Journal of Child Neurology

Diagnosis and management of pediatric epilepsy are challenging for a variety of reasons; however, one of the most common yet difficult situations involves treatment of the patient with pediatric epilepsy with coexistent cognitive impairment or psychiatric disturbance. The etiologies and presentations of these comorbidities are myriad, making diagnosis problematic ; furthermore, interactions between epilepsy and its treatments and the neuropsychiatric problem and its treatments add another layer of complexity to the management of these patients. Antiepileptic drugs are often blamed for cognitive or behavioral problems in children treated for epilepsy, but the actual contribution to such problems in a particular child can be difficult to ascertain. (J Child Neurol 2004;19(Suppl 1):S1-S5).

Antiepileptic drugs exert their anticonvulsant effects by interfering with brain processes that involve structures that are also involved in learning, memory, and emotional behavior. Thus, modulation of ion channels, neurotransmitters, second messengers, and other processes by antiepileptic drugs, although helpful in controlling seizures, can interfere with normal brain function in undesired ways. The specific mechanism(s) of action of an antiepileptic drug can increase the risk for particular types of adverse events. In this review, we examine the cognitive and behavioral effects of antiepileptic drugs in animal models. Although animal studies, in many respects, do not mimic clinical experience, the data suggest a connection between certain mechanisms of antiepileptic action and the occurrence of cognitive adverse effects. Specifically, antiepileptic drugs with traditional γ-aminobutyric acid (GABA)ergic mechanisms have the most detrimental effects on cognitive function, possibly because they impair attention. Conversely, drugs with the predominant effects at Na + channels appear to have minimal impact on cognition. Levetiracetam, with its nonconventional GABAergic and Ca2+ channel effects, has shown positive cognitive effects in animal studies. Antiglutamatergic drugs have the potential to be a double-edged sword: they can interfere with consolidation of learning and memory but can also provide neuroprotection in addition to their antiseizure effects. (J Child Neurol 2004;19(Suppl 1):S6-S14).

The majority of children with epilepsy are of normal intelligence; however, a significant subset suffers from temporary or permanent cognitive impairment. Factors that affect cognitive function are myriad and include the neuropathology underlying the epilepsy, seizures, epileptiform activity, psychosocial problems, and antiepileptic drug side effects. Although cognitive impairment is often wrongly attributed to the effects of antiepileptic drugs, antiepileptic drugs do impair cognition in some children. Clinicians should be aware of the differential cognitive effects of antiepileptic drugs and should monitor cognitive function closely when adding or changing therapy. Based on published data from prospective, chronic dosing studies, phenobarbital and topiramate have the highest potential for causing cognitive dysfunction. (J Child Neurol 2004;19(Suppl 1):S15-S24).

Multiple factors—including the efficacy of the antiepileptic drug for the particular seizure type, availability of pediatrics-friendly formulations, the ease of dosing and titration, and tolerability issues, such as possible drug interactions and adverse events—affect the selection of the best antiepileptic drug for a child with epilepsy. Behavioral problems are common in children with epilepsy and can be aggravated or initiated by antiepileptic drug therapy. The types and frequencies of antiepileptic drug-associated behavioral events can influence a clinician's drug selection, drug management, and counseling of parents. Unfortunately, appreciating differences among antiepileptic drugs in behavioral adverse event profiles is problematic because, among other reasons, methodologies for reporting, collecting, and analyzing adverse events are not uniform across trials, and there is marked heterogeneity in study design among trials. This review summarizes incidence rates for behavioral and psychiatric adverse events taken from studies of children with epilepsy. These rates are reported for the 10 most commonly prescribed antiepileptic drugs (valproic acid, carbamazepine, phenobarbital, lamotrigine, phenytoin, levetiracetam, oxcarbazepine, topiramate, zonisamide, and gabapentin), grouped according to their predominant mechanism of action. Despite the numerous methodologic inconsistencies, some similarities in adverse event profiles among antiepileptic drugs that share mechanisms of action are apparent. Moreover, the overwhelming body of data on the behavioral effects of phenobarbital should convince clinicians that, whenever possible, it should not be used as the initial—or even the second—monotherapy in children with epilepsy. (J Child Neurol 2004;19(Suppl 1):S25-S38).

Antiepileptic drugs are often used for the treatment of both epilepsy and a wide range of behavioral and psychiatric disorders. The treatment of patients with epilepsy has been the proving ground for antiepileptic drugs, not only with respect to their efficacy in the treatment of seizures but also for clarifying their dose-related and idiosyncratic adverse events. This information has been useful in treating patients with behavioral and psychiatric disorders. Indeed, the number of prescriptions written for many antiepileptic drugs for nonepileptic uses far exceeds those written for the same drugs for epilepsy. Because patients with chronic epilepsy have a higher incidence of axis I psychiatric disorders, physicians can choose an antiepileptic drug to treat both the epilepsy and psychiatric comorbidity in selected patients. Guided by the principles of evidence-based medicine as outlined by the American Academy of Neurology and the American Academy of Pediatrics, this article reviews the application of antiepileptic drugs for epilepsy and behavioral and psychiatric disorders in children. (J Child Neurol 2004;19(Suppl 1):S39-S48).

Clinical and subclinical seizures occur frequently among children with autistic spectrum disorders. Electrographic status epilepticus in sleep, or continuous spike-wave in slow-wave sleep, is a typical feature of acquired epileptic aphasia and Landau-Kleffner syndrome. Seizures and epilepsy are more common among children with autistic spectrum disorder who experience language regression, especially those who experience language regression after the age of 2 years. Although the seizures associated with Landau-Kleffner syndrome and with acquired epileptic aphasia can be easily treated, improvement in language function often does not follow successful treatment of seizures. There are no published randomized clinical trials of treatments for Landau-Kleffner syndrome or for autistic language regression. Broad-spectrum antiepileptic drugs not associated with cognitive slowing are probably the treatment of choice for epilepsy among children with autistic spectrum disorder. Large multisite trials are needed to determine treatment efficacy among children with Landau-Kleffner syndrome and acquired epileptic aphasia and to establish whether there is a cause-effect relationship between electrographic status epilepticus in sleep or continuous spike-wave in slow-wave sleep and autistic language regression. (J Child Neurol 2004;19(Suppl 1):S49-S57).

Clusters of seizures, prolonged seizures, and status epilepticus occur more frequently in children with multiple disabilities, and chronic seizures are more likely to be refractory to treatment. In many patients, the seizures appear to contribute to the mental retardation. Thus, if the lives of these children are to improve, seizure control is essential. However, medical treatment can interfere with cognition and cause behavioral disturbances, making life very difficult for the child and the child's family. With the introduction of 10 new antiepileptic drugs in the last decade, the treatment of epilepsy in multiply handicapped children has significantly advanced. These new antiepileptic drugs may improve seizure control, medication tolerance, or both. Although the ultimate therapeutic goal is to keep children seizure free and alert, compromises regarding medication choice and dosage are still necessary in many cases. Novel treatment options, such as the vagus nerve stimulator, may decrease seizure frequency without behavioral or cognitive side effects. In carefully selected children with specific epilepsy syndromes, epilepsy surgery can provide partial or complete relief from seizures. (J Child Neurol 2004;19(Suppl 1):S58-S64).

The neurologic dysfunction underlying epilepsy can predispose patients to psychiatric disorders, and the incidence of both depression and psychosis is increased in people with epilepsy. Depressive disorders are the most frequently recognized psychiatric comorbidities in people with epilepsy, but depression in children can be particularly difficult to recognize. Clinicians need to inquire about not only classic symptoms of depression such as anhedonia but also less obvious symptoms such as unprovoked irritability, unsubstantiated complaints of lack of love from family members, somatic complaints, and problems with concentration and poor school performance. The diagnosis of depressive disorders in children with epilepsy and mental retardation is even more difficult. Physicians need to be alert for the presence of iatrogenic depression, which may result from antiepileptic drugs or epilepsy surgery. People with epilepsy are also at increased risk for psychosis, which can be interictal, postictal, or (rarely) an expression of ictal activity. This psychosis can be related to seizure remission (ie, alternative psychosis) or iatrogenic (eg, related to antiepileptic drugs or following temporal lobectomy). Although both antidepressants and antipsychotic drugs have the potential to lower the seizure threshold and increase seizures, careful drug selection, dosing, and slow titration can minimize this risk, allowing treatment to proceed. (J Child Neurol 2004;19(Suppl 1):S65-S72).