The electrical discharge of neurons associated with seizure activity stimulates a marked rise in cerebral metabolic activity. Estimates from animal experiments indicate that energy utilization during seizures increases by more than 200", while tissue adenosine triphosphate (ATP) levels remain at more than 95" of control, even during prolonged status epilepticus. The brain generally withstands the metabolic challenge of seizures quite well because enhanced cerebral blood flow delivers additional oxygen and glucose. Mild to moderate degrees of hypoxemia that commonly accompany seizures are usually harmless. However, severe seizures and status epilepticus can sometimes produce an imbalance between metabolic demands and cerebral perfusion, especially if severe hypotension or hypoglycemia is present. A marked increase in glutamate release, which occurs during a prolonged seizure, is likely to result in the activation of all types of glutamate receptors. Although kainic acid produces seizures in the immature brain, it produces little cytotoxicity.

Many children who have had a previous seizure have a normal electroencephalogram (EEG) in the interictal period, or they may only have nonspecific abnormalities. The child should be evaluated for signs of elevated intracranial pressure and signs of meningeal irritation. Any infant or young child with poorly controlled seizures should also be tested for pyridoxine dependency using a trial of pyridoxine supplementation. Nonepileptic neurologic disorders can produce recurrent, paroxysmal changes of movement, consciousness, or behavior that are similar to those exhibited by a child with epilepsy. No formal guideline exists for diagnosing psychogenic nonepileptic seizures in children. Psychogenic nonepileptic seizures (PNES) can sometimes be elicited by suggestion, usually by giving the patient a saline infusion, but this may raise an ethical dilemma because some patients are extremely suggestible and may have both epileptic and nonepileptic events.

Panayiotopoulos syndrome is considered a self-limited epilepsy syndrome. It occurs in children who are otherwise normal. Two-thirds of seizures occur during sleep, including daytime naps. Tachycardia is certainly a feature of seizures recorded on electroencephalogram (EEG) with simultaneous electrocardiographic (ECG) recording. Cardiorespiratory arrest requiring resuscitation has been reported during typical seizures of Panayiotopoulos syndrome, and other children with a diagnosis of Panayiotopoulos syndrome are also suspected to have had cardiorespiratory arrest. Behavioral changes may be associated with an increased seizure burden in Panayiotopoulos syndrome. Some seizures in Panayiotopoulos syndrome include features suggestive of syncope, with the child becoming pale, flaccid, and unresponsive. A consensus statement concluded that regular prophylactic antiepileptic drugs (AED) was probably best reserved for children whose seizures were unusually frequent, distressing, or otherwise significantly interfering with the child’s life. There is an urgent need for high-quality studies exploring the most appropriate treatment for Panayiotopoulos syndrome.

The search for mutated genes in several hereditary forms of epilepsy affecting infants and children has resulted in the identification of epileptic channelopathies (i.e., epilepsies resulting from mutations in ion channel genes). It is intuitively obvious to most readers that changes in ion channel proteins would lead to altered neuronal excitability. This chapter evaluates how even genes that do not directly code for ion channels may participate in modifying cellular and network excitability as well as participate in processes that adversely influence neurodevelopment. It explores how distinct mutations in the same gene may yield different syndromic phenotypes while mutations in many distinct genes may result in a similar syndrome. The chapter also explains the aspects of age-selective presentation or resolution of certain epilepsy syndromes, as well as the coexistence of epilepsy and neurodevelopmental disorders.

This chapter provides an overview of antiepileptic drug (AED) development from a historic perspective to discern major patterns in our thinking about epilepsy, which is in reality a collection of disorders that share seizures as a common symptom. It traces the evolution of our approach rather than duplicate readily available references such as the reports on the biennial Eilat conferences on AEDs under development, which contain details of the extent to which human clinical trials have progressed. The chapter also traces the evolution of pharmacologic treatment of epilepsies from the application of rational therapy based on irrational beliefs, libido and hysteria, to the serendipitous discovery of phenobarbital. Improvements from this point on leveraged the synthetic prowess of medicinal chemistry and systematic screens using animal models. The diversity of animal models has increased, and molecular tinkering by medicinal chemists continues to yield important new compounds.

Lacosamide may be a useful adjunct in children with seizures refractory to traditional antiepileptic drugs (AEDs). Lacosamide was approved by the U.S. Food and Drug Administration (FDA) in 2008 and is currently indicated for use as monotherapy or adjunctive therapy in patients 17 years of age and older with focal onset seizures. The antiseizure effect of lacosamide was first demonstrated in screening tests, including the maximal electroshock (MES) test in mice. The pharmacokinetic profile of lacosamide has been evaluated in several studies of adults, including those with renal and hepatic impairment. Despite the positive response in some patients with Lennox-Gastaut syndrome (LGS), the role of lacosamide in treating children and young adults with this syndrome remains unclear. Lacosamide has also been used in the management of refractory status epilepticus. In pooled data from placebo-controlled clinical trials in adults, the most reported adverse reactions were dizziness, headache, diplopia, and nausea.

Rufinamide is a valuable anticonvulsant medication treatment option in medication-refractory pediatric epilepsy, substantiated by efficacy and safety data from both clinical trials and clinical practice. It was the first time that a new anticonvulsant medication was approved for use in the United States with an initial pediatric indication when rufinamide received its approval from the U.S. Food and Drug Administration (FDA) in November 2008. Rufinamide is well absorbed with oral administration, and this absorption is enhanced when taken with food. The approval of rufinamide by the FDA was advanced by pivotal trials focusing on refractory seizures in patients with Lennox-Gastaut syndrome (LGS). Several large randomized placebo-controlled trials have been published evaluating rufinamide as an adjunctive treatment in older adolescents and adults for partial-onset seizures, demonstrating significant differences in favor of rufinamide versus placebo in responder rates and with a significant linear trend of dose response.

In years past, when the choice of antiepileptic medication was limited to phenobarbital and phenytoin, while there were concerns about adverse effects, side effects were accepted as a ‘necessary evil’ in the management of epilepsy. In the early 1970s the availability of carbamazepine as an alternative to phenytoin for focal seizures generated interest in the cognitive side effects of medications; specifically, whether carbamazepine had a preferable side effect profile to phenytoin and phenobarbital. An important confounding factor in assessing the cognitive effects of antiepileptic drug (AED) is the epilepsy itself. Epilepsy can result in cognitive problems by virtue of the intrinsic neuropathology underlying the epilepsy. Neuropsychologic assessment typically encompasses several different cognitive and behavioral domains. On multivariate analysis, there were more intolerable cognitive side effects associated with topiramate than with most other AEDs, including carbamazepine, gabapentin, levetiracetam, lamotrigine, oxcarbazepine, and valproate.