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infantile spasms west syndrome epilepsy seizures hypsarrhythmia eeg
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Diabetes Drug May Hold Potential As Treatment For Epilepsy, Using Same Mechanism As Ketogenic Diet
ScienceDaily (Apr. 11, 2008) — Two years ago, University of Wisconsin-Madison scientists reported they had suppressed epileptic seizures in rats by giving them a glycolytic-inhibitor, inhibiting the brain's ability to turn sugar into excess energy and blocking the expression of seizure-related genes. The discovery was greeted with excitement and hope for a new class of drugs for epilepsy, which afflicts more than 50 million people worldwide.
Now, in a presentation at Experimental Biology 2008 in San Diego,* Dr. Avtar Roopra describes a next step in this research that may mean a drug already widely used by people with diabetes could also be an effective and safe therapy for epilepsy, especially for that one third of patients who have recurrent seizures despite therapy with the best available antiepileptic drugs.
Although the earlier work by Dr. Roopra and his colleagues marked the first time a compound had been used for metabolic regulation of neuronal genes, epilepsy patients had been attempting to achieve the same goal - fewer seizures - for centuries through severe dietary restriction, in some cases with near starvation, more often with a high-fat, high-protein diet completely free of starches and sugars. Half of all drug-resistant people with epilepsy experience seizure control with this kind of severe ketogenic diet (although even a mild lapse can sometimes result in seizures).
The mechanism was completely unknown but the researchers reasoned it had to involve glycolysis, the recognition of sugar and its conversion to energy. And if that were correct, they asked, could they tap into this same biological pathway, bypassing dietary requirements altogether? The answer, published in Nature Neuroscience in October 2006, was 2-Deoxy-D-glucose, a compound that tricked the body into thinking it was sugar so that the cells stopped using the real thing as an energy source.
Now, in the new work, the researchers have identified a small molecule in the neurons that senses how much energy in available. Glucose turns on this sensor -- but so does Metformine, a FDA-approved prescription drug used by millions of people with diabetes to control their blood sugar. Dr. Roopra and his colleagues are now testing Metformine in the brains of mice to see how it affects the functioning of the hippocampus, the part of the brain involved with learning and memory and also the seat of seizures for many patients with epilepsy. The goal is to tamp down a mechanism called Long Term Potenciation enough to reduce the rate of epilepsy but not enough to affect the brain's ability to learn and remember.
At this early stage of the research, it appears to be hitting the right balance, says Dr. Roopra. In the meantime, he points out, there have been no reports of learning and memory side effects in any of the adults or children who have used Metformine for years.
The next step will be to take Metformine to a mouse model of epilepsy. It's still early, says Dr. Roopra, but the researchers already are pleased with the increased understanding of the likely mechanism of the positive effect of the ketogenic diet on epileptic seizures and the focus on new drug targets for this often-devastating disease
Other researchers used a chemical called 2-deoxy-D-glucose (2DG) to block carbohydrate breakdown in a rat model of epilepsy. This chemical reduced the expression of genes involved in epilepsy and reduced the number and severity of seizures in the rats. If this substance works in people, it might be the basis for a new class of antiepileptic drugs.
Spontaneous remission of infantile spasms and hypsarrhythmia following acute infection with high-grade fever.
To elucidate the pathogenesis of spontaneous remission of infantile spasms (ISs) and hypsarrhythmia following infection, we reviewed 58 patients with ISs from 1986 through 2006 in our hospital. Five patients showed spontaneous remission of spasms or hypsarrhythmia following infections with high-grade fever (SR group). In control, we analyzed five patients with complete improvement of ISs for ACTH therapy (ACTH group). In the SR group, ISs stopped in an average of 4.0 days after the onset of infection. In three patients performing EEG during the infection, hypsarrhythmia disappeared within an average of 8 days after the onset of infection. In the ACTH group, ISs stopped an average of 4.6 days and hypsarrhythmia disappeared within an average of 10 days after ACTH therapy. During the remission course of ISs, low-voltage background activity (BGA) on EEG showed in one patient of the SR group and in all patients of the ACTH group. ACTH is known to the efficacy for ISs and suppression of cortical activity on human EEG. This similar remission course between in the SR group and in the ACTH group suggest neuroendocrinal products in response to infection, which is resembled ACTH-related cascade, may play a role for spontaneous remission following infection.
Antiepileptic Drugs
The large amount of research on epilepsy in recent decades has led to the development of many potential antiepileptic drugs. Some are similar to drugs that are already in use.
Brivaracetam and seletracetam are two new drugs that are chemically related to levetiracetam. Because of the way these drugs work, researchers believe they may be more potent than levetiracetam. Both drugs are now being tested in large clinical trials. Another drug, eslicarbazepine, is similar to oxcarbazepine, and the new drugs fluorofelbamate and RWJ-333369 are similar to felbamate. Several other drugs – isovaleramide, valrocemide, and DP-VPQ – are chemically similar to valproate.
Some new drugs appear to work in completely new ways. These include retigabine, rufinamide, and lacosamide. Retigabine affects potassium channels in the cell membrane and may also affect the response to GABA. Rufinamide appears to affect sodium channels, and early clinical trials have shown that it can reduce treatment-resistant partial seizures and the seizures associated with Lennox-Gastaut syndrome. Both retigabine and rufinamide are now in clinical trials. Investigators do not yet know how lacosamide works, but some clinical studies have shown that it can help prevent partial seizures. Animal studies have suggested that it also may help protect neurons from damage.
Other new drugs include talampanel, ganaxolone, and safinamide. Talampanel works by blocking one kind of glutamate receptor. Ganaxolone is a steroid that interacts with GABA receptors. Researchers do not yet know how safinamide works.
A study in newborn rats showed that seizures could be blocked by bumetanide, a commonly used diuretic (urine-increasing) compound that blocks the effects of GABA release. While these results are preliminary, they suggest that bumetanide or related drugs might be a new way of treating seizures in young children.
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epilepsy seizures infantile spasms west syndrome hypsarrhythmia eeg
childhood epilepsy infant seizures developmental delay information myclonic baby acth
