In several series of cases of temporal lobe excisions in prior decades, such as the often cited one described by Falconer, a specific pattern of neuronal loss with gliosis (sclerosis) in the hippocampal and amygdaloid region was found in the majority, and this abnormality is being increasingly recognized with MRI, as already noted (medial temporal sclerosis; see Fig. 15-4). The most common associated histologic finding is loss of neurons in the CA1 segment (Sommer sector) of the pyramidal cell layer of the hippocampus, often unilateral, extending into contiguous regions of both the pyramidal layer and the underlying dentate gyrus. It is still undetermined whether this neuronal loss is primary or secondary and, if the latter, whether it was incurred at birth or happened later as the consequence of recurrent seizures.
However, early life head trauma, infections, and a variety of less-common perturbations may also cause the combination of neuron loss and mild gliosis of medial temporal sclerosis. The cessation of seizures in many patients following surgical resection of the medial temporal lobe favors the first interpretation that the pathologic change is primary in most cases (see further on under “Surgical Treatment of Epilepsy”). Attesting to the uncertainty of cause or effect are numerous surgical series that favor one view or the other (see editorial by Sutula and Pitkänen).
Role of Genetics
Most primary epilepsies have a genetic basis and, as in many other diseases such as diabetes and atherosclerosis, the mode of inheritance is complex, that is, some are likely to be polygenic but increasingly, single mutations are being found. That a genetic factor is operative in the primary generalized epilepsies is suggested by a familial incidence in 5 to 10 percent of such patients and, in certain families, the inheritance of a seizure disorder through specific genes (Afawi et al). The importance of genetic factors in the primary epilepsies is also underscored by evidence from twin registries; the overall concordance rate has been up to 70 percent for monozygotic twins and, 30 percent for dizygotic pairs (Vadlamudi et al).
Of course, epilepsy is a component of many genetic syndromes that are defined by their dysmorphic appearance, neurocutaneous disorder, or maldevelopment of the cerebra with or without mental retardation. What we consider first the few idiopathic seizure disorders that are inherited by a simple (mendelian) pattern. These include a subgroup of benign neonatal familial convulsions inherited as an autosomal dominant trait (Leppert et al), and a similar disorder of infantile onset and a benign myoclonic epilepsy of childhood (autosomal recessive). Particularly informative are a special group of epileptic disorders in which monogenic genetic defects are related to abnormalities of ion channels or neurotransmitter receptors (Table 15-3). These were mentioned earlier in the discussion of the physiology of seizures and despite their rarity they suggest that idiopathic epilepsy may be caused by a disruption in the function of these same channels.
The consequences of almost all of these mutations are to enhance overall neuronal excitability. Examples include autosomal dominant nocturnal frontal lobe epilepsy, which may present as a partial seizure (in which the offending mutations are in subunits of the nicotinic acetylcholine receptor subunit); so-called “generalized epilepsy with febrile seizures plus” (subunits of a neuronal sodium channel associated with various combinations of uncomplicated febrile seizures, febrile seizures persisting beyond childhood, generalized, absence, myoclonic, atonic, and complex partial seizures); benign familial neonatal convulsions (two different potassium channels); and forms of juvenile myoclonic epilepsy and childhood absence epilepsy (subunits of the brain GABAA receptor).