Seizure disorders

Introduction:

Seizures happen when your brain cells, which communicate through electrical signals, send out abnormal signals. Having several seizures (recurrent seizures) is considered epilepsy. Seizures are not considered to be epilepsy if they occur only once or are correctable. Epilepsy can happen at any age, but it is most common in the elderly. Many children with epilepsy outgrow the condition. However, even mild seizures that happen more than once should be treated, because they could cause harm if they happen while you are driving, walking, or swimming, for example.

Signs and Symptoms:

Seizures are classified in two main categories:

Partial seizures -- involve a part of the brain. They can be:

• Simple partial seizures -- Symptoms may include involuntary twitching of the muscles or arms and legs; changes in vision; vertigo; and experiencing unusual tastes or smells. The person does not lose consciousness.
• Complex partial seizures -- Symptoms may be similar to those of partial seizures, but the person does lose awareness for a time. The persona may engage in repetitive behavior (like walking in a circle or rubbing their hands) or stare.

Generalized seizures -- involve much more or all of the brain. They can be:

• Absence seizures (petit mal) -- Symptoms may include staring and brief loss of consciousness.
• Myoclonic seizures -- Symptoms may include jerking or twitching of the limbs on both sides of the body.
• Tonic-clonic seizures (grand mal) -- Symptoms may include loss of consciousness, shaking or jerking of the body, and loss of bladder control. The person may have an aura or an unusual feeling before the seizure starts. These seizures can last from 5 - 20 minutes.

What Causes It?:

Seizures are caused by overexcited nerve cells in the brain (cerebral cortex) that fire abnormally. In many cases (about half), the cause isn' t known. Some things that can cause seizures include:

• Head injury
• Genes, in some cases -- researchers have linked specific genes to epilepsy
• Dementia
• Injury to the brain before birth
• Some medical conditions (such as meningitis)
• Stroke and heart attack

Treatment Options:

The goal of therapy is to stop the seizures, minimize drug side effects, stop seizures from coming back, and help you readjust to your home life and work environment after a seizure.

Drug Therapies

Your health care provider will most likely prescribe medication to help control your seizures. About 30 - 70% of people who have one seizure will have a second seizure within 1 year. You may need to try several medications or combinations before you find one that works for you. There are a number of drugs available to help treat seizures, including anticonvulsants (anti-seizure drugs) and sedatives.

If medications do not work, ask your doctor about a procedure called vagus nerve stimulation.

Early diagnosis and treatment of seizure disorders with a single appropriate agent provides the best prospect of achieving seizure-free periods with the lowest risk of toxicity. Treatment should be based on seizure type, tolerability, laboratory monitoring, drug interaction profile, and dosing frequency.

HYDANTOINS (eg, phenytoin, fosphenytoin):

The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited. By possibly promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of post-tetanic potentiation at synapses. Loss of post-tetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas.Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of tonic-clonic seizures. Additional monitoring and caution with phenytoin therapy is necessary due to its binding to serum proteins (about 90%), nonlinear elimination kinetics, and its metabolism by CYP450.

BARBITURATES (eg, phenobarbital): 

Barbiturates cause a nonselective depressant effect throughout the CNS, with actions ranging from mild sedation, to hypnosis, anesthesia, and anticonvulsant activity. The anticonvulsant effects of barbiturates are mediated by activity on gamma-amino benzoic acid (GABA) in the polysynaptic midbrain reticular formation, which controls CNS arousal. Barbiturates potentiate GABA response by increasing the length of time chloride channels are open, resulting in a hyperpolarized cell membrane, which prevents further excitation of the cell. Phenobarbital is effective for treating generalized tonic-clonic and partial seizures, however it is limited by its sedative effects and behavioral toxicity in children and the elderly. It is also an inducer of CYP450.

IMINOSTILBENES (eg, carbamazepine, oxcarbazepine):

Similar to hydantoins, iminostilbenes act by reducing polysynaptic responses and blocking the post-tetanic potentiation. Carbamazepine is used in patients with generalized tonic-clonic seizures and both simple and complex partial seizures. The pharmacokinetics of carbamazepine can be erratic since it induces its own metabolism and is potentiated and antagonized by other antiseizure drugs (see Tegretol monograph). Although rare, aplastic anemia and agranulocytosis have been reported with its use. Oxcarbazepine, a keto analog of carbamazepine, is approved as monotherapy or adjunct therapy for partial seizures. It induces hepatic enzymes to a lesser extent than carbamazepine.

SUCCINAMIDES: 

Ethosuximide suppresses the paroxysmal three cycle per second spike and wave activity associated with lapses of consciousness, which is common in absence seizures. The frequency of epileptiform attacks is reduced, apparently by depression of the motor cortex and elevation of the threshold of the CNS to convulsive stimuli. Ethosuximide may be administered in combination with other anticonvulsants when other forms of epilepsy coexist with absence.

VALPROIC ACID:

 Valproic acid dissociates to the valproate ion in the GI tract. It has been suggested that its activity in epilepsy is related to increased brain concentrations of GABA. Equivalent oral doses of Depakote(divalproex sodium) products and Depakene (valproic acid) capsules deliver equivalent quantities of valproate ion systemically. Although the rate of valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle), conditions of use (eg, fasting or postprandial) and the method of administration (eg, whether the contents of the capsule are sprinkled on food or the capsule is taken intact) these differences should be of minor clinical importance under the steady state conditions achieved in chronic use in the treatment of epilepsy. 

However, differences among products may be seen upon initiation of treatment, therefore close monitoring should accompany any dosage changes. Valproic acid is used to treat complex partial seizures as well as simple and complex absence seizures. Hepatic failure resulting in fatalities has occurred in patients receiving valproic acid. Valproate can produce teratogenic effects such a neural tube defects.

BENZODIAZEPINES (eg, clonazepam, diazepam): 

The mechanism by which benzodiazepines exert their antiseizure effects is believed to be related to their ability to enhance the activity of GABA, the major inhibitory neurotransmitter in the CNS. Clonazepam is useful in the treatment of Lennox-Gastaut syndrome, akinetic and myoclonic seizures, and in absence seizures (in patients who have failed to respond to succinamides). When used in patients with several different types of seizure disorders, clonazepam may increase the incidence or precipitate the onset of generalized tonic-clonic seizures. The concomitant use of valproic acid may produce absence status. Tolerance to the antiseizure effects of clonazepam may develop after 1–6 months of use.Diazepam and lorazepam are effective in the treatment of status epilepticus.

OTHER CLASSES:

Gabapentin and pregabalin are effective as adjunctive therapy in the treatment of partial seizures. The anticonvulsant mechanism of action of gabapentin and pregabalin is unknown.

Lamotrigine is indicated as adjunctive therapy for partial seizures, the generalized seizures of Lennox-Gastaut syndrome, and primary generalized tonic-clonic seizures. It is also indicated for conversion to monotherapy in patients with partial seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single antiepileptic drug. The mechanism by which lamotrigine exerts its anticonvulsant effects has not been established. Serious rashes requiring hospitalization and discontinuation of treatment have been reported in association with the use of lamotrigine.

Levetiracetam is indicated as adjunctive therapy in the treatment of partial onset seizures, myoclonic seizures, and primary generalized tonic-clonic seizures. The anticonvulsant effect of levetiracetam is not fully understood. Levetiracetam and its major metabolite are neither inhibitors of nor high affinity substrates for hepatic CYP450 isoforms.

Tiagabine is approved for adjunctive therapy in the treatment of partial seizures. The exact mechanism of action is unknown, although it is believed to be related to its ability to enhance the activity of GABA. Tiagabine is considered to be a non-enzyme inducing antiepileptic drug. Dosing recommendations are dictated by whether a patient is also taking enzyme-inducing antiepilepsy drug (eg, carbamazepine, phenytoin, primidone, phenobarbital). These patients are considered induced. Use in non-induced patients requires lower doses of tiagabine; these patients may also require a slower titration of tiagabine compared to that of induced patients.

Topiramate is effective against a variety of seizure types including, partial onset or primary generalized tonic-clonic seizures, and in seizures associated with Lennox-Gastaut syndrome. Although the precise mechanism by which topiramate exerts its anticonvulsant effects is unknown, it is suggested that this agent has four properties: 1) it blocks voltage-dependent sodium channels, 2) augments the activity of GABA at some subtype of the GABAA receptor, 3) antagonizes the AMPA/kainite subtype of the glutamate receptor, and 4) inhibits the carbonic anhydrase enzyme, particularly isozymes II and IV.

Felbamate is effective in treating patients with poorly controlled partial seizures, with or without generalization, and as an adjunct in Lennox-Gastaut syndrome. It is not considered a first-line treatment. Therapy with felbamate has been associated with cases of aplastic anemia.

Zonisamide is indicated for adjunctive therapy in the treatment of partial seizures. Although the mechanism of action is unknown, zonisamide may produce its antiseizure effects through action at sodium and calcium channels. Zonisamide is a sulfonamide; if signs of hypersensitivity or other serious reactions occur, the drug should be discontinued immediately. Zonisamide is not expected to interfere with the metabolism of other drugs that are metabolized by CYP450 isozymes.

Nutrition and Supplements

A ketogenic diet -- high in fat and low in protein and carbohydrates -- may help control the frequency of seizures in some people. It has been studied most often for children, and seems to work better for children than adults. A doctor needs to closely monitor this diet, both for side effects and to make sure you are following its rigid structure. You may need to take vitamin and mineral supplements, because this diet is very restricted.

Some studies have shown a connection between food allergies and seizures in some children, but the evidence isn' t clear. Avoid alcohol, caffeine, and any supplements that have stimulating effects. A holistically oriented health care provider may help you pinpoint possible food allergies.

Some supplements may make certain anti-seizure medications less effective. Be sure to ask your doctor before taking any herbs or supplements.

• Taurine (500 mg three times per day) is an amino acid that may be involved in the brain' s electrical activity and is often low in people with seizures. It acts in a similar fashion to GABA (gamma aminobutyric acid, 500 mg two times per day), another amino acid that is often low in people with seizures. But there is no scientific evidence that taking either supplement will reduce seizures. Do not take either of these supplements without your doctor' s supervision.
• Folic acid levels may drop during seizures and may be low in some people with seizures. But taking extra folic acid may make anticonvulsant drugs less effective, raising your risk for more seizures. Do not take folic acid without your doctor's supervision.
• Vitamin B12 (100 - 200 mcg per day) -- Some anticonvulsant drugs may cause low levels of B12 in the body.
• Vitamin E (400 IU per day) may help reduce the frequency of seizures when used with prescription drugs, but some studies show that it doesn' t help.
• Anticonvulsant drugs may cause low levels of calcium, vitamin D, and vitamin K, so people who take anticonvulsant drugs should ask their doctor about taking a supplement. Calcium can interfere with anticonvulsant drugs, so do not take calcium without your doctor's supervision.