Comorbidity refers to the effect of other diseases and conditions on the management of epilepsy and to the special problems posed by the underlying condition of epilepsy and its association/causation with other disorders. This chapter is concerned with comorbidity in children; Chapter 191 addresses comorbidity in adults. Potential overlap between the two chapters is considerable with respect to drug interactions and the effect of systemic diseases on seizure control, especially those disorders that compromise hepatic and renal function. To avoid repetition, this chapter concentrates on child development and leaves much of the material on drug interactions and the effects of systemic disease to Chapter 191.

Multiple factors contribute to “comorbidity” in childhood epilepsy, and the relative contributions of these factors are a matter of continuing debate. The core issues that relate to comorbidity include the underlying substrate of the seizures, the effect of the seizures themselves, adverse effects of antiepileptic medications, and the psychosocial burden of coping with a stigmatizing paroxysmal disorder that limits employment, driving, and other “lifestyle” activities. This chapter reviews the extent to which these variables, both individually and together, affect developmental, cognitive, and psychosocial outcomes of childhood epilepsy.

Although epilepsy is widely known to be multifactorial in origin, a high proportion of seizures in childhood are developmentally based. Approximately two thirds of new-onset seizures in children have no apparent etiology.²³ This close relationship of childhood epilepsy with disordered brain maturation allows for significant and complex relationships with other developmental disorders, including behavioral problems, learning disabilities, attention-deficit hyperactivity disorder, autism, depression, and psychiatric disturbances. The frequent occurrence of one or more comorbid disability significantly complicates the management of the epilepsy and seriously impairs overall quality of life. It is therefore critical that clinicians caring for children with epilepsy understand comorbid conditions and be knowledgeable about their treatment.

There are no studies that comprehensively define the incidence of all comorbid conditions in children with epilepsy. Methodologic difficulties arise because childhood epilepsy often occurs in developmentally disabled populations, making it difficult comprehensively to assess the entire spectrum of disability and epilepsy. General cohort studies report that a high proportion of children experience at least some degree of socially unacceptable behavior. In a study of 127 preadolescent children with chronic epilepsy, Austin et al.³ noted that approximately half experienced some form of behavioral problem. A more recent population-based retrospective survey conducted over a 15-year period identified a similar prevalence rate in 134 children and adolescents.²⁴ This cohort was surveyed for a mean follow-up period of 117 months and found to have a psychiatric comorbidity of 51%, as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV).

It is also difficult precisely to time the onset of comorbid disorders, but several studies suggest that comorbidity can begin early in children with seizure disorders and occasionally pre-dates seizure onset. Both Austin et al.² and Oostrom et al.⁴² found the incidence of behavior disorder to be significantly higher than in the general population. Although the incidence in newly diagnosed patients (32%) was slightly lower than the incidence in children with chronic epilepsy, the high incidence underscores the selective vulnerability of children as well as their potential to deteriorate further. Problems with attention and socializing were particularly prevalent.

Children with structural brain damage are at even greater risk of comorbid disability and, in general, experience risk proportional to the severity of the brain damage. Children with cerebral palsy who have four-limb spasticity have the highest incidence of seizures, whereas children with milder forms of cerebral palsy such as spastic diplegia affecting predominantly the lower limbs have the lowest incidence.⁵¹ Factors responsible for the occurrence of cerebral palsy in most children are acquired prior to birth, confirming that in childhood, even seizures clearly attributable to brain damage are developmentally based.

Children with chronic epilepsy are at considerable risk for cognitive disability.^4,8 Learning problems and school failure are common and are due to heterogeneous causes. Impairment of attention plays a significant role and is affected by medication in conjunction with seizures. There is evidence, however, that cognitive deterioration in childhood epilepsy is a progressive process that is independent of medication and begins soon after seizure onset.⁴⁰

Studies using standardized measures to assess attention suggest that as many as one third of children with epilepsy suffer some form of attentional impairment.⁴⁶ In a study of 175 children with epilepsy of at least 6 month’s duration who were administered subscales for attention from the Child Behavior Checklist,¹⁹ 58% were found to have some degree of attentional impairment and 37% had overt symptoms of attention-deficit hyperactivity disorder. The Analysis of the Child Symptom Inventory indicated that 24% were experiencing predominantly the inattentive type, 11% had the combined type, and 2% had the hyperactive-impulsive type. Of note, this
population had a gender ratio of 1:1 and a significant overrepresentation of the inattentive type compared to the general population.

Children with frontal lobe epilepsy are at even greater risk of developing cognitive dysfunction. In a comparison of 16 children with frontal lobe epilepsy to 8 children with temporal lobe epilepsy and 8 children with generalized absence seizures, Hernandez et al.²⁷ found that the frontal lobe group scored more poorly on tasks assessing attention, impulse control, and working memory. Poorer perceptual organization and a range of maladaptive behaviors were also observed. These observations suggest that school performance and social patterns of children with frontal lobe seizures may need to be monitored even more closely than those of children with other seizure types or other anatomic localizations.

The ways in which recurrent seizures contribute to cognitive and attentional impairment remain to be elucidated. There is experimental evidence that recurrent seizures affect the developing brain, leading to consequences in later life. Although seizures in early development may not produce discernible cellular loss, synaptic reorganization is known to follow neonatal seizures. Both pentylenetetrazol- and flurothyl-induced seizures alter mossy fiber distribution in the hippocampus of rats after neonatal convulsions.^30,37 Alterations in neuronal circuits render the brain more susceptible to further seizures and cognitive dysfunction. Lipp et al.³⁶ showed that conditioned learning in the rat is directly influenced by the extent of mossy fiber projections to the pyramidal layers of the CA3 region, with a larger number of fibers associated with poorer performance.

Even less is known about the direct effects of antiepileptic drugs (AEDs) on cognition and learning. Many studies are either poorly controlled for seizure type or use methodologies that do not lead to definitive conclusions. In clinical experience, higher rates of depression, learning problems, and negative behavior are associated with the long-term administration of barbiturates and benzodiazepines in children. Psychiatric and behavioral side effects are seen more commonly in AEDs with mechanisms that are associated with a γ-aminobutyric acid (GABA)-ergic component.

Genetic contributions to learning disabilities have recently been described in children with inherited forms of epilepsy. Chang et al.¹³ reported a deficit in reading skill despite normal cognition in 10 patients with periventricular nodular heterotopia. All had a diagnosis of epilepsy, and most manifested partial seizures with or without secondary generalization. Patients with autosomal-dominant lateral temporal lobe epilepsy have been shown to have abnormal phonologic processing.⁴³ Genetic molecular analysis revealed a new LG11 missense mutation causing a Leu154Pro substitution in six affected and one unaffected individual.

Depression is a well-known accompaniment of adult epilepsy but has received relatively less scrutiny in children. The rate of depression in children and adolescents with chronic epilepsy as described by self-reporting instruments has been estimated at one fourth of patients.¹⁸ Children and adolescents remain vulnerable to the same risk factors that exist in adults, whereas epilepsy may lead to further stress on their families. Using DSM-IV-R criteria, it has recently become possible to diagnose depression in children as young as age 6 years.⁵⁵ A detailed family history is an important part of the evaluation because rates of depression are higher in children with a family history of mood disorder.⁵⁴ Recognizing depression is an important element in the overall care of the child with epilepsy because treatment is available in the form of counseling and, in certain circumstances, pharmacotherapy.

Appropriate treatment is based on the proper evaluation of the biologic, family, social, and iatrogenic factors, including choice of AED. Unlike the situation in adults, the role of seizure type and lateralization of the epileptic focus has not been shown to influence the incidence of depression. Age of seizure onset and electroencephalogram (EEG) findings also do not appear to exert an influence. However, depression in children with epilepsy has been linked to seizure recurrence, high seizure frequency, and longer duration of epilepsy.⁴⁴

The role of anxiety in children with epilepsy and depression is more controversial. Williams et al.⁵⁹ noted mild to moderate symptoms of anxiety in 23% of 101 children between the ages of 6 and 16 years who were administered the Revised Children’s Manifest Anxiety Scale. The investigators noted, however, that a high proportion of their patients had other comorbid conditions. In contrast, Baki et al.⁵ studied 35 children and adolescents with seizures and found higher rates of depression compared to normal controls but no differences in rates of anxiety. They also noted no differences in rates of depression or anxiety in mothers of children with epilepsy and controls.

In a structured psychiatric interview administered to 100 children with complex partial seizures (CPS), 71 children with childhood absence epilepsy (CAE), and 93 normal children ages 5 to 16 years and a behavioral checklist given to parents, Caplan et al.¹⁰ found that significantly more patients had affective and anxiety disorder diagnoses and suicidal ideation compared to the normal group. Children with both CPS and CAE were five times more likely to have an affective or anxiety disorder. Despite this, very few patients were receiving mental health services, but there were no suicide attempts. These observations emphasize the importance of early detection and treatment of symptomatic children.

The diagnosis of psychotic thinking and behavior can be difficult in childhood, especially in the developmentally disabled population. Impaired thinking, delusions, and hallucinations may go unrecognized if there is significant language impairment. Despite these methodologic limitations, interictal psychosis in the children with epilepsy appears to be rare. The prevalence rate of interictal psychosis was reported to be 0.7% in Japanese children, but even this prevalence may have been biased in favor of patients with long-standing epilepsy.³⁸ One study of children with complex partial seizures found possible early symptoms of psychotic thinking including hallucinations.¹⁰ Similar symptoms were not observed in children with generalized seizures.

The occurrence of interictal psychosis is generally regarded to be an adult-onset disorder. Several investigations have shown that seizures, especially of temporal lobe origin, must be present for at least 10 years before the onset of psychotic symptoms.⁴⁵ Thus, it is unlikely that frank interictal psychotic symptomatology will present in the preadolescent child. The onset of frank psychosis in a child with epilepsy should trigger a suspicion of another underlying neurologic disorder or adverse medication effect.

Almost one third of children with autistic spectrum disorder will experience at least one seizure in childhood.⁵⁷ Epileptiform discharges are noted in almost half during overnight video/EEG studies.⁵⁶ In a population of children at a tertiary care epilepsy clinic, Clarke et al.¹⁴ noted that 32% fit criteria for autism spectrum disorder. Children with the higher risk had a younger age of seizure onset, approximately age 2 years. This interval correlates with the known timing of the onset of autistic regression.

A comprehensive understanding of the consequences of unremitting seizures that have their onset in childhood is in its early stages. Apart from the social stigma attached to epilepsy and the potential consequences of long-term AED administration, the effects of recurrent seizures on the developing brain represent a major cause for concern. There is considerable evidence that when epilepsy is acquired in early life, multiple functional domains are affected to a degree that is often more severe than for other chronic childhood illnesses.^17,29 Even children who are intellectually normal are prone to emotional and social problems that may compromise their development and school performance.⁴⁴