Of epilepsy

Benzodiazepines. Several BZs have anticonvulsant activity and ate used for the treatment of epilepsy producing their anticonvulsant actions via interactions with the GABA /BZ receptor complex to enhance inhibitory GABAergic transmission (1). The anticonvulsant actions of the BZs tend to tolerate upon chronic usage in six months, and BZs also lead to withdrawal symptomatology. Other side effects include sedation, ataxia, and cognitive impairment. 

Fohc acid is safe, even at levels of daily oral supplementation up to 5—10 mg (97). Gastrointestinal upset and an altered sleep pattern have been reported at 15 mg/day (98). A high intake of foHc acid can mask the clinical signs of pernicious anemia which results from vitamin deficiency and recurrence of epilepsy in epileptics treated with dmgs with antifolate activity (99). The acute toxicity (LD q) is approximately 500 and 600 mg per kg body weight for rats and mice, respectively (100). 

The success of quinine inspired the search for other antimalarials. The greatest impetus for the development of synthetic dmgs came this century when the two World Wars intermpted the supply of cinchona bark to the combatants. A stmcturally related 4-quinolinemethanol is mefloquine (65, Lariam [51773-92-3]) which now serves as an effective alternative agent for chloroquine-resistant P. falciparum. This is a potent substance that requires less than one-tenth the dose of quinine to effect cures. There are some untoward side effects associated with this dmg such as gastrointestinal upset and dizziness, but they tend to be transient. Mefloquine is not recommended for use by those using beta-blockers, those whose job requires fine coordination and spatial discrimination, or those with a history of epilepsy or psychiatric disorders. A combination of mefloquine with Fansidar (a mixture of pyrimethamine and sulfadoxine) is known as Fansimef but its use is not recommended. Resistance to mefloquine has been reported even though the compound has not been in wide use. 

Because alcohol intoxication may be simulated by many pathologic conditions, including diabetic acidosis, the postconvulsive depression of epilepsy, uremia, head injuries, and poisonings by any other central nervous depressant and some stimulants (280), a diagnosis of acute alcoholism should not be made casually chemical testing of blood, urine, or expired air is always desirable. 

Bromide therapy introduced by Lacock as a sedative and anticonvulsant for treatment of epilepsy... 

Epilepsy is a chronic neurological disorder that affects about 0.6-0.8% of the general population worldwide. The clinical hallmark of epilepsy is... 

Benign familial neonatal convulsion is an idiopathic form of epilepsy beginning within the first six months after birth. Seizures include generalized and mixed, starting with tonic posture, ocular symptoms, and apnea, and often progress to clonic movements and motor automatisms. 

Epilepsy is a heterogeneous group of syndromes characterized by abnormal, rhythmic electrical activity of the brain or parts of the brain. The term epilepsy is reserved for chronic diseases, while a single, isolated seizure does not justify the diagnosis of epilepsy. 

Deletion of the Cav3.1 channel in thalamocortical relay neurons prevents absence epilepsy. Block of the neuronal LVA channels alleviates certain forms of epilepsy. Deletion of Cav3.2 leads to coronary artery constriction and focal myocardial fibrosis. 

Epilepsy may be defined as a permanent, recurrent seizure disorder. Examples of the known causes of epilepsy include brain injury at birth, head injuries, and inborn errors of metabolism, hi some patients, the cause of epilepsy is never determined. 

Mr. Parks, age 32 years, has recently received a diagnosis of epilepsy. He has been taking the anticonvulsant carbamazepine, but his seizures are not yet under control. Mr. Parks asks you how long it will take to cure his epilepsy. Determine how you would respond to Mr. Parks. 

Folate supplements will rectify the megaloblastic anemia of vitamin Bj2 deficiency but may hasten the development of the (irreversible) nerve damage found in B,2 deficiency. There is also antagonism between fohc acid and the anticonvulsants used in the treatment of epilepsy. 

Rogawski, MA (2000) KCNQ2/KCNQ3 K+ channels and the molecular pathogenesis of epilepsy. 

In parallel with the identification of distinct transporters for GABA there has been continued interest in the development of selective blockers of these transporters and the therapeutic potential that could result from prolonging the action of synaptically released GABA. It has been known for a long time that certain pro-drugs of nipecotic add (e.g. nipecotic acid ethyl ester) are able to cross the blood-brain barrier and are effective anticonvulsants in experimental models of epilepsy. More recently, several different systemically active lipophillic compounds have been described that act selectively on GAT-1, GAT-2 or GAT-3 (Fig. 11.4). Of these, tiagabine (gabitiil), a derivative of nipecotic acid that acts preferentially on GAT -1, has proved clinically useful in cases of refractory epilepsy. 

All such animal procedures suffer from the obvious and basic problem that laboratory animals do not behave like humans and that humans cannot reliably interpret their reactions and behaviour. Thus we know that Parkinson s disease is caused by a degeneration of the dopaminergic nigrostriatal tract but its lesion in animals does not produce any condition which resembles human Parkinsonism, except in primates, even though there are functional tests (e.g. rotational movements) which readily establish that loss of dopamine function and also respond to its augmentation (Chapter 15). By contrast, there are many ways, e.g. electrical stimulation and the administration of certain chemicals, to induce convulsions in animals and a number of effective antiepileptic drugs have been introduced as a result of their ability to control such activity. Indeed there are some tests, as well as animals with varied spontaneous seizures, that are even predictive of particular forms of epilepsy. But then convulsions are a very basic form of activity common to most species and epileptic seizures that are characterised by behavioural rather than motor symptoms are more difficult to reproduce in animals. 

That an episode arises and spreads from the synchronous as well as excessive discharge of a group of neurons (focus) means that not only must those neurons be in some way predisposed to so discharging but they can also recruit neurons that are otherwise normal. How that discharge manifests itself, i.e. which type of epilepsy occurs, will depend not only on where the abnormal focal neurons are located but also to what extent the activity they initiate can and does spread through the brain. There are consequently a number of different forms of epilepsy, i.e. the epilepsies. 

Other NTs have been implicated in the aetiology of epilepsy but direct evidence is lacking. They will be considered briefly. 

Irrespective of the cause of epilepsy, the spread of seizure activity will be attenuated by either decreasing the excitation or increasing the inhibition of neurons. This may be achieved in a number of ways, either directly by... 

How the drugs currently available for the treatment of epilepsy may utilise these mechanisms will now be considered. 

There is no shortage of AEDs (Fig. 16.7) but it is not appropriate to consider them in detail in this text other than to see how their mechanisms of action comply with and illustrate those proposed above (Fig. 16.6) for the control of epileptic seizures (see Meldrum 1996 Upton 1994). The decision on which drug to use depends not only on their proven efficacy in a particular type of epilepsy (some drugs are inactive in certain forms) but also what side-effects they have—many are sedative — how they interact with other drugs and how often they need to be taken. Compliance is a problem over a long period if dosing is required more than once a day. It is probably acceptable in reality, if not scientifically, to divide the drugs into old-established AEDs and new AEDs. Only the latter have been developed chemically to modify the known synaptic function of the amino acids. 

Figure 16.7 The structure of some established antiepileptic drugs (AEDs) and some newer ones. Note that while the structures of phenytoin and ethosuximide are similar and also close to that of phenobarbitone, they are effective in different forms of epilepsy. Vigabatrin, progabide and gabapentin are clearly related to GABA. Muscimol is a GABAa agonist but is not an effective antiepileptic drug...

Introduced initially for absence seizures, this drug is now known to be effective in and used to treat tonic lonic seizures and most types of epilepsy. It was found to inhibit GABA transaminase and so elevate GABA concentrations and inhibition. This is achieved, however, over a slower time-course than its anti-seizure effect, especially experimentally, which is now thought to be due to its phenytoin-like, use-dependent block of sodium channels. Since, unlike phenytoin, the full effect of valproate takes some weeks to develop, its slower effect on GABA metabolism and activity should not be ignored. 

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