Epilepsy: A Comprehensive Textbook
2nd Edition

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.

Seizures are a common manifestation of the mitochondrial encephalopathies, although the frequency is highly variable among the different mitochondrial syndromes. Specific gene defects in many of these disorders have been identified, and they include both mitochondrial and nuclear mutations. In some cases, the type of mutation is quite different in patients that commonly present with seizures than in those in which epilepsy is rare. Thus, seizures are the rule in MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) and MERRF (myoclonus epilepsy with ragged red fibers), which are almost always associated with point mutations in the tRNA^Lys gene.¹⁰ However, seizures are rare in Kearns-Sayres syndrome, which is related to large deletions or duplications of mtDNA. Hirano and colleagues (Chapter 262) believe that the spatial distribution within the brain of the mitochondrial mutation underlies the association of particular mutations with epilepsy.

Seizures occur in the majority of children with Rett syndrome,⁶ and these can sometimes be intractable. Some of these patients also have syncopal episodes that are occasionally misdiagnosed as epilepsy, and the characteristic stereotypic movements (e.g., hand-wringing) also may be erroneously considered to reflect seizure activity.

Except for major malformations such as anencephaly, holoprosencephaly, and schizencephaly, abnormalities of cortical development were largely unrecognized as a common cause of epilepsy until high-resolution MR brain imaging became widely available and part of the routine diagnostic evaluation
of patients with seizures. Cortical developmental malformations are now known to be common, especially as a cause of intractable epilepsy. They are found in up to 20% of adults² and >50% of children referred to epilepsy centers because of drug-resistant seizures or as possible surgical candidates.⁵ Of equal interest is the growing recognition that cortical dysgenesis can be found in a wide spectrum of patients, including some without seizures, in patients with only one or a few seizures, and as associated pathology in patients with temporal lobe epilepsy due to mesial temporal sclerosis. The movement of cortical developmental abnormalities from the domain of the neuropathologist to that of the neurologist has been one of the most significant changes in modern epileptology (Chapter 259). Some critical questions are beginning to be addressed:

Seizures are the presenting symptom in the majority of patients with astrocytomas and oligodendrogliomas, but they are also common at some point in the course of more malignant brain tumors (Chapter 264). With slowly growing neoplasms, seizures typically occur early, when there may be no other clinical symptoms or signs to suggest a tumor. CT may be normal at the time of a first seizure caused by well-differentiated, relatively benign tumors, so MRI is essential. Seizures are also common in many infectious and inflammatory diseases (Chapter 265). Parasitic, bacterial, and viral agents all cause various syndromes in which seizures or chronic epilepsy are common, including as the presenting manifestation. Both mental retardation and cerebral palsy (Chapter 263) are major risk factors for epilepsy, probably because they are markers of brain damage, and the risk for epilepsy is additive when both conditions are present. Alcohol and drug abuse are common causes of symptomatic seizures, but alcohol use itself is also a dose-dependent risk for chronic epilepsy (Chapter 268). Heroin and cocaine, but usually not marijuana, also raise the risk of unprovoked seizures, although symptomatic seizures related to acute toxic effects on the brain are far more common.

Certain epileptic syndromes, associated neurologic abnormalities, age at first seizure, drug resistance, and associated morphologic or systemic abnormalities should warrant a search for a specific diagnosis. High-resolution brain MR imaging will generally establish structural causes of epilepsy, including cortical developmental malformations and brain tumors, although serial scans and special imaging sequences may be necessary fully to define the abnormality. In those circumstances in which epilepsy is due to or associated with an underlying disease, proper treatment, genetic and prognostic counseling, and clinical investigation depend on accurate diagnosis.