Epilepsy in children: Comorbidities, complications, and outcomes

INTRODUCTION — The impact of epilepsy on the child is determined by many factors other than recurrent seizures. This topic provides an overview of the comorbidities, complications, and outcomes of epilepsy in children.

Other aspects of seizures and epilepsy in children are presented elsewhere:

Seizures and epilepsy in children: Classification, etiology, and clinical features
Seizures and epilepsy in children: Clinical and laboratory diagnosis
Seizures and epilepsy in children: Initial treatment and monitoring
Seizures and epilepsy in children: Refractory seizures
Epilepsy syndromes in children

PSYCHIATRIC AND BEHAVIORAL HEALTH — Children with epilepsy are at increased risk for psychologic, behavioral, cognitive, neurologic, academic, and social problems caused by their chronic neurologic condition, which may have a significant impact on quality of life independent of the seizures [1-8]. Frequent subclinical or subtle seizures may also have a direct impact [9].

Depression and suicidality — There is a high burden of mood disorders in children with epilepsy [10-12].

●Prevalence – In population-based studies, depression and anxiety are more prevalent in children with epilepsy compared with the general population. A 2011 systematic review of evidence from population-based studies suggested that the prevalence of depression in children with epilepsy was 12 to 14 percent [13].

●Risk associated with antiseizure medications – Increased suicidality has been linked to several antiseizure medications in randomized placebo-controlled studies of patients with epilepsy over five years of age [14]. The elevated risk (0.43 versus 0.22 percent) was observed as early as one week after starting medication and continued though the 24 weeks of study observation. The effect was consistent in the 11 antiseizure medications studied, and the US Food and Drug Administration (FDA) considered this risk likely to be shared by all antiseizure medications. However, the actual suicidal risk is thought to be very low [15]. By contrast, the risk of stopping or avoiding treatment with antiseizure medications is much worse and can lead to serious harm and even death.

●Screening – Patients taking antiseizure medications should be regularly monitored for emergence or worsening of suicidal ideation or depression [11].

●Treatment – An overview of the treatment of depression and the approach to the assessment of suicidality in children are discussed in separate topic reviews. (See "Suicidal ideation and behavior in children and adolescents: Evaluation and management" and "Overview of prevention and treatment for pediatric depression".)

Attention deficit hyperactivity disorder — Recognition of attention deficit hyperactivity disorder (ADHD) in children with epilepsy is important because effective treatments exist, and ADHD has been associated with decreased health-related quality of life in children with epilepsy [16].

●Prevalence – In our experience, and that of others, ADHD is one of the most common psychiatric comorbidities in children with epilepsy, with a reported prevalence ranging from 12 percent in a general population-based survey to as high as 60 percent in patients with severe epilepsy treated at tertiary care epilepsy clinics [16-18]. Children with ADHD and epilepsy are more likely than those without epilepsy to manifest the predominantly inattentive subtype of ADHD, rather than the hyperactive-impulsive subtype [16,19]. (See "Attention deficit hyperactivity disorder in children and adolescents: Clinical features and diagnosis", section on 'Diagnostic criteria'.)

●Screening – We recommend that all children with epilepsy undergo standardized psychoeducational testing through their school or in the clinic. The International League Against Epilepsy (ILAE) endorses annual screening for ADHD beginning at six years of age or at the time of epilepsy diagnosis, with re-evaluation after a change of antiseizure medication [20].

●Treatment – Once a diagnosis of ADHD is made, behavioral therapies are offered as first-line intervention. If academic problems persist, then therapy with stimulant medication is offered to all but the most unstable patients. Caregivers and classroom teachers are advised to monitor the child's seizure burden carefully when the stimulant medication is first introduced. In our experience, it is rare to see a significant deterioration in seizure control.

Stimulants have not been well studied in patients with epilepsy because of concern that they may lower the seizure threshold, and patients with epilepsy were excluded from clinical trials establishing the safety and efficacy of stimulant medications. Although one dose-escalation study of sustained-release methylphenidate in children with epilepsy found a slight increase in seizure frequency at high doses [21], other data, including several prospective studies, suggest that low to medium doses of methylphenidate are safe and effective, even in children with active seizures [22-30].

The treatment of children and adolescents with ADHD is discussed in detail separately. (See "Attention deficit hyperactivity disorder in children and adolescents: Overview of treatment and prognosis".)

COGNITIVE IMPAIRMENT — Epilepsy is often accompanied by cognitive and developmental delay, including autism and language deficits [31-36].

●Prevalence and risk factors – One study compared 282 children with normal intelligence quotient (IQ) and a first recognized seizure with 147 healthy siblings and found that children with seizures scored lower on all neuropsychologic tests; 27 percent had a neuropsychologic deficit [31]. Risk factors for neuropsychologic impairment included a symptomatic/cryptogenic etiology, a second unprovoked seizure, use of antiseizure medications, and epileptiform activity on the initial electroencephalogram (EEG). Another study of population-based data found that academic underachievement, defined as performance one standard deviation below that predicted by assessed IQ, was present in 42 percent of children with active epilepsy [37]. Underachievement was attributed in part to reduced school attendance, specific cognitive deficits, younger age at onset of first seizure, and effects of antiseizure medications.

●Screening – When developmental delay, intellectual impairment, and/or poor performance in school is overt, the child should be referred for appropriate evaluation. (See "Intellectual disability (ID) in children: Clinical features, evaluation, and diagnosis" and "Intellectual disability in children: Evaluation for a cause".)

●Management – The approach to cognitive impairment and intellectual disability in children with epilepsy should be individualized and multidisciplinary. Optimal control of seizures is crucial. Depending upon the individual's needs, other interventions may include speech and language therapy, occupational therapy, physical therapy and rehabilitation, feeding therapy, vision and hearing services, family counseling and support, behavioral interventions, interventions to improve social participation, educational assistance, community integration, independent functioning and life skills learning, advocacy, and other aids. (See "Intellectual disability (ID) in children: Management, outcomes, and prevention".)

●Cognitive outcomes – Cognitive deficits are not limited to children with uncontrolled or symptomatic epilepsy. Neuropsychologic testing in children with new-onset focal and generalized epilepsy syndromes has demonstrated a range of cognitive abnormalities that tend to persist even with successful control of seizures [38,39]. In a prospective study of 69 children with new-onset focal or generalized epilepsy and normal imaging and neurologic examinations, abnormalities in arithmetic, psychomotor speed, attention, response inhibition, and fine motor dexterity were present at baseline and persisted, relatively unchanged, over a follow-up period of five to six years [40]. Children with generalized epilepsy tended to perform worse than those with focal epilepsy. More specific patterns of deficits have been described in association with some of the more common syndromes, including childhood absence and juvenile myoclonic epilepsy. (See "Childhood absence epilepsy", section on 'Behavioral and psychiatric comorbidities' and "Juvenile myoclonic epilepsy", section on 'Cognition and behavior'.)

Children with intractable seizures may manifest a decline of cognitive function and memory with no attributable etiology other than the frequent seizures [1]. Data, particularly from animal research and human surgical specimens, increasingly indicate that the pervasive excitatory synaptic activity accompanying seizures, and probably interictal epileptiform discharges as well, lead to neuronal injury, abnormal neuronal sprouting, and interference with the normal pruning and complex rearrangement of neuronal connectivity that characterizes the developing nervous system [41]. Observational studies in children with epilepsy also suggest that poorly controlled seizures have a deleterious impact on cognition, particularly when they occur at a young age [42-46]. (See "Seizures and epilepsy in children: Refractory seizures".)

SLEEP DISTURBANCES — Sleep disturbances are more common in children with epilepsy, compared with children without epilepsy, even among those without nocturnal seizures or sleep-related epilepsy syndromes [47-49]. Some authors describe a vicious cycle of interactions between epilepsy, antiseizure medications, and sleep, with multiple factors leading to sleep fragmentation, increased seizure frequency, and lowered seizure threshold [50]. Certain antiseizure medications can have a detrimental effect on sleep, including phenobarbital, phenytoin, carbamazepine, and valproate [51,52]. In turn, sleep disturbances can result in excessive daytime sleepiness, poor learning, behavioral disturbance, and reduced quality of life [50].

Sleep-related epilepsy syndromes are characterized by seizures that occur exclusively or predominantly during sleep or in the period shortly after arousal from sleep. Across the lifespan, these syndromes account for approximately 10 to 15 percent of all epilepsy syndromes. The clinical features, diagnosis, and treatment of common sleep-related epilepsy syndromes discussed in detail separately. (See "Sleep-related epilepsy syndromes".)

Patients with epilepsy may be sensitive to seizure precipitation by sleep deprivation, and children and their families should be instructed to adhere to good sleep hygiene and to obtain adequate amounts of sleep on a consistent basis. Children with suspected sleep disorders may benefit from an overnight sleep study (polysomnography) and referral to a sleep specialist. (See "Assessment of sleep disorders in children" and "Overview of polysomnography in infants and children".)

BONE HEALTH — Screening for vitamin D deficiency and supplementation with calcium and vitamin D are low-risk interventions that are suggested for children and adults on long-term antiseizure medication therapy. (See "Antiseizure medications and bone disease", section on 'Calcium and vitamin D'.)

Both epilepsy and antiseizure medications are associated with adverse effects on bone health. Children with epilepsy who are treated with antiseizure medications are at increased risk for reduced bone density, impaired bone growth, and vitamin D deficiency [53]. Both enzyme-inducing and nonenzyme-inducing antiseizure medications as well as the ketogenic diet have been implicated in the risk of bone disease. However, few studies have rigorously evaluated strategies for prevention and treatment of bone disease in patients with epilepsy. (See "Antiseizure medications and bone disease" and "Ketogenic dietary therapies for the treatment of epilepsy", section on 'Adverse effects'.)

ACTIVITY RESTRICTIONS — Children with epilepsy may face questions about participating in athletics or other physical activities, and adolescents may encounter issues related to driving.

●Sports – In school-aged children with epilepsy, clinicians may be asked to provide medical clearance before a child can participate in certain sports or other physical activities. These decisions should be individualized, weighing not only the potential risks of participation but also the benefits of physical exercise and social engagement [54]. Factors to consider include the type of sport, the probability of a seizure occurring during the activity and related implications, the amount of supervision available during the activity, the patient's seizure type and severity, the consistency of any prodromal symptoms, relevant seizure precipitants, a history of seizure-related accidents or injuries, recent seizure control, degree of adherence to therapy, and the willingness of the patient and parents to take on risk. The International League Against Epilepsy (ILAE) has published a consensus-based guideline on this topic, which divides sports into three risk categories and proposes a decision-making framework for each risk category [54].

●Driving – States vary widely in driver licensing requirements for patients with epilepsy as well as the responsibilities of clinicians to notify state authorities [55]. This topic is discussed in more detail elsewhere. (See "Driving restrictions for patients with seizures and epilepsy".)

QUALITY OF LIFE — The psychologic stresses associated with epilepsy can be the major problem confronting the child or family. Health-related quality of life (HRQOL) can be affected even after a single seizure, but overall, deficits in HRQOL in children with epilepsy are related to seizure frequency and severity, as well as socioeconomic status [56-59]. The child may have difficulty at school because of peer ridicule, a poor academic performance as a result of limited cognitive function, low self-esteem, and/or depression.

OUTCOMES

Freedom from seizures — The long-term prognosis for seizure cessation tends to be better in children than adults, particularly those who are neurologically intact [60]. In one community-based cohort, complete seizure remission occurred in one-half of children with nonsyndromic epilepsy [61]. Early seizure control, younger age of onset, and an absence of underlying brain disorder were associated with favorable outcomes.

In one study, 594 of 613 children with newly diagnosed epilepsy were followed for at least two years [62]. Seizure remission occurred in 74 percent; of these, 24 percent subsequently relapsed. Children with idiopathic generalized epilepsy and age of onset between five and nine years were more likely to have remission. Those with a remote symptomatic etiology, family history of epilepsy, frequent seizures, and slowing on the initial electroencephalography (EEG) were less likely to have remission. Approximately one-half of relapses occurred in children who had stopped or were tapering medication, while one-fourth occurred while on medication.

A smaller study followed 144 patients with epilepsy with onset before 16 years [63]. After 37 years follow-up, remission occurred in 67 percent, 86 percent of whom were off medication. Of the one-third of patients who did not achieve remission, 19 percent were drug-resistant (medically intractable), while 14 percent had experienced five-year remissions. A symptomatic origin was associated with failure to achieve remission and with medical intractability. Low intelligence quotient (IQ) was also a risk factor for intractability.

Injuries — Children with epilepsy are at increased risk for nonfatal injuries. In a population-based cohort study of over 11,000 children and young adults with epilepsy and over 45,000 controls, those with epilepsy were at increased risk for long bone fracture (hazard ratio [HR] 1.23, 95% CI 1.10-1.38), thermal injury (HR 1.49, 95% CI 1.27-1.75), and poisoning from medicinal products (HR 2.54, 95% CI 2.16-2.99) [64]. Other studies have reported similar results with respect to childhood fractures [65-67]. Proposed mechanisms for the increased risk of injuries include seizures themselves, adverse effects of anticonvulsants (eg, metabolic bone disease), inadvertent overdose, and increased access to medications in the home more generally. (See "Antiseizure medications and bone disease" and "Prevention of poisoning in children", section on 'Prevention'.)

Mortality — Children with epilepsy are at increased risk for premature death compared with children without epilepsy as well as adults with epilepsy [68-71]. The increased risk of death is highest in children with symptomatic epilepsy and is much lower in patients with idiopathic epilepsy [72,73]. Important causes of death directly attributable to epilepsy include convulsive status epilepticus, injuries, and sudden unexpected death in epilepsy (SUDEP). (See "Sudden unexpected death in epilepsy".)

In a population-based study that included over 13,000 children with epilepsy from 2000 through 2011, the overall mortality rate was 8.8 deaths per 1000 person-years [69]. The annual risk for death was nearly fourfold higher among children with epilepsy compared with age-matched children without epilepsy (0.84 versus 0.22 percent). Comorbid developmental conditions (eg, congenital malformations, chromosomal abnormalities, intellectual disability, cerebral palsy), cardiovascular disorders, and injuries accounted for 18, 13, and 11 percent of deaths, respectively. Eight percent of deaths were attributed to seizure or status epilepticus and 7 percent to malignant neoplasms. The contribution of sudden unexpected death could not be estimated.

In another prospective cohort study with a mean follow-up of 40 years, 60 of 245 patients with epilepsy died, a rate threefold higher than expected in the general population [68]. The risk of death was especially high among children who were not in remission. Thirty percent of deaths were classified as SUDEP. Other causes of death included seizure and accidental drowning. (See "Sudden unexpected death in epilepsy".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Seizures and epilepsy in children".)

SUMMARY AND RECOMMENDATIONS

●Children with epilepsy may have psychologic, behavioral, cognitive, neurologic, academic, and social problems caused by their seizures or by their chronic neurologic condition, independent of the seizures. (See 'Psychiatric and behavioral health' above.)

●Depression and anxiety are more prevalent in children with epilepsy compared with the general population. Patients taking antiseizure medications should be regularly monitored for emergence or worsening of suicidal ideation or depression. (See 'Depression and suicidality' above.)

●Recognition of attention deficit hyperactivity disorder (ADHD) in children with epilepsy is important because effective treatments exist, and ADHD has been associated with decreased health-related quality of life in children with epilepsy. (See 'Attention deficit hyperactivity disorder' above.)

●Epilepsy is often accompanied by cognitive and developmental delay. When developmental delay, intellectual impairment, and/or poor school performance is overt, the child should be referred for appropriate evaluation. (See 'Cognitive impairment' above.)

●Sleep disturbances are more common in children with epilepsy, compared with children without epilepsy, even among those without nocturnal seizures or sleep-related epilepsy syndromes. Some antiseizure medications can have a detrimental effect on sleep. (See 'Sleep disturbances' above.)

●Both epilepsy and antiseizure medications are associated with adverse effects on bone health. Supplementation with calcium and vitamin D are low-risk interventions that are suggested for children and adults on long-term antiseizure medication therapy. (See 'Bone health' above.)

●The long-term prognosis for seizure cessation tends to be better in children than adults, particularly those who are neurologically intact. Early seizure control, younger age of onset, and an absence of underlying brain disorder have been associated with favorable outcomes. (See 'Freedom from seizures' above.)

●Children with epilepsy are at increased risk for nonfatal injuries. In addition, mortality is increased in children with epilepsy compared with those without. Important causes of death directly attributable to epilepsy include convulsive status epilepticus, injuries, and sudden unexpected death in epilepsy (SUDEP). (See 'Injuries' above and 'Mortality' above.)