Drug Treatment of Epilepsy Neuropsychiatric Comorbidities in Children

Abstract

There is increasing recognition that epilepsy can be associated with a broad spectrum of comorbidities. While epileptic seizures are an essential element of epilepsy in children, there is a spectrum of neurological, mental health and cognitive disorders that add to the disease burden of childhood epilepsy resulting in a decreased quality of life.

The most common comorbid conditions in childhood epilepsy include depression, anxiety, autism spectrum disorders, sleep disorders, attention deficits, cognitive impairment and migraine. While epilepsy can result in comorbidities, many of the comorbidities of childhood have a bi-directional association, with the comorbid condition increasing risk for epilepsy and epilepsy increasing the risk for the comorbid condition. The bidirectional feature of epilepsy and the comorbidities suggest a common underlying pathological basis for both the seizures and comorbid condition.

While recognition of the comorbid conditions of pediatric epilepsies is increasing, there has been a lag in the development of effective therapies partly out of concern that drugs used to treat the comorbid conditions could increase seizure susceptibility. There is now some evidence that most drugs used for comorbid conditions are safe and do not lower seizure threshold. Unfortunately, the evidence showing drugs are effective in treating many of the childhood comorbidities of epilepsy is quite limited. There is a great need for randomized, placebo-controlled drug trials for efficacy and safety in the treatment of comorbidities of childhood epilepsy.

1. Introduction

While epileptic seizures are the quintessential defining element of epilepsy, there has been increasing recognition that there is a spectrum of cognitive, behavioral, and psychiatric disorders that accompany epilepsy [1, 2]. Reflecting the idea that epilepsy can be associated with a broad spectrum of comorbidities, epilepsy is now defined as “a disease characterized by an enduring predisposition to generate epileptic seizures and by the neurobiological, cognitive, psychological, and social consequences of this condition” [3]. Indeed, comorbid conditions, defined as a greater than coincidental association of two conditions in the same individual [4], may be more problematic than the seizures, greatly impacting quality of life [5-8]. The additional cost and burden on the health care system of comorbidities associated with epilepsy, while difficult to quantify, are likely to be substantial [9].

Prominent comorbidities among children with prevalent epilepsy include neurological disorders, mental health conditions and cognitive disorders (Table 1) [9]. The relationship between comorbid conditions and epilepsy is complex (Figure 1 and Figure 2). In some conditions, epilepsy can result in the comorbid condition. For example, epilepsy can lead to an anxiety disorder or sleep disorder. In other situations, disorders such as brain neoplasms can result in epilepsy. Effectively treating the epilepsy in the first condition could reduce or eliminate the comorbid conditions whereas, in the second scenario, treating the cause of the epilepsy could eliminate the epilepsy. Rather than a cause-effect, in other comorbid conditions a common pathophysiological substrate leading to both conditions is likely [10-12]. For instance, attention deficit hyperactive disorder (ADHD), autism spectrum disorder (ASD), depression and migraine are risk factors for epilepsy and epilepsy is a risk factor for ADHD, ASD, depression, sleep disorders and migraine. In these cases, effective treatment of the epilepsy would not necessarily treat the comorbid condition. However, targeting the pathophysiological mechanism common to both conditions with one drug could conceivably treat both the epilepsy and comorbid condition.

Table 1.

Common comorbid conditions in children with epilepsy [9].

Neurological disorders	Brain neoplasm Autism spectrum disorder Cerebral palsy Migraine Sleep disorders
Mental health conditions	Mood disorders (depression) Anxiety disorders Attention deficit hyperactivity disorders (ADHD)
Cognitive disorders	Intellectual disability Learning disability Memory impairment Executive dysfunction

Figure 1.

Comorbidity paradigm. The relationship between epilepsy and comorbidities. Brain disorders can result in both epilepsy and comorbidities including cognitive impairment, ASD depression/anxiety, sleep disturbances, ADHD and migraines. Ongoing epileptic seizures can exacerbate comorbidities and epilepsy comorbidities can increase risk of seizures. Many comorbidities are bidirectional with epilepsy with the comorbidities occurring before the onset of the seizures. The bidirectionality of epilepsy and comorbidities suggest a common underlying pathogenetic mechanism in some children. In these cases, targeting the underlying mechanism of both conditions has the potential of reducing both the epilepsy and comorbidity.

Figure 2.

Schematic of relationship between epilepsy and AED therapy and common comorbidities of epilepsy in children. Children with epilepsy have a high risk for cognitive impairment, ASD depression/anxiety, sleep disturbances, ADHD and migraines. There is bidirectionality between epilepsy and the comorbidities. In addition, there is also a relationship between all of the epilepsy comorbidities as designated by the external circle.

Assessment and treatment of the comorbidities can be challenging. The clinical presentations of comorbid conditions in children are often different from adults. Similarly, children with epilepsy may present with comorbid symptoms that differ from children without epilepsy. The behavioral features of the seizures or the adverse effect of antiepileptic drugs (AEDs) may mask underlying comorbidities. AEDs are often attributed to behavior problems which often present even prior to the onset of seizures. This is challenging as it can lead to multiple medication changes for presumed behavioral side effects. When comorbid conditions are correctly diagnosed, there are concerns about exacerbation of the seizures, drug interactions and adverse effects when contemplating drug therapy. In addition, there is a paucity of data regarding drug efficacy for the comorbidities in childhood epilepsy.

2. Role of drug treatment of pediatric epilepsy in comorbidities

AEDs are the mainstay of treatment of childhood epilepsy. Although dietary therapy such as the ketogenic diet and surgical approaches are sometimes used in children with pharmacoresistant epilepsy, this group of patients makes up a relatively small percentage of cases.

It is important to recognize that a number of the first generation of AEDs (barbiturates [phenobarbital, primidone], benzodiazepines [clonazepam, diazepam, lorazepam], carbamazepine, ethosuximide, phenytoin and valproate) have adverse side effects that in some children could result in or exacerbate epilepsy comorbidities such as ADHD, depression, sleep disorders or anxiety (Table 2). While some of the second and third generation AEDs have fewer adverse effects, in any individual child the AED could contribute to the comorbidity. Children with the new onset of a comorbid condition following introduction of an AED should be re-evaluated to determine if the comorbidity is AED-related.

Table 2.

Antiepileptic drugs with favorable and unfavorable neuropsychological features [260].

Drug	Favourable neuropsychological features	Unfavourable neuropsychological features
Barbiturates	Anxiolytic	Depression Exacerbates ADHD
Benzodiazepines	Anxiolytic	Depression Exacerbates ADHD
Brivaracetam	None	None
Cannabinoids (CBD)	Anxiolytic	None
Carbamazepine	Mood stabilization (mild)	None
Eslicarbamazepine	None	None
Ethosuximide	None	None
Felbamate	None	Depression
Fenfluramine	Possible mood stabilization	None
Gabapentin	Anxiolytic	Irritability
Lamotrigine	Mood stabilization	None
Levetiracetam	None	Irritability Anxiety
Oxcarbazepine	Mood stabilization (mild)	None
Pregabalin	Anxiolytic	None
Rufinamide	None	None
Tiagabine	Anxiolytic	Depression Irritability
Topiramate	None	Depression Cognitive slowing
Zonisamide	None	Depression Cognitive slowing
Valproate	Mood stabilization	Irritability (uncommon) Agitation (uncommon)

ADHD attention deficit hyperactive disorder

3. Mental Health Comorbidities

Mental health comorbidities have been recognized in people with epilepsy since the time of the ancient Greeks with Hippocrates opining in 400 B.C. “Melancholics ordinarily become epileptics, and epileptics, melancholics” [13, 14]. This statement remains true today, with a significant percentage of people with epilepsy having mental health conditions that remain undiagnosed and untreated. The term “mental health conditions” is used here to reflect a range of conditions that occur in children including depression, anxiety, ADHD, ASD, oppositional defiant disorder, conduct disorder, phobias, obsessive convulsive disease (OCD), panic attacks and functional neurological symptom disorders [15-19]. Many of the conditions listed are also comorbid with each other in children. For example, ASD, anxiety, depression and ADHD frequently co-occur (Fig. 2).

3.1. Depression and anxiety

Depressive and anxiety disorders are among the most common psychiatric comorbid conditions in epilepsy [2, 20-29]. Anxiety and depression are highly comorbid with each other, and together they are considered to belong to the broader category of internalizing disorders [30]. Since both conditions are comorbid with epilepsy [20], in this section they will be considered together.

Studies of the prevalence of common psychiatric comorbid conditions in pediatric epilepsy have estimated an overall risk of 21-60% for childhood psychopathology, a risk at least 3-6 fold higher than the general population [20-22], making the diagnosis of depression and anxiety in children with epilepsy difficult [27]. In children, depression does not necessarily equate to sadness and children with depression are more likely to show anxiety disorders, irritability, separation anxieties, and behavioral problems such as anger and aggression. The adolescent may present with academic decline, disruptive behavior, loss of interest in activities, problems with friends, aggression, irritability and suicidal ideation. Children with epilepsy and depression may also have psychogenic non-epileptic behavioral seizures [31, 32]. The clinical features of non-epileptic behavioral seizures are similar in children with epilepsy as those without epilepsy.

As noted by Hippocrates [13], epilepsy and depression are bidirectional with depression increasing the risk for epilepsy and epilepsy increasing the risk for depression. In both children and adults, a history of depression is associated with an increased risk for developing epilepsy [33-36]. Austin et al [10] reported that approximately a third of children with new-onset seizures had psychiatric issues, primarily depression and anxiety symptoms, prior to the onset of seizures.

In addition to being debilitating conditions, depression is associated with a worse prognosis for seizure control. In a study of 780 children and adults with epilepsy followed at a single center over a 20-year period, Hitiris et al.[37] found that psychiatric comorbidity, particularly depression, was correlated with pharmacoresistance. People with epilepsy and clinical depression reported higher levels of perceived seizure severity, recovery time and disability than did individuals with epilepsy without depression who experienced similar types of seizures [38]. These studies suggest that the deleterious neurobiological processes underpinning depression, anxiety and epilepsy interact to increase the extent of brain dysfunction and likelihood of developing medically intractable epilepsy.

In view of the detrimental effects of depression on quality of life and increased seizure susceptibility, identifying and treating depression is important. Unfortunately, until recently, antidepressants were thought to cause seizures and were contraindicated in children and adults with epilepsy. As recently as 2005, it was written that “most, if not all, antidepressant agents have a propensity to lower the seizure threshold, and most are associated with a risk for seizures” [39], making their use in people with a history of seizures problematic [40].

However, seizure risk in patients with epilepsy and depression who receive the newer generation antidepressants, particularly selective serotonin reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitor (SNRI) is low [39, 41, 42]. Kanner et al. [41] prospectively assessed the seizure frequency of 100 consecutive patients with partial and primary generalized epilepsy during a trial with sertraline, a SSRI, for the treatment of depression or OCD. While six patients (6%) experienced an increase in seizure frequency after starting sertraline, only one patient had a definite causal relationship between sertraline and seizure worsening. Thomé-Souza et al. [42] analyzed the impact of SSRIs on the severity and frequency of seizures in 36 children and adolescents with epilepsy and depression. All had an improvement in depression and seizures worsened in only two patients.

To extensively assess the effect of psychotropic medication on reported seizures, Alper et al. [43] examined data from 75,873 patients enrolled in Phase II and III clinical trials of psychotropic drugs that reported seizure incidence in United States trials between 1985 and 2004, The incidence of seizures among the active drug and placebo groups was compared with incidence data from the published rates of unprovoked seizures in the general population and from psychopharmacological clinical trials. The incidence of seizures was significantly lower among patients assigned to antidepressants, other than bupropion, compared to placebo (Table 3). The authors concluded that other than bupropion, second-generation antidepressants have an apparent anticonvulsant effect [43]. For anxiolytic drugs, alprazolam was shown to have a higher risk for seizures in the 1983 trial, but not in the 1990 trial.

Table 3.

Incidence of seizures in antidepressant and anti-anxiolytic drugs [43].

Category	Incidence of Seizures
	N	# of seizures	%
Antidepressant drugs
Group 1
Buproprion IR	4419	26	6.0
Group 2
Citalopram	4168	12	0.3
Fluoxetine	6000	12	0.2
Venlafaxine	2181	3	0.1
Bupropion SR	3094	3	0.1
Paroxetine	2963	2	0.07
Nefazodone	2256	1	0.04
Mirtazapine	2796	1	0.04
Escitalopram	715	0	0
Duloxetine	2314	0	0
Sertraline	2979	0	0
Anti-anxiety drugs
Group 1
Alprazolam (1983 trial)	1723	46	2.7
Group 2
Alprazolam (1990 trial)	1698	7	0.4
Buspirone	3558	3	0.8

Bupropion, an atypical antidepressant that acts as a norepinephrine–dopamine reuptake inhibitor and nicotinic receptor antagonist, is frequently associated with seizures [44, 45]. The incidence of seizures with bupropion is dose related [46]. Seizure risk was lower in clinical trials of sustained release (SR) versus immediate release (IR) formulation. Since peak concentrations are higher with IR versus SR formulations, the implication is that pharmacokinetic factors are involved in bupropion’s proconvulsive effect [47, 48]. Alprazolam is a short acting (half-life of ~11-13 hours) benzodiazepine used primarily in the treatment of anxiety disorders. While not all authors found an increased risk for seizures with alprazolam [49], when seizures do occur it is most commonly in the situation of sudden drug withdrawal [50, 51].

Thus, SSRIs and SNRIs now have a strong record of safety in children and are the most widely used group of drugs used to treat depression in epilepsy [52]. The relationship between L-5-hydroxytryptophan (5-HT), the immediate precursor of serotonin, and seizures [53-55] suggests serotonergic mechanisms are likely involved in the bidirectionality of epilepsy and depression. Agents that elevate extracellular serotonin levels, such as 5-HT and serotonin reuptake blockers, inhibit both focal and generalized seizures and depletion of brain 5-HT lowers the threshold to audiogenic, chemical and electrically evoked convulsions [56-60]. Genetic deletion of 5-HT2C receptors in mice causes audiogenic seizures [61] and knockout of 5-HT1A receptors reduces the threshold for kainate-induced seizures [62]. In humans, functional neuroimaging studies with positron emission tomography (PET) targeting the 5-HT1A receptor have suggested a potential common pathogenic role of 5-HT in epilepsy and depression [63-66]. Several AEDs including phenytoin, lamotrigine, carbamazepine, valproic acid and zonisamide cause an increase in extracellular 5-HT, and the elevated 5-HT is thought to contribute partially to their mechanism of action [55, 67-71]. In three small open trials using SSRIs in nondepressed adults with epilepsy, fluoxetine [72] and citralopam [73, 74] reduced seizure frequency. Fenfluramine, a potent 5-HT releaser/reuptake inhibitor activating multiple 5-HT receptor subtypes [75], is a highly efficacious AED in Dravet syndrome, a condition with severe epilepsy [76]. However, the antiepileptic effect of fenfluramine may not be linked fully to a serotonergic effect. Efficacy of fenfluramine may be related to its known modulatory effect at sigmal (σ1) receptors in vitro and in vivo [77].

While the evidence that SSRIs are safe in children with epilepsy is strong, the evidence that they are effective in treating depression is quite limited. In a Cochrane Library meta-analysis of eight studies (three randomized clinical trials and five prospective cohorts) investigating 471 children and adults with epilepsy treated for depression, treatment with a SSRI did not increase seizure frequency [78]. Evidence of the effectiveness of antidepressants in treating depressive symptoms associated with epilepsy, however, was very limited and only one small randomized clinical trial demonstrated a statistically significant effect of venlafaxine, a SNRI, on depressive symptoms. The authors concluded that high-quality evidence to inform the choice of antidepressant drug or class of drug in treating depression in people with epilepsy is not available [78].

Concomitant treatment of children with antidepressants or anxiolytic agents can result in drug interactions [79]. Most antidepressants inhibit one or more of the cytochrome P450 isoenzymes in the liver [80, 81]. Levels of enzyme-inducing AEDs (phenytoin, phenobarbital, primidone and carbamazepine) which induce the activity of CYP1A2, CYP2C9, CYP2C19 and CYP3A4, can increase with concomitant antidepressants. For example, elevated levels of carbamazepine have been observed with SSRI use [82-84]. Low doses of sertraline, venlafaxine, or citalopram have little effect on enzyme inhibition and therefore should not produce clinically significant interactions [80, 85]. Monitoring levels of AEDs can be helpful if toxicity is suspected in children receiving antidepressant or anxiolytic drugs.

In summary, children with epilepsy often have the comorbid conditions of depression and anxiety which can have profound effects on quality of life and possibly even seizure control. AEDs that can result in depression should be avoided, when possible (Table 1). While the new generation of antidepressants and anxiolytic agents are safe and may even reduce seizure burden, clinical evidence that antidepressants and anti-anxiolytics are effective in children with epilepsy is lacking.

3.2. ADHD

ADHD is a common comorbidity in childhood epilepsy with prevalence figures as high as 77% [86-93]. ADHD in epilepsy is associated with a significantly poorer quality of life with predominantly inattentiveness symptoms [94, 95]. In the general population, the prevalence of ADHD is approximately 5%, is more common in boys than girls, and most children have the combined type of ADHD with both attention deficits and hyperactive behavior. Children with epilepsy and ADHD differ from children without epilepsy and ADHD by having a higher proportion of inattentive symptoms and by an equal male to female ratio [86, 96].

ADHD has been found to have a bidirectional relationship with epilepsy, with either condition increasing the risk for the other [10, 11, 36, 96-98]. In studies of children with their first recognized, unprovoked seizure, ADHD was more frequent before the onset of the first seizure among children who developed epilepsy than among siblings without epilepsy or children with no additional seizures [10, 11]. A population based, case controlled study conducted among Icelandic children found that those with an unprovoked seizure were 2.5 times more likely than age- and gender-matched controls to have a prior history of ADHD [96]. In a study of 53 children aged 8 to 18 years with recent onset epilepsy (<1 year in duration) of idiopathic etiology, ADHD was two-fold higher in children with epilepsy than controls [36]. The increased prevalence of ADHD antedating epilepsy onset is consistent with the presence of underlying neurobiological factors independent of seizures and AEDs [36].

Approved drugs by the United States Food and Drug Administration (USFDA) for the treatment of ADHD include stimulants (amphetamine [AMP]–based and methylphenidate [MPH]–based agents) and nonstimulants (atomoxetine, clonidine, and guanfacine)(Table 4) [99, 100]. The primary pharmacologic effect of both amphetamine and methylphenidate is to increase central dopamine and norepinephrine activity, which impacts executive and attentional function [101]. Atomoxetine is a selective norepinephrine-reuptake inhibitor [102] and guanfacine and clonidine are selective α2-adrenergic agonists [103-105]. Stimulants are considered first-line therapy in children, adolescents, and adults with ADHD because of their greater efficacy over other approved drugs for ADHD [99, 100, 106, 107]

Table 4.

Drugs used to treat attention-deficit hyperactive disorder.

Drug	Mechanism of Action	Drugs	Adverse Effects	Effect on Seizure Susceptibility
Methylphenidate	DA and NA reuptake inhibitor	Methylphenidate Dexmethylphenidate	Appetite suppression Emotional lability Insomnia Psychotic symptoms	None
D,L-Amphetamine	DA and NA reuptake inhibitor Monoamine oxidase activity inhibition VMAT-2 inhibition	Amphetamine sulfate Dextroamphetamine Lisdexamfetamine	Appetite suppression Emotional lability Insomnia Psychotic symptoms	None
Atomoxetine	NA-reuptake inhibition Increases DA indirectly	Atomoxetine	Appetite suppression Nausea Drowsiness	None
Guanfacine	Selective α2-adrenergic agonists	Guanfacine	Drowsiness Dizziness Dry mouth Constipation Tiredness	None
Clonidine	Selective α2-adrenergic agonists	Clonidine	Constipation. Dizziness Drowsiness Dry mouth Weakness Irritability	None

DA dopaime; NA noradrenaline (norepinephrine)

AMP and MPH have been shown to exhibit comparable efficacy in two meta-analyses [108, 109], with other analyses reporting that AMP has moderately greater beneficial effects than MPH [110-112]. The tolerability and safety profiles of AMP and MPH in terms of adverse events, treatment discontinuation and cardiovascular effects are generally comparable [101].

As with antidepressants, treatment of ADHD in children with epilepsy has lagged behind the use of drugs in children without epilepsy because of the concern about stimulant medications lowering seizure threshold. In a study of 105 subjects with ADHD and epilepsy (mean age = 14.8±3.4 years), treatment with MPH resulted in aggravated seizures in 20% and worsening EEG abnormalities in 32% [113]. MPH was effective in controlling ADHD symptoms in both the seizure aggravation and non-aggravation groups. Children with poor seizure control or anxiety disorders at baseline were more likely to show an aggravation of seizures. The authors concluded that MPH may increase seizures and worsen EEG findings in individuals with ADHD and epilepsy [113]. In a randomized controlled trial of extended release MPH in 33 children (6-18 yrs) with ADHD and epilepsy taking AEDs participated in a multiple dose, double-blind placebo-controlled crossover trial with MPH [114]. MPH reduced ADHD symptoms more than placebo and there were too few seizures during the active and placebo arms to confidently assess seizure risk; however, considering exposure time, an increased daily risk of seizures with increasing dose of MPH was observed, suggesting potential safety concerns.

However, other studies did not find an exacerbation of seizures with MPH [93, 115, 116]. In a retrospective study of 36 children under the age of 18 with epilepsy and ADHD, symptoms were treated with MPH or an AMP preparation [116]. Responders were defined as those who remained on medication and had an improvement score of ≤ 2 on the Conners’ Global Index-Severity scale, a 7-point scale used to indicate severity of a patient’s symptoms with 1 indicating “normal” and 7 “extremely ill”. No patients who were seizure-free at the start of the medication trial experienced an increase in seizures. Of the patients having seizures at the start of the trial, one patient on MPH and two patients on AMP had increased seizures during the trial. Seizures returned to baseline frequency after stimulant discontinuation or anticonvulsant adjustment. MPH was associated with a higher response rate, with 12 of 19 given MPH compared with 4 of 17 given AMP responding.

To determine whether ADHD medication treatment increases risk of seizures among patients with and without preexisting seizures, Wiggs et al [93] assessed a database of 801,838 treated patients with ADHD to examine whether ADHD medication increased the likelihood of seizures among ADHD patients with and without a history of seizures. Patients with ADHD were at higher odds for any seizure compared with non-ADHD controls (odds ratio [OR] = 2.33, 95% confidence interval [CI] = 2.24–2.42 males; OR = 2.31, 95% CI = 2.22–2.42 females). In adjusted within-individual comparisons, ADHD medication was associated with lower odds of seizures among patients with (OR = 0.71, 95% CI = 0.60–0.85) and without (OR = 0.71, 95% CI = 0.62–0.82) prior seizures. Long-term within-individual comparisons suggested no evidence of an association between medication use and seizures among individuals with (OR = 0.87, 95% CI = 0.59–1.30) and without (OR = 1.01, 95% CI = 0.80–1.28) a seizure history. While the authors reaffirmed that patients with ADHD are at higher risk of seizures, ADHD medication was associated with lower risk of seizures in individuals while they were receiving medication.

In summary, children with epilepsy have a high prevalence of ADHD which can adversely affect school performance and reduce quality of life. ADHD often precedes epilepsy and is independent of seizures. In children with epilepsy and ADHD, a stepwise approach, beginning with non-drug interventions and then moving to pharmacological treatment in those most severely affected is warranted. Since in individual children some AEDs including phenobarbital, topiramate and valproate may worsen ADHD [88], AED therapy should be re-evaluated in children whose ADHD begins or is exacerbated with the introduction of an AED. If necessary, ADHD drug treatment can be safely started, and clinical response followed.

3.4. ASD

Autism, an early neurodevelopmental syndrome is characterized by abnormal language development, impairments in reciprocal social interactions, behavioral inflexibility and repetitive and ritualized behaviors [117]. While these are the core features of ASD, children with ASD often have co-morbid conditions such as ADHD, anxiety, depression, obsessive-compulsive disorder, schizophrenia and sleep disorders [118, 119].

There has been a known association of ASD with epilepsy for over fifty years [120]. The prevalence of epilepsy with ASD has varied widely, with a prevalence in some studies reaching almost 50% [121]. While population-based studies provide the best estimate of true prevalence of epilepsy in ASD. even those rates have been variable. In a prospective, population-based study of epilepsy in 120 young adults with autism, 38% had epilepsy [122]. In a study of 90 children with ASD between 6-12 years, 46% had epilepsy [123]. While there is a strong association between ASD and low IQ in children with epilepsy [123, 124], even in cases with a normal IQ, ASD is associated with an elevated risk of epilepsy [125-127].

Likewise, the prevalence of ASD in individuals with epilepsy is higher than in the general population [128, 129]. In a large population-based cohort of 64,188 people with epilepsy, the odds ratio of having ASD was 22.2 [130]. In a study of 48 young children (1-7 years) with epilepsy, 18% met ASD criteria and 40% met ADHD criteria [131]. Seizures early in life appear to place children at a particularly high risk for developing ASD [132-134].

In addition to an increased prevalence of epilepsy in individuals with ASD, there is also a marked increased incidence of epileptiform activity on EEGs in ASD. While interictal spikes occur in less than 5% of normal children without a history of epilepsy [135], studies have demonstrated that up to 60% of EEG records from individuals with autism have interictal spikes [136]. The high comorbidity rate between ASD and epilepsy and EEG epileptiform activity does not mean that there is a causal relationship between the conditions. More likely is the idea that epilepsy and ASD have a complex interaction and share common pathophysiological properties. This shared pathophysiology viewpoint is supported by the findings of Sundelin et al. [137] who found that ASD was more common in siblings and offspring of individuals with epilepsy than expected in the normal population. Seizure frequency is not associated with ASD [131, 138-140], suggesting that treating seizures does not prevent ASD from emerging.

The effectiveness of treatments for seizures has not been studied in individuals with ASD. Even though children with ASD and seizures appear to represent a large ASD subgroup, seizure treatments for individuals with ASD have not been systematically studied [141]. However, there is no evidence that seizures in children with ASD respond any differently to AEDs than seizures in children without ASD. Several lines of evidence point to valproate, lamotrigine, and levetiracetam as the most effective and tolerable AEDs for individuals with ASD [141]. A major consideration in the AED therapy of children with ASD is the side effect profile of the AED used. As discussed in Section 2, AEDs that exacerbate co-morbid conditions in ASD should be avoided.

There are currently no drugs that treat core autistic symptoms. Rather drug treatment aims at treating comorbid disorders, such as ADHD, sleep disturbances, irritability, agitation and aggressiveness and anxiety [142]. Psychomotor agitation or irritability is one of the more troublesome problems seen in children with ASD and atypical antipsychotics (also known as serotonin–dopamine antagonists) have emerged as helpful therapies.

The efficacy of risperidone, a dopamine type 2 (D2) and serotonin type 2A (5-HT2A) receptor antagonist, for the treatment of irritability in ASD, is supported by multiple placebo-controlled studies [143, 144]. In an 8-week double-blind, placebo-controlled trial of 101 children and adolescents with autism (ages 5–17 years), the Research Units on Pediatric Psychopharmacology (RUPP) Autism Network demonstrated a significant risperidone effect marked by a 69% drug treatment response versus a 12% response in those receiving placebo [143]. These findings were replicated by Shea et al. [145] who demonstrated in an 8 week double-blind, placebo-controlled trial of 79 children (5–12 years) with ASD that risperidone treatment was associated with significant improvement compared with placebo on several outcome measures [145].

Aripiprazole, a D2 and 5-HT1A receptor partial agonist and 5-HT2A receptor antagonist [146], has been shown to be effective in two double-blind, placebo-controlled studies, as well as in several open-label studies in the treatment of irritability in children with ASD [147, 148]. In an 8 week double-blind, placebo-controlled study involving 98 youth with ASD (ages 6–17 years), Owen et al. [148] reported a significant effect of aripiprazole on irritability, marked by a 52% drug treatment response rate compared with a 14% placebo response rate. Marcus et al. [149] reported on a fixed dose four arm (3 doses plus placebo) 8 week double-blind, placebo-controlled study of aripiprazole targeting irritability in children and adolescents with ASD (ages 6–17 years). Treatment response was seen in all three treatment arms compared with placebo.

Fallah et al [150] evaluated eight trials comparing four interventions (risperidone, aripiprazole, lurasidone, and placebo) in 878 children with ASD and irritability. Both risperidone and aripiprazole had significantly reduced Aberrant Behavioral Checklist Irritability (ABC-I) scores than placebo. Risperidone and aripiprazole are the only two medications approved by the US Food and Drug Administration (FDA) for the treatment of irritability associated with ASD. The risk of seizure with either risperidone or aripiprazole is quite low [151-153]. While there are no drug trials targeting irritability in children with epilepsy and ASD, there is no reason to believe the drugs would not be equal in efficacy, safety and tolerability in children with ASD and without epilepsy.

Cannabidiol is an FDA approved drug for the treatment of seizures associated with tuberous sclerosis complex, Lennox-Gastaut syndrome and Dravet syndrome. While it has been proposed as a drug that could be useful in treating the anxiety associated with ASD, there have been no conclusive studies indicating that any of the pathological symptoms of ASD such as hyperactivity, sleep disorders, self-injury, anxiety, behavioral problems, and communication benefit from the drug [154, 155].

4. Sleep Disorders

Sleep disorders and epilepsy are two conditions that interact with each other in a complex bi-directional way [156, 157]. Epilepsy can result in sleep disorders and sleep disorders can exacerbate epilepsy. There is a strong relationship between stages N1-N3 (drowsiness, light sleep and slow wave sleep [SWS]) and seizures and interictal EEG abnormalities [158]. Sleep is a powerful activator of seizures and interictal spikes, sharp waves and spike and wave complexes [158, 159]. The number of the epileptiform discharges as well as their propagation increase during all periods of sleep except during rapid-eye movement (REM) [160], unmasking the epileptic network that is often suppressed during wakefulness. Several epilepsy syndromes such as grand mal upon wakening [161], autosomal dominant nocturnal frontal lobe epilepsy [162] and benign Rolandic epilepsy (also termed Benign Epilepsy with Centro-Temporal Spikes) [163] have a strong relationship between seizures and sleep states.

Children with epilepsy are at risk for a variety of sleep disturbances including sleep anxiety, insomnia, fragmentation of sleep, excessive arousals, increased REM latency and reduced REM duration, obstructive sleep apnea and daytime sleepiness [19, 164-167]. Cortesi et al [166] assessed sleep problems in 89 children with idiopathic epilepsy compared with 49 siblings and 321 healthy control children using parental questionnaires. Children with epilepsy had poorer sleep quality and more sleep anxiety than the control population. In a study of 30 children with epilepsy, 80% exhibited sleep disruption because of either clinically significant obstructive sleep apnea syndrome, disturbance of sleep architecture or sleep fragmentation [164]. In a study of 79 school aged children with epilepsy by parental questionnaires, Stores et al [168] found a high incidence of poor-quality sleep and sleep anxieties which correlated with daytime behavioral abnormalities. Excessive daytime sleepiness occurs in a third to a half of patients with epilepsy [165]. although in many of the patients the sleepiness could be caused by sedating AEDs.

One of the most vexing sleep problems with children with epilepsy is insomnia which may be associated with cognitive, emotional, and psychosocial impairments resulting in significant caregiver burden [169]. Insomnia in children with epilepsy is complex and is often co-morbid with other conditions in children with epilepsy, including ADHD and anxiety [170]. Within the group of children with epilepsy, those with ASD are at particularly high risk for insomnia [119]. While children with epilepsy and other chronic illnesses go to bed at the same time as children without chronic illnesses, children with epilepsy have more problems falling asleep and more nighttime awakenings than healthy control children [171].

The consequences of insomnia in children are substantial, resulting in symptoms such as hyperactivity, inattention, learning difficulties, and impulsive behaviors [169, 172, 173]. In a study of 4175 children and adolescents aged 11-17 years, approximately 5% met criteria for chronic insomnia, and this was shown to increase risk for subsequent psychological problems, interpersonal difficulties and impairments in daily activities [174].

Seizures and interictal EEG activity can also have considerable effects on memory. SWS supports the consolidation of newly acquired information in memory. During SWS, slow oscillations in the delta activity (0-4 Hz), sleep spindles (11-15 Hz) and sharp wave-ripples (140–200 Hz) bandwidths [175-177] coordinate the re-activation and redistribution of hippocampus-dependent memories to neocortical sites, whereas REM sleep favors the subsequent synaptic consolidation of memories in the neocortex [178]. It known that both seizures and interictal spikes during sleep impact long-term memory consolidation [179] An association has been found between nocturnal interictal abnormalities and the frequency and severity of sleep disturbance [166].

Nocturnal seizures can disrupt sleep with both focal and generalized seizures resulting in arousal and disrupted sleep [180]. Some studies have reported that seizure frequency is positively associated with behavioral problems in children with epilepsy [166, 181, 182]. However, in a small series of 30 children with epilepsy, Becker et al. [164] found that behavioral problems were positively correlated with sleep disruption but not with seizure frequency, suggesting that behavioral problems may be a reflection of a coexisting sleep disorder in children with epilepsy. Further, children with epilepsy without nocturnal seizures can have sleep abnormalities, suggesting that sleep disturbances may be an intrinsic component in some patient with epilepsy [165].

AED therapy in children with epilepsy may play a role in sleep disturbances. As shown in Figure 3, a number of AEDs that have a GABAergic effect such as the benzodiazepines, barbiturates, vigabatrin and tiagabine can result in decreased sleep latency and daytime somnolence where others such as felbamate and lamotrigine can result in insomnia [183-187]. While AEDs can affect sleep efficiency and SWS and REM sleep durations (Figure 3), for the most part, these AED effects on sleep are not of clinical importance. While many of the AEDs are non-sedative, all of the AEDs can lead to sleepiness in selected patients, particularly if used at high doses. Finally, while AEDs have been shown to alter time spent asleep, sleep latency, and sleep architecture [187], sleep disturbances have been found to continue even after the discontinuation of anticonvulsant therapy [188], again suggesting that sleep disorders in children with epilepsy are intrinsic to the epilepsy, rather than caused by AEDs or seizures.

Figure 3.

Summary of the effects of antiepileptic drugs on sleep [183]. (↓ indicates decreases, ↔ indicates no changes, ↑ indicates increases, ? indicates effects unknown). REM rapid eye movement; SWS slow wave sleep.

Treatment of pediatric sleep disorders is likely to improve the quality of life for children with epilepsy by reducing seizure frequency as well as improving attentional difficulties [189]. For example, treatment of obstructive sleep apnea in patients with epilepsy may improve seizure control [189]. Parent-based sleep interventions are effective in randomized controlled trials for typically developing younger children, attention-deficit hyperactivity disorder and ASD [190-193] and applicable for children with epilepsy. If behavioral strategies are not helpful and contributing coexisting conditions and use of concomitant medications have been addressed, melatonin can be useful [194] }.

5. Cognitive Dysfunction

Cognitive dysfunction is a major concern for children with epilepsy. In a study of children with intellectual disabilities, approximately 15% developed epilepsy by 22 years of age [195], reflecting a 43-fold increased risk in comparison to children without intellectual disability [196]. When adjustment is made for age, socioeconomic status and gender, among children with intellectual disabilities, a 9-fold increased risk to have one or more seizures was found when compared to controls [197]. Furthermore, the presence of cerebral palsy associated with intellectual disability strongly increases the risk for developing epilepsy [195, 198]. Executive dysfunction, such as deficits in working memory and planning abilities, has been noted in many children and adolescents with epilepsy [199, 200].

The distribution of IQ scores of children with epilepsy is skewed toward lower values [201, 202] and the number of children experiencing difficulties in school because of learning disabilities or behavioral problems is greater than in the normal population [97, 203, 204]. Even children with normal IQs and well-controlled seizures are at high risk for learning problems [203]. Memory impairment, mental slowing and attentional deficits are the most frequently reported problems.

A variety of factors - many of which are not intrinsically associated with having seizures or treatment - impact the neurobehavioral status of people with epilepsy [205]. For example, a cohort of people over the age of 15 years with newly diagnosed epilepsy and without other neurological disorders had significantly worse results than healthy volunteers in several cognitive domains even before AEDs were started [206]. Similarly, Hermann and colleagues [207] found that children with new-onset epilepsy had cognitive impairment and academic underachievement in comparison to children without epilepsy.

While most of the cognitive problems that occur in children precede the onset of epilepsy, young children with active epilepsy have a significant risk for a variety of problems involving cognition and behavior. Children appear to be more vulnerable to the adverse effects of seizures, EEG abnormalities, and epilepsy treatment than adults [208-211]. There is evidence that some children with epilepsy are slow in their cognitive development [202] or even have progressive declines of IQ on serial intelligence tests and behavioral and psychiatric deterioration over time [201, 210-215]. In a community-based cohort of 198 children, aged <8 years with new-onset epilepsy followed prospectively and reassessed with the Wechsler Intelligence Scales for Children (WISC-III), 8-9 years later, Berg et al. [216] found that children with medically intractable seizures had an 11.4 point lower full scale IQ with similar decrements in each WISC-III domain. The authors concluded that young children with pharmacoresistant seizures suffered from cognitive decline over time.

For children who have cognitive problems before the onset of the epilepsy, there is little one can do to improve cognition with pharmacological interventions. However, if the child has another comorbid condition such as depression or ADHD, pharmacological treatment could be helpful in allowing the child to maximize cognition. If the child has cognitive decline following the onset of the seizures, optimizing seizure control with AEDs, preferably using monotherapy, may be helpful. While all AEDs are likely to have some effect on cognition based on their mechanism of action on neural networks, for the most part, AEDs do not have major adverse effects on cognition in children with epilepsy [217-219]. In the first generation of AEDs (carbamazepine, clonazepam, ethosuximide, felbamate, gabapentin, phenobarbital, phenytoin, primidone and valproate), cognitive issues have been raised with clonazepam, phenobarbital and primidone [220, 221]. Children treated with phenobarbital for febrile seizures have had cognitive issues compared to non-treated children [222, 223]. In a review of the second and third generation AEDs (eslicarbazepine, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, rufinamide, tiagabine, topiramate, vigabatrin and zonisamide), it was found that the drugs had few cognitive side effects [219]. The highest rate of cognitive side effects occurred with topiramate which has been associated with cognitive impairment (attention, memory, and language function) in children in some [224, 225], but not all studies [226].

There is one important group of children with epileptic encephalopathies in which treatment of seizures and interictal EEG abnormalities can influence cognitive outcome. Epileptic encephalopathies refer to a group of disorders in which the unremitting epileptic activity contributes to severe cognitive and behavioral impairments above and beyond what might be expected from the underlying pathology alone, and these can worsen over time, leading to progressive cerebral dysfunction [227]. The epileptic encephalopathies encompass disorders such as early myoclonic encephalopathy, Ohtahara syndrome, migrating partial seizures of infancy, infantile spasms and Lennox-Gastaut syndrome. Inherent in the concept of epileptic encephalopathy is the idea that suppression of epileptic activity may improve cognition and behavior. Effective and early intervention may in fact improve seizure control and developmental outcome in some cases [228-230]. In two other rare syndromes in the epileptic encephalopathies category, Landau-Kleffner Syndrome [231-233] and Electrical Status Epilepticus of Sleep (ESES)(also known as Continuous Spike Wave of Sleep [CSWS]) [234-236], there is evidence that interictal discharges are contributing to the neurological symptoms. However, there is little evidence that treating interictal spikes improves cognition [237].

In conclusion, cognitive impairment is a common comorbidity in childhood epilepsy and usually precedes or occurs concomitantly with the onset of epilepsy. In most cases the etiology of the epilepsy is the cause of the cognitive impairment. Recurrent seizures and interictal spikes, or both, account for cognitive decline in only a small percentage of children. In this group of children, optimizing seizure control with AEDs that do not contribute to the cognitive impairment is important.

5. Migraine

Migraine and epilepsy are common comorbidities in children [238-240] and contribute to a poor quality of life [241, 242]. In children, an association between migraine and several epilepsy syndromes - childhood epilepsy with occipital paroxysms, Benign Rolandic Epilepsy and Panayiotopoulos syndrome have been reported [243, 244]. Migraines have been each associated with a more severe epilepsy course [242]. In a study of adults with epilepsy with and without migraine, patients with epilepsy and migraine had a significantly lower cumulative probability of being seizure-free over 10 years compared with patients without migraine [245].

As with many of the other comorbid conditions associated with childhood epilepsy, there is a bidirectional relationship between migraine and epilepsy, where having a history of one condition is associated with an increased risk for the other [246, 247]. Migraine is associated with a fourfold increased risk for developing epilepsy, an association explained by migraine with aura (odds ratio, 8.1; 95% confidence interval, 2.7-24.3), whereas migraine without aura did not increase risk for epilepsy in children [246]. Velioğlu and colleagues [248] found that people (>15 years) with both epilepsy and migraine had poorer seizure control than people with epilepsy but without migraine. The nature of the association of migraine and epilepsy is complex but suggests that a common pathophysiological mechanism may be present.

A diverse group of medications is used to prevent migraine attacks including antiepileptics, antidepressants, antihistamines, and antihypertensive agents, in addition to newer classes of medications; yet, there remains a dearth of controlled studies in children [249]. There have also been no formal, prospective trials designed to treat migraine in children with epilepsy. Indeed, for pediatric migraine in children without epilepsy, clinical practice guidelines for migraine treatment are consensus based rather than evidence based with no USFDA–approved migraine prevention medication for children younger than 12 years of age [250]. In a randomized, double-blind, placebo-controlled trial of amitriptyline, topiramate and placebo in 361 children and adolescents 8 to 17 years of age with migraine, there were no significant differences in reduction in headache frequency or headache-related disability in childhood and adolescent migraine with amitriptyline, topiramate, or placebo over a period of 24 weeks and a higher rate of adverse events in the patients receiving active drug [250].

Two AEDs, topiramate and valproate, are approved for migraine prevention in children (≥ 12 yrs) and adults by the USFDA [251, 252]. Topiramate is the most widely used migraine preventative agent and is approved for children [243, 253, 254]. Valproate is also widely used and is effective in adolescent and adult patients with migraine [254]. Efficacy of topiramate and valproate in children with epilepsy and migraine is not known.

Available evidence does not allow robust conclusions regarding the efficacy of AEDs other than topiramate and valproate in migraine [255]. In a Cochran review the pooled evidence derived from trials of gabapentin suggests that it is not efficacious for the prophylaxis of episodic migraine in adults and is associated with significant side effects [255]. There is no published evidence from controlled trials of pregabalin for the prophylaxis of episodic migraine in adults [255]. Acetazolamide, carbamazepine, clonazepam, lamotrigine, oxcarbazepine, and vigabatrin were not found to be more effective than placebo in reducing headache frequency [256]. In small trials, carbamazepine and levetiracetam were better than placebo in reducing headache [256].

For the acute therapy of migraines in children with epilepsy, ibuprofen, prochlorperazine, and certain triptan medications are the most effective and safe agents for acute management of migraine and other benign headache disorders in the pediatric population [257, 258]. These drugs are not contraindicated in children with epilepsy. Of note, sumatriptan has been effectively used in post-ictal migraine headaches [259].

In summary, children with epilepsy have a higher than expected increase in migraine, which can adversely affect quality of life and potentially contribute to seizure severity. In the child with both migraine and epilepsy, consideration may be given to using an AED which has proven to be efficacious for migraine in children (>12 years) and adults, namely, topiramate and valproate. However, there is limited data indicating that topiramate, valproate or any other drugs are effective in preventing migraine in children with epilepsy. Abortive therapy used for migraines in children without epilepsy can be used safely in children with epilepsy.

6. Conclusions

Comorbidities in children with epilepsy are common and can greatly add to the disease burden of the condition. Recognizing that certain AEDs can cause or exacerbate the comorbidities can lead to a better therapeutic plan for the child. When the comorbid condition can be treated with an AED this should be considered. Most drugs used to treat depression, anxiety, ADHD and migraine in children without epilepsy can be used safely in children with epilepsy. While there are a paucity of studies providing clear data on efficacy of drugs to treat the comorbidities of childhood epilepsy, there is no evidence that drugs used to treat comorbidities in children without epilepsy are any less effective in children with epilepsy.

KEY POINTS.

• Children with epilepsy have a high prevalence of comorbid conditions.

• For most comorbid conditions epilepsy is not causative but has a bidirectional association with the comorbidity.

• Most psychotropic medications are not contraindicated in children with epilepsy.

• Drug treatment of comorbid conditions in children with epilepsy is similar to treatment of children without comorbidities.

• Efficacy information on treatment of comorbid conditions in childhood epilepsy is based on limited data.