least some cases, reverse all these changes

New therapeutic options were suggested for ASD and epilepsy, based on the opinion that gene defects could determine all the symptoms of these disorders. This also includes modulators of GABA A receptors, GABA agonists, modulators of GABA metabolism, glutamate receptor antagonists, insulin-like growth factor 1 and m-TOR inhibitors for ASD-epilepsy comorbidity [113]. M-TOR inhibitors like Everolimus (Rapamycin) and Sirolimus have positive results in patients with TSC, ASD and PTEN-related disorders. After treatment with conventional GABAnergic agonists, a paradoxical result was reported in ASD [101]. In addition, ASD with epilepsy having 15q11.2 duplication, effectiveness of benzodiazepines was reported

In addition to the treatment, the usual management of autism should be

**10.1 Management of additional comorbidities in the presence of both epilepsy** 

ADHD is common in children with autism and in children and adolescent with epilepsy. Diagnosing ADHD in epilepsy sometimes becomes difficult, because some of the children with epilepsy present with features of ADHD. This is due to frequent epileptiform discharge. In those cases, treating these epileptic discharges with AEDs will alleviate these symptoms. Few children with epilepsy may have inattention, hyperactivity and distractibility as a result of antiepileptic medication, as for example, treatment with phenobarbitone, benzodiazepine or vigabatrin [110]. So, review of antiepilepetic medication is very important before diagnosing the child as

Epilepsy is a highly variable condition and after treatment with AED, there might be is no change in seizure or even there is high frequency of seizure and since ADHD medication is started, it may be incorrectly concluded that this increase in

There are two groups of medication currently used to treat ADHD: stimulants (methylphenidate, amphetamine) and non-stimulants (Atomoxetine, alpha-2 agonists). When children with symptoms of ADHD require medication, current guidelines recommend starting with a trial of a stimulant like methylphenidate. If this first stimulant does not prove to be effective, the alternative stimulant is then used [115]. If stimulants are not effective or cause intolerable adverse effects, then nonstimulants like atomoxetine, alpha-2 agonists, and antidepressants are used.

**26**

Methylphenidate is the most commonly used medicine for ADHD. Large observational studies conducted in children and adolescents with epilepsy have found that ADHD medications in general and stimulants like methylphenidate are not associated with increased risk of seizures [116]. Use of low and moderate doses of methylphenidate has been observed in reduction of seizure frequency and severity along with improved quality of life in a Brazilian study done in 2015 [117]. However, it is important to monitor seizure frequency in the first few weeks and months after prescribing methylphenidate [116] as there are still questions regarding use of this drug in epilepsy.

Guidance for identification and treatment of individuals with attention deficit/hyperactivity disorder and ASD based upon expert consensus in the UK in 2020 [118] emphasized on non-pharmacological interventions and care management, including psychoeducation, carer interventions, behavioral/environmental and Cognitive Behavioral Therapy (CBT) approaches and educational interventions, followed by pharmacological treatments. They have commented that in children, pharmacological intervention should be preceded by behavioral observation and psychological intervention as the first-line treatment. And if psychological/environmental interventions fail in children, then ADHD medication may be helpful for treating symptoms of inattention. Medication should be used in a 'low and slow' approach as people with both ADHD with epilepsy may be more treatment resistant and more prone to develop side effects to medication. Medication should be given for the shortest time possible and side effects should be monitored carefully.

Researchers also mentioned about the relative little evidence, on using other ADHD treatments, such as atomoxetine, guanfacine and clonidine in children with autism, having both epilepsy and ADHD [110]. However, several research papers and reviews found no clear evidence about exacerbation of seizures with these medications. Besag et al., in their paper summarized, about 30% of children with epilepsy had ADHD and about 70% among those with epilepsy and ADHD benefited from treatment of their ADHD symptoms with methylphenidate [119].

#### *10.1.2 Anxiety*

Anxiety is commonly found in young people with autism and epilepsy. Children with epilepsy with co-morbid psychiatric disorders like — ADHD, depression, and anxiety disorders, end up with significant compromise in academic performance and social skills, leading to deterioration in the Quality of life [120].

Risperidone and Aripiprazole in low dose can improve the behavior in children with autism. The mechanism is probably through decreasing anxiety. But the dose used should be very low because of the risk of seizure exacerbation with high doses of these antipsychotic drugs. On the other hand, the antiepileptic drugs like carbamazepine, phenobarbital and phenytoin may decrease the blood levels of antipsychotic drugs and a larger dose of antipsychotics may be required who are taking these AEDs. The management goals in pediatric epilepsy with anxiety disorders are — adequate seizure control, optimization of the functioning of the child and keeping the patient in best and simple pharmaco-therapeutic regimen [121].

The clinician should avoid an antiepileptic drug which is having side effects like behavioral problems.

Behavioral therapy should be the first-line approach to managing anxiety. Despite the effectiveness of selective serotonin reuptake inhibitors in decreasing anxiety in adults and teenagers there is a lack of evidence for a beneficial role of these drugs in treating anxiety in children with autism, according to a Cochrane review.

#### *10.1.3 Sleep*

Sleep disturbances are very common in children with autism. Epilepsy and sleep have reciprocal relationships. In some of the cases, sleep facilitates seizures and, in some seizures, adversely affects sleep architecture. If sleep problems are present, possibility of nocturnal seizures should it is eliminated. In that case careful history and if required antiepileptic medication should be tried. And if the sleep disturbance is not due to nocturnal seizures, melatonin is the drug of choice [110]. There is no good evidence of exacerbating seizures using melatonin. Animal work suggests that melatonin might have an antiepileptic effect. Identification and management of sleep disorders may improve seizure control and challenging behaviors of autism

#### **11. Future direction**

No single unifying ASD–epilepsy phenotype is there till now but understanding possible commonalities in subgroups of children with an ASD– epilepsy phenotype should help us in understanding the pathophysiology of both ASD and epilepsy [110].

Prospective, population-based studies are recommended, whenever there is any history of regression [110]. These studies should include investigations like genetic and chromosomal studies, searching for metabolic/mitochondrial disorders, EEG including sleep EEG and also testing for possible neuronal antibodies.

Environmental factors, prenatal factors such as maternal exposure to infection, toxic chemicals, pollution, alcohol and drugs should be searched for as these are the risk factors of autism and they might also cause epilepsy. A history of exposure to antiepileptic drugs like maternal valproate and learning problems/probable autism in the offspring and thorough obstetric and neonatal factors should also be an essential part of the history-taking.

#### **12. Conclusions**

Epilepsy is a common co-occurrence in children and persons with ASD. Determining the bidirectional prevalence of autism and epilepsy is important. Understanding the specific effects of the genes/metabolic/environmental pathways affected may give a better insight into the pathogenesis of the developmental problems. ID is also an important association in epilepsy and ASD. Multiple interrelated factors are there in the pathogenesis of ASD-epilepsy connection. Further, understanding these comorbidities will have a profound effect on the management of these challenging patient populations. For example, it has been found that autistic symptoms can be minimized when epilepsy is being treated in patients with both the conditions. Well-managed epilepsy, autism, and associated comorbidities can significantly improve the quality of life in both patient and caregiver. Further population-based studies and investigations including genetic, and, metabolic, in addition to EEG are needed, especially in case of regression in order to detect both these conditions in the early years of life.

#### **Acknowledgements**

I am grateful for the input of Dr. Tania Saad, FCPS (Pediatrics), MD (Pediatric Neurology), Consultant, Dhaka Medical College Hospital, Dhaka, Bangladesh

**29**

**Author details**

Shaheen Akhter

Mujib Medical University, Dhaka, Bangladesh

provided the original work is properly cited.

\*Address all correspondence to: shaheenk33@gmail.com

Institute of Paediatric Neurodisorder and Autism (IPNA), Bangabandhu Sheikh

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

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

support.

for her insightful feedback and suggestions on writing this chapter. And I also wish to acknowledge Dr. Ramisha Maliha, MBBS, lecturer of physiology in Dhaka Community Medical College and Hospital and student of Masters of Public Health (MPH) in North South University, Dhaka, Bangladesh, for her input and constant

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

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

Sleep disturbances are very common in children with autism. Epilepsy and sleep have reciprocal relationships. In some of the cases, sleep facilitates seizures and, in some seizures, adversely affects sleep architecture. If sleep problems are present, possibility of nocturnal seizures should it is eliminated. In that case careful history and if required antiepileptic medication should be tried. And if the sleep disturbance is not due to nocturnal seizures, melatonin is the drug of choice [110]. There is no good evidence of exacerbating seizures using melatonin. Animal work suggests that melatonin might have an antiepileptic effect. Identification and management of sleep disorders may improve seizure control and challenging behaviors of autism

No single unifying ASD–epilepsy phenotype is there till now but understand-

Prospective, population-based studies are recommended, whenever there is any history of regression [110]. These studies should include investigations like genetic and chromosomal studies, searching for metabolic/mitochondrial disorders, EEG

Environmental factors, prenatal factors such as maternal exposure to infection, toxic chemicals, pollution, alcohol and drugs should be searched for as these are the risk factors of autism and they might also cause epilepsy. A history of exposure to antiepileptic drugs like maternal valproate and learning problems/probable autism in the offspring and thorough obstetric and neonatal factors should also be an

Epilepsy is a common co-occurrence in children and persons with ASD. Determining the bidirectional prevalence of autism and epilepsy is important. Understanding the specific effects of the genes/metabolic/environmental pathways affected may give a better insight into the pathogenesis of the developmental problems. ID is also an important association in epilepsy and ASD. Multiple interrelated factors are there in the pathogenesis of ASD-epilepsy connection. Further, understanding these comorbidities will have a profound effect on the management of these challenging patient populations. For example, it has been found that autistic symptoms can be minimized when epilepsy is being treated in patients with both the conditions. Well-managed epilepsy, autism, and associated comorbidities can significantly improve the quality of life in both patient and caregiver. Further population-based studies and investigations including genetic, and, metabolic, in addition to EEG are needed, especially in case of regression in order to detect both

I am grateful for the input of Dr. Tania Saad, FCPS (Pediatrics), MD (Pediatric Neurology), Consultant, Dhaka Medical College Hospital, Dhaka, Bangladesh

ing possible commonalities in subgroups of children with an ASD– epilepsy phenotype should help us in understanding the pathophysiology of both ASD and

including sleep EEG and also testing for possible neuronal antibodies.

*10.1.3 Sleep*

**11. Future direction**

essential part of the history-taking.

these conditions in the early years of life.

**Acknowledgements**

epilepsy [110].

**12. Conclusions**

**28**

for her insightful feedback and suggestions on writing this chapter. And I also wish to acknowledge Dr. Ramisha Maliha, MBBS, lecturer of physiology in Dhaka Community Medical College and Hospital and student of Masters of Public Health (MPH) in North South University, Dhaka, Bangladesh, for her input and constant support.
