1 sec partial seizure EEG
frontal site temporal site occipital site partial seizure EEG
frontal site temporal site occipital site
E.yn.Lhrijnous abnormE I d~i£hE rges In I-I
E.yn.Lhrijnous abnormE I d~i£hE rges In I-I
Figure 12.3. Changes in the EEG of a patient showing partial seizures.
human epilepsy is undoubtedly photically induced seizures in the Senegalese baboon.
Chronic focal epilepsy can be induced in rats, cats and monkeys by the topical application of metals such as aluminium, cobalt and iron. Alumina paste applied to the motor cortex of the monkey initiates spontaneous convulsive seizures that eventually generalize to the rest of the brain. It has been shown that neurons in the vicinity of the seizure focus have a reduced glutamate decarboxylase activity, which suggests that gamma-aminobutyric acid (GABA) synthesis in this area is impaired. Not all animal models of epilepsy show such changes in GABA content, however. Some strains of Mongolian gerbil exhibit myoclonic and clonic-tonic seizures in early adulthood, but in such species the GABA content of the hippocampus has been shown to increase, which suggests that a process of disinhibition of inhibitory transmitter pathways may occur in this model.
Recently there has been much interest in the kindling of epileptic seizures in rodents. This occurs following focal electrical stimulation of cortical regions, usually the temporal region, by a current that is sufficient to cause an after-discharge but insufficient to cause a direct seizure. When such stimuli are repeated at regular intervals for several days, a stage is reached whereby a subthreshold stimulus results in a full seizure. This suggests that kindling is associated with the lowering of the seizure threshold consequent upon the induction of enhanced neurotransmitter receptor sensitivity. There is no evidence that brain damage is responsible for such changes but it has been suggested that the alterations in receptor sensitivity are similar to those occurring in long-term potentiation, a phenomenon produced by high frequency stimulation of afferent inputs to the hippocampus that leads to enhancement of excitatory synaptic potentials and increased memory formation.
Whereas the genetic and kindling models have been widely used to investigate possible neurotransmitter defects that cause different types of epilepsy, rodent models in which seizures are induced by electroshock, or by convulsant drugs such as pentylenetetrazol (also called pentetrazol, leptazol), picrotoxin or bicuculline, are mainly used in screening procedures to identify potential anticonvulsants.
Membrane-bound enzymes, particularly the ATPases involved in the ionic pumps for calcium, sodium and potassium, have been found to function abnormally in the brains of epileptic patients and animals. A reduction in Na+K+-ATPase activity has been reported in human focal epileptogenic tissue, but it is uncertain whether such changes are due to the disease itself or a reflection of drug treatment. Similar changes have, however, been reported in experimental animals following the localized application of alumina cream and in DBA/2 mice that exhibit sound-induced seizures; a reduction in calcium-dependent ATPase has also been found in the brain of DBA/2 mice. Such findings are consistent with the hypothesis that a defect in ion channels may occur in epilepsy.
Another possibility is that endogenous epileptogenic compounds may be produced in the brain of the epileptic patient. Both tetrahydroisoquinolines and beta-carbolines have been detected in the human brain, as has the tryptophan analogue quinolinic acid, which all have convulsant and excitotoxic properties. The enzymes that synthesize quinolinic acid have also been identified in human brain tissue.
Of the various amino acid neurotransmitters which have been implicated in epilepsy, the inhibitory transmitter glycine has been shown to be present in normal concentrations, or even slightly elevated, in the vicinity of the epileptic focus. Conversely, the concentration of GABA has been found to be reduced in the cerebrospinal fluid (CSF) of chronic epileptics and in patients with febrile seizures. The central role of GABA in epilepsy is further suggested by the observation that drugs that reduce the GABA concentration are epileptogenic, while those that raise the GABA concentration are generally anticonvulsants. The observation that the concentration of glutamate may be reduced in the epileptic focus lends further support to the view that there may be a defect in GABA synthesis which predisposes the individual to the disease.
Despite early studies suggesting that the acetylcholine concentration was raised in epileptogenic foci, which would be consistent with the finding that anticholinesterases cause seizures in both animals and man, it now appears that overactivity of the central cholinergic system is unlikely to be the cause of seizures in the human epileptic. Other candidates that have been implicated in the aetiology of epilepsy include adenosine and the enkephalins, but conclusive evidence for their involvement is presently lacking.
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