Topics and Speakers Helen E. Scharfman, PhD
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Synopsis
The term seizure derives from the historic belief that people who suffered from epilepsy were "seized" by demonic possession. Vincent Van Gogh was epileptic himself and was afflicted with the notion that he was possessed by some kind of evil. Even though much has changed since the dark ages, epilepsy is still shrouded in mystery. In this lecture, Dr Helen E. Scharfman reviews epilepsy terminology, the components of the electrical basis of the central nervous system (CNS), normal versus abnormal synaptic transmission, the phenomenon of synchronization that occurs after a seizure, and concludes with a discussion on temporal lobe epilepsy.
Dr Scharfman begins by defining the critical terms. A seizure is the clinical manifestation of an abnormal and excessive excitation of a population of neurons, whereas epilepsy is the state of recurrent seizures that are unprovoked by systemic or neurological insults. Epileptogenesis is the development of the state of epilepsy.
Dr Scharfman then moves on to the components of the electrical basis of CNS function, in particular the control of resting membrane potential (RMP). When the ionic balance that controls RMP is perturbed, rapid depolarization occurs and there is a discharge of action potentials. For instance, acute electrolyte imbalance, wherein a change in the sodium gradient or a disruption in the sodium pumps can dramatically change action potentials, may lead to a seizure. Recent studies have found that mutations in neurons' sodium channels can potentially lead to more release of transmitter, such as the excitatory glutamate, which in turn can lead to excitotoxcity, and then a seizure.
Delving further into synaptic transmission abnormalities, Dr Scharfman focuses on GABA, another major neurotransmitter linked to epilepsy. In contrast to glutamate, GABA is an inhibitory neurotransmitter. Ironically, too much inhibition can also lead to seizures. Anticonvulsants work to modulate the amount of GABA in the brain in order to counterbalance the excitotoxcity elicited by too much glutamate. However, it has been found that GABA receptors are highly plastic: their subunits change with seizures. This result can render certain anticonvulsants ineffective. Another feature of GABAergic neurons is that they control glutamatergic neurons. When a seizure occurs, GABAergic neurons are destroyed, leading to decreased GABA activity, and more seizures.
New studies offer hope of reversing this devastating cycle. It was recently discovered that neuropeptide Y (NPY), a found in GABAergic neurons and released in seizure-like conditions, actually works by decreasing glutamate release. Current research is focusing on using NPY as an endogenous braking mechanism.
A frightening component of epilepsy is the phenomenon of synchronicity. It has been observed that principal cells across the brain are somehow synchronized together and discharge potentials in synchronous waves of activity. Synchronity can occur in two ways: intrinsically or through neural plasticity. Regarding intrinsic mechanisms, animal studies have shown that a collection of gap junctions can allow a low resistance pathway of current from one neuron to another. Hence, if one neuron is excited, it is not long until a chain of events causes other neurons to be excited. Regarding neural plasticity, animal studies have shown that there is a reorganization of pathways between old neurons and the new neurons that sprout after a seizure through neurogenesis. This new network of pathways could potentially synchronize granule cells in a lethal way that was never present before in the brain.
Dr Scharfman concludes with a discussion of temporal lobe epilepsy, which affects people with hippocampal sclerosis. Most of these patients present the following pathophysiology: an early life insult, then a silent period where no seizures occur, and finally recurrent epilepsy that is usually intractable to pharmacological treatment. Anatomically, patients show almost a complete loss of the CA1 region, sparing of the CA2 region, and loss in the endofolium, which includes the hilus and CA3 region. It has also been observed that there are elevated levels of brain-derived neurotrophic factor (BDNF) and also an increase in granule cells that do not find themselves in the granule layer but in other parts of the brain, thereby becoming abnormal. Genetics have imparted only partial information, such as the p35 or the Reelin mutant, which render neurons in the wrong place. What is important, in treating epilepsy however, is targeting the new connections that form between the old and new neurons that impart new circuits that lead not only to epilepsy but intractable epilepsy.
