Epilepsy is a very common neurological disorder. Some reports estimate that five in one-thousand people suffer from this problem. Throughout history, people with epilepsy have been shunned or considered inferior. Even today, ignorance leads many people to treat the epileptic as "abnormal" or "retarded". Although the etiology of epilepsy is still not fully understood, it is quite treatable due to advances in modern medicine.

Epilepsy is characterized by uncontrolled excessive activity of either a part of, or all of the central nervous system. A person who is predisposed to epilepsy has attacks when the basal level of excitability of the nervous system rises above a certain critical threshold. As long as the degree of excitability is held below this threshold, no attack occurs. Basically, epilepsy can be classified into three major types: grand mal, petit mal, and focal or partial epilepsy.

Grand mal epilepsy is characterized by extreme neuronal discharges in all areas of the brain: in the cortex, in the deeper parts of the cerebrum, and even in the brain stem and thalamus. Also, discharges into the spinal cord cause generalized tonic convulsions of the entire body, followed toward the end of the attack by alternating tonic and then spasmodic muscular contractions called tonic-clonic convulsions. Often the person bites or "swallows" the tongue and usually has difficulty in breathing, sometimes to the extent of developing cyanosis. Also, signals to the viscera frequently cause urination and defecation. The grand mal seizures lasts from a few seconds to as long as three to four minutes and is characterized by post-seizure depression of the entire nervous system; the person remains in stupor for one to many minutes after the attack is over and then often remains severely fatigued or even asleep for many hours thereafter. During these seizures, high-voltage, synchronous discharges occur over the entire cortex. Furthermore, the same type of discharge occurs on both sides of the brain at the same time, showing that the abnormal neuronal circuitry responsible for the attack strongly involves the basal regions of the brain that drive the cortex. In humans, grand mal attacks can be initiated by administering neuronal stimulants, such as the drug Metrazol, or they can be caused by insulin hypoglycemia or by the passage of alternating electrical current directly through the brain. Electrical recordings from the thalamus and also from the reticular formation of the brain stem during the grand mal attack show typical high-voltage activity in both of these areas similar to that recorded from the cerebral cortex. Presumably, therefore, a grand mal attack is caused by abnormal activation in the lower parts of the brain activating system itself.

Most persons who have grand mal attacks have a hereditary predisposition to epilepsy. In such persons, some of the factors that can increase the excitability of the abnormal "epileptogenic" circuitry enough to precipitate attacks; are strong emotional stimuli, alkalosis caused by hyperventilation, drugs, fever, and loud noises or flashing lights. Even in persons not genetically predisposed, traumatic lesions in almost any part of the brain can cause excess excitability of local brain areas and these too, can elicit grand mal seizures. The cause of the extreme neuronal overactivity during a grand mal attack is presumed to be massive activation of many reverberating pathways throughout the brain. Presumably, one of the major factors that stops the attack after a few minutes is the phenomenon of neuronal fatigue. However, a second factor is probably active; inhibition by inhibitory neurons that have also been activated by the attack. The stupor and total body fatigue that occur after a grand mal seizure is over, are believed to result from the intense fatigue of the neuronal synapses following their intensive activity during the grand mal attack.

Petit mal epilepsy is closely allied to grand mal epilepsy in that it too almost certainly involves the basic brain activating system. It is usually characterized by 3 to 30 seconds of unconsciousness during which the person has several twitch-like contractions of the muscles, usually in the head region, especially blinking of the eyes. This is followed by return of consciousness and resumption of previous activities. The patient may have one such attack in many months or in rare instances may have a rapid series of attacks, one following the other. However, the usual course, is for the attacks to appear late in childhood and then to disappear entirely by the age of 30. On occasion, a petit mal epileptic attack will initiate a grand mal attack. The brain wave pattern of a petit mal attack is typified by a spike and dome pattern. The spike portion is almost identical to that which occur in grand mal epilepsy, but the dome portion is entirely different. The spike and dome pattern can be recorded over most or all of the cerebral cortex, illustrating that the seizures involves the entire activating system of the brain.

Focal epilepsy can involve almost any part of the brain, either localized regions of the cerebral cortex or deeper structures of both the cerebrum and brain stem. Almost always, focal epilepsy results from some localized organic lesion or functional abnormality, such as a scar that pulls on the neuronal tissue, a tumor that compresses an area of the brain, a destroyed area of brain tissue, or congenitally deranged local circuitry. Lesions such as these can promote extremely rapid discharges in the local neurons. When the discharge rate rises above approximately 1000 per second, synchronous waves begin to spread over the adjacent cortical regions. These waves presumably result from localized reverberating circuits that gradually recruit adjacent areas of the cortex into the discharge zone. The process spreads to adjacent areas at a rate as slow as a few millimeters a minute, to as fast as several centimeters per second. When such a wave of excitation spreads over the motor cortex, it causes a progressive "march" of muscular contractions throughout the opposite side of the body, beginning most characteristically in the mouth region and marching progressively downward to the legs; at other times marching in the opposite direction. This is called Jacksonian epilepsy. A focal epileptic attack may remain confined to a single area of the brain, but in many instances the strong signals from the convulsing cortex or other part of the brain excite the mesencephalic portion of the brain activating system so greatly that a grand mal epileptic attack ensues as well.

Another type of focal epilepsy is the so called psychomotor seizure, which may cause: (1) a short period of amnesia; (2) an attack of abnormal rage; (3) sudden anxiety, discomfort, or fear; (4) a moment of incoherent speech or mumbling of some trite phrase; or (5) a motor act to attack someone, to rub the face with the hand, and so forth. Sometimes the person cannon remember his activities during the attack, but at other times he will have been conscious of everything that he had been doing, but is unable to control it. Attacks of this type characteristically involve part of the limbic system, such as the hippocampus, the amygdala, the septum, and the temporal cortex.

Epilepsy is not a disease, but a collection of diverse syndromes, some of which are secondary to other brain derangement’s, and some which are primary. Any serious injury can lead to epilepsy. Common ones include: major head trauma, stroke, hemorrhage, infection, vascular malformations, and benign or malignant tumors. The paroxysmal depolarizing shift (PDS) remains the best cellular marker of an epileptic event, corresponding to the interictal spike of the EEG. The PDS represents a sustained movement of the neuronal resting potential above threshold for 10--15 times the duration of a normal action potential. Positive charge is initially carried in through Na⁺ channels, but Ca⁺⁺ channels open within a few ms. The Ca⁺⁺ that enters the cell during the PDS is rapidly bound to calcium binding proteins and sequestered in mitochondria. This prevents the intracellular free Ca⁺⁺ concentration from becoming excessive and triggering a cascade of cytotoxic events. Below this toxic threshold, Ca⁺⁺ entry produces a proportional degree of K⁺ channel opening, which serves to terminate the PDS and induces a prolonged after-hyperpolarization. Failure of this Ca⁺⁺-dependent K⁺ current appears to be crucial to the transition from interictal spike to seizure. Why this failure occurs is the subject of current work.

The cause or etiology of epilepsy has been studied intently but still remains somewhat unclear. For example, whole tissue samples of epileptic patients showed a trend to higher GABA concentrations. However, the affinity of GABA for binding sites was found to be decreased in this study; thus, the former may simply be the result of the latter. Several neuropeptides, especially the opioid like peptides, ACTH, and some hypothalamic releasing factors, have been found to alter neuronal excitability. This finding has led to the proposal that these peptides may play a role in the pathogenesis of the epilepsies. At nontoxic doses, several exogenously administered peptides properties had anti-convulsant properties, while others were pro-convulsant. Pro-convulsant included TRH and corticotropin hormone while anti-convulsant included oxytocin, ACTH, and vasopressin. However, the most potent anticonvulsant was B-endorphin. One possible role for the endogenous opioid peptides may be to limit the spread of seizures or to modulate postictal susceptibility to further seizures.

Many neurochemical analyses suggest that inhibitory neurotransmitter concentrations, especially that of GABA, are focally diminished in the brains of patients with focal (partial) epilepsy. Other neurotransmitters involved may be ACh, glutamate, aspartate, and/or taurine. One study found that a factor common to all of the subjects was the presence of hypokalemia and a tendency toward alkalosis. Hypokalemia may be associated with the elaboration of an alkaline urine. In the presence of an alkaline urine, the diffusion of ammonia from the renal tubular cells into the urine is diminished, in turn exposing the brain to higher concentrations of ammonia. Detoxification of ammonia in the brain involves the formation of less toxic glutamine. The preferential formation of glutamine appears to deplete the available glutamic acid, which is a precursor of GABA, the major mediator of central inhibition. This may lead to epilepsy, or at least make one more prone to having epileptic attacks.

In attempting to answer the question of whether epilepsy is a result of a decrease of inhibitory or of an increase of excitatory central processes, it appears that presently the available experimental data emphasize the importance of disinhibition in epileptogenesis. Neuronal epileptic behavior seems primarily to result from a blockade of neurotransmitter-activated increase in chloride conductance which is mediated by a release of GABA from GABAergic neurons. However, there is data showing that inhibitory mechanisms appear to be preserved at some stage of some experimentally induced epileptic activities. Three possible hypotheses may explain these findings: 1). It may be that an increase of neuronal excitatory mechanisms(i.e., an enhancement of the postsynaptic effects induced by excitatory neurotransmitters) without any change in central inhibitory processes underlies the appearance of epileptic behavior. 2). This suggests that in some types of epilepsy inhibitory mechanisms may be only partially impaired, i.e., that there exist different levels of epileptogenecity in relation to a more or less pronounced weakening of the chloride-mediated postsynaptic inhibition. Thus in some instances, the inhibitory synaptic drive might be decreased only up to a point in which the proportion of synaptic excitation over inhibition is increased without, however, any complete blockage of the latter. 3). This hypothesis suggests that more than one postsynaptic inhibitory mechanism may be involved. In addition to the chloride- mediated IPSP there may exist hyperpolarization’s which are dependent upon an increase in potassium conductance. Consequently, the degree of epileptogenecity might be dependent upon the differential impairment of one or both types of inhibition. Even with all the research that has taken place and the many proposed hypotheses that have been put forth, the etiology or mechanism of epilepsy remains to be accurately pinpointed.

Epilepsy was among the first neurological disorders treated effectively with medication. Not suprisingly, anti-convulsant’s are the most common means of treating epilepsy. The following chart summarizes the major drugs used today for treating epilepsy.

Seizure type                                                       Drug(s) of choice
Partial, including secondarily                                Carbamazepine
    Generalized                                                       Phenytoin(Dilantin)

Generalized
    Absence                                                            Ethosuximide
                                                                            Valproic acid

Tonic-clonic                                                        Carbamazepine
                                                                            Phenytoin
                                                                            Valproic acid

Myoclonic, Atonic                                               Valproic acid

Schmidt, D., C. Cornaggia, and W. Loscher. (1984) Comparative Studies of the GABA System in Neurosurgical Brain Specimens of Epileptic and Non-epileptic Patients. Neurotransmitters, Seizures, and Epilepsy II, p.275-283.