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.

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.

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.

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.