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Pathophysiology of Post Traumatic Epilepsy: Treatment and Side EffectsBY: Shikha Sharma | Category: Healthcare | Submitted: 2010-11-04 06:59:05
Article Summary: "This article is intended to provide a brief review of the basic pathophysiology underlying the pathogenesis of post-traumatic epilepsy with special emphasis on the current treatment modalities available with their possible side-effects on the quality of human health and the urgent need to search for key anti-epileptic molecules..."
This article is intended to provide a brief review of the basic pathophysiology underlying the pathogenesis of post-traumatic epilepsy with special emphasis on the current treatment modalities available with their possible side-effects on the quality of human health and the urgent need to search for key anti-epileptic molecules.
It is one of the most prevalent neurological disorders, defined as an inclination towards recurrent seizures. In simpler terms, seizure (commonly called as fit) is the uncontrolled abnormal excessive electrical discharges in the brain, which may produce a physical convulsion, minor physical signs, thought instability, or a combination of these symptoms. Epileptic bursts result from a large population of hyperexcitable neurons. Epileptogenesis is the multiphase process comprising of an array of cellular and molecular events that cause normal neurons to undergo alterations, resulting in the generation of spontaneous seizures.
Post-traumatic epilepsy (PTE) is characterized by recurrent epileptic seizure disorder caused by physical trauma to the brain; about 5% of all the cases of epilepsy are attributable to head injury. Although the mechanisms are poorly understood, physical injury to the brain is considered to be the initiating event in a cascade of processes underlying epileptogenesis. The incidence of PTE is highest among young adults as they are more prone to head injury. It is difficult to predict who will develop epilepsy after traumatic brain injury and who will not, but in general, individuals sustaining TBI have on average a three-fold higher risk of developing epilepsy than the general population.
Mechanisms underlying the pathogenesis of post traumatic epilepsy
The precise mechanisms of epileptogenesis in post-traumatic epilepsy are still poorly understood and there are multiple theories, which support the mechanisms behind this annihilative disease. Among these, the most widely accepted is the formation of damaging free radicals by iron from blood in the parenchyma of the brain, increase in excitatory activity following injury, and changes in the inhibitory functions of the brain.
One of the widely popular schools of thought has explored the role of haemoglobin as an agent involved in epileptogenesis. Contusion or cortical laceration causes bleeding into brain tissue, followed by red blood cell lysis with a subsequent release in haemoglobin that result into two disintegration products, hemin and iron. The latter, deposited as hemosiderin within the neuropil, is found within the brain of patients with PTE. Both of these breakdown products have physiological effects on synaptic transmission that may lead to epileptogenesis. The epileptogenetic effect of iron is thought to be mediated through the formation of free radicals that cause neuronal cell death. Besides, iron has also been found to affect the release and metabolism of excitatory neurotransmitter glutamate.
Causes: Oxidative injury/stress
Imbalance between cellular production of free radicals and the ability of cells to defend against them is referred to as oxidative stress (OS). With respect to epilepsy, oxidative injury/stress has been recognized as a potentially important factor through which free radicals lead to neuronal hyperexcitability and thus epileptogenicity. These include abnormal activation of N-methyl-D-aspartate (NMDA) receptors with consequent changes in neuronal activity, adverse changes in patterns of synaptic transmission, and increase in the activity of excitatory amino acids such as glutamate. This demonstrates a direct cause-and-effect relationship between free radicals and epileptogenesis.
Fe2+ + O2 => Fe3+ + ·O2- (Haber-weiss reaction)
Fe2+ + H2O2 => Fe3+ + ·OH- + ·OH- (Fenton reaction)
Anti-epileptic strategy: Current drug regimen
Anti-epileptic drugs available for treatment are phenytoin, sodium valproate, carbamazepine, and phenobarbital. Their mode of action is generally believed to involve alteration in ion fluxes across neuronal cell membranes, resulting in neuronal inhibition.
Anti-epileptics are not benign drugs; as example, a high rate of side effects has been demonstrated in patients treated with phenytoin that include intravenous site reactions, exfoliative dermatitis, granulocytopenia, transient hemiparesis etc. Briefly, there are three types of side effects:
• Common or predictable side effects: These are generic and dose-related side effects, which can occur with any epilepsy drug. These side effects include blurry or double vision, fatigue, sleepiness, unsteadiness, as well as stomach upset.
• Idiosyncratic side effects: These side-effects are rare and unpredictable reactions not related to the dose intake. Most often, these side effects are skin rashes, low blood cell counts, and liver problems.
• Unique side effects: These are those that are not shared by other drugs in the same class. For example, Dilantin or Phenytek can cause the gums to swell and Depakene can cause hair loss.
Need for new medications in epilepsy
The currently available anti-epileptic drugs are able to prevent the course of disease only to a limited extent, hence there has been much interest and constant demand for better therapeutic alternatives that control epilepsy or change the intensity of seizures, for possible use in disease modification. To date, treatments of neurological disorders have met with limited success due to side effects and toxicities associated with these therapies. Accordingly, a need exists for better approaches to neuroprotection and for improved therapies for epilepsy, and other neurological disorders.
New light of hope for treatment
Since oxidative stress has been recognized as a potential contributing factor in the initiation and progression of epilepsy, therefore, it can be suggested that the therapies aimed at reducing oxidative stress may ameliorate tissue damage and favorably alter the clinical course. Survey of literature ascertains a considerable evidence from both in-vitro and in-vivo studies that early intervention with antioxidant therapy ameliorates oxidative injury and reduces epileptogenic potential. Treatment with antioxidants that help to prevent peroxidation may theoretically act to prevent propagation of tissue damage and can possibly alter the basic pathology of the disease.
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