It is estimated that 2 million Americans experience the symptoms of alcohol withdrawal each year (1). Generalized tonic–clonic seizures (rum fits) are the most dramatic and dangerous component of the alcohol withdrawal syndrome. The brain substrates that trigger these seizures are largely in the brainstem and, therefore, are distinct from those believed to be responsible for other clinically important seizure types. Moreover, because alcohol withdrawal seizures are pharmacologically induced, the pathophysiologic mechanisms almost certainly are different from those of the seizures that occur in genetic and acquired epilepsies. This review provides an overview of the current understanding of the cellular and molecular events that lead to alcohol withdrawal seizures.
Ethanol is a central nervous system depressant that produces euphoria and behavioral excitation at low blood concentrations and acute intoxication (drowsiness, ataxia, slurred speech, stupor, and coma) at higher concentrations. The short-term effects of alcohol result from its actions on ligand-gated and voltage-gated ion channels (2–4). Prolonged alcohol consumption leads to the development of tolerance and physical dependence, which may result from compensatory functional changes in the same ion channels. Abrupt cessation of prolonged alcohol consumption unmasks these changes, leading to the alcohol withdrawal syndrome, which includes blackouts, tremors, muscular rigidity, delirium tremens, and seizures (56). Alcohol withdrawal seizures typically occur 6 to 48 hours after discontinuation of alcohol consumption and are usually generalized tonic–clonic seizures, although partial seizures also occur (78).
Rodent models that mimic human alcohol withdrawal–related tonic–clonic seizures have been useful in defining the physiologic mechanisms underlying ethanol withdrawal seizures (9). In these models, animals are exposed to alcohol by intragastric intubation, inhalation, or feeding in a nutritionally complete liquid diet for periods of 2 to 21 days. The animals exhibit sound-evoked audiogenic seizures or handling-induced convulsions during the 1- to 3-day period after cessation of alcohol intake and may also experience spontaneous generalized seizures.