Seizures and epilepsy are common manifestations of disturbed cerebral function; thus, they may be symptoms of other diseases that involve the brain and not of epilepsy sui generis. This association has long been recognized in the case of brain tumors and tuberous sclerosis, for example, but the modern era of brain imaging and molecular diagnosis has greatly expanded our recognition of specific disease entities in which epilepsy is a major feature. This section reviews major categories of disease that present with seizures or in which epilepsy constitutes a significant aspect of the illness. Certain presentations or evolution should always raise the question of a specific underlying disorder.

The diagnosis of infantile spasms (West syndrome; Chapter 229) or Lennox-Gastaut syndrome (Chapter 241) should always lead to a search for a specific cause. Both syndromes can occur as either idiopathic or symptomatic conditions, and therein lies one of the disadvantages of the current classification. Both are electroclinical syndromes and therefore etiologically heterogeneous. Neither is a singular pathologic entity, and cerebral malformations, perinatal asphyxia, anoxic encephalopathy from cardiopulmonary arrest, central nervous infection, postimmunization encephalopathy, and progressive degenerative or metabolic syndromes have all been implicated in individual children. Tuberous sclerosis is the most common disease entity causing infantile spasms,⁷ but untreated phenylketonuria, nonketotic hyperglycinemia, and other metabolic and structural disorders are also encountered occasionally.⁴ A small subgroup of children with spasms but no identifiable causes have normal developmental outcome and may represent an idiopathic condition.³ Similar disorders are found in children with Lennox-Gastaut syndrome (Chapter 241),^1,8 and of course infantile spasms and Lennox-Gastaut syndrome are not fully independent entities: The 6-year-old child designated as having Lennox-Gastaut syndrome may well have carried a diagnosis of West syndrome as an infant. Indeed, with computed tomographic (CT) and magnetic resonance (MR) brain imaging and the availability of sophisticated and highly specific biochemical and genetic tests, the percentage of cryptogenic cases has steadily declined.

Persistent seizures despite appropriate therapy are often an indication to consider medical illnesses or treatments that can contribute to or cause recurrent seizures, such as systemic lupus erythematosus, hypoglycemia, drug abuse, and theophylline toxicity (Chapters 127, 191, and 192). The use of molecular techniques to establish linkage or a gene defect has clearly demonstrated that variability in phenotype is common and that syndromic fidelity, defined traditionally by seizure semiology and electroencephalographic (EEG) features, is not invariable. Thus, older children and even adults with seemingly stable (or only very slowly progressive) neurologic abnormalities are now found to have progressive metabolic or degenerative encephalopathies due to adrenoleukodystrophy, ceroid lipofuscinosis, storage diseases such as Tay-Sachs or sialidosis, various aminoacidurias and urea cycle disorders, or one of the progressive myoclonus epilepsies. Other genetic disorders (also referred to as chromosomal abnormalities), including trisomy 13 and 21, fragile X syndrome, and Aicardi syndrome, as well as cortical malformations such as lissencephaly (e.g., Miller-Dieker syndrome) and Angelman (“happy puppet”) syndrome, may present with seizures that prove to be drug resistant (Chapter 261). Associated physical abnormalities often provide clues to the diagnosis in most of these conditions.