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Epilepsy

Description

An in-depth report on the types, causes, diagnosis, and treatment of epilepsy.

Long-Term Treatment

Treatment with anti-epileptic drugs (AEDs) is usually initiated or strongly considered for the following patients:

• Children and adults who have had two or three seizures, unless there is either a long separation between seizures or the seizure is provoked by an injury or other specific causes. (In children, risk for recurrence after a single unprovoked seizure is rare. The risk even after a second seizure is low, even when the seizure is prolonged.)
• Children and adults after a single seizure if tests reveal any brain injury, or if specific syndromes put a person at special risk for recurrence, for instance, in cases of myoclonic epilepsy.

There is some debate about whether to treat every adult patient with an AED after a single initial seizure. Some experts do not recommend treating adult patients after a single seizure if they have a normal neurologic examination, EEG, and imaging studies. A 2005 study of patients with single or infrequent seizures found that while early AED treatment reduced the risk of seizure for a few years, it had no effect on long-term outcomes. This study also suggested that delaying AED treatment does not increase the risk of developing lifelong epilepsy.

Some doctors believe, however, that any adult who has a first seizure should begin on-going AED treatment, since 30 - 70% of these patients are likely to experience a subsequent event. According to one study, when young adults were given a single drug (usually carbamazepine) after a first generalized seizure, only 22% had a subsequent seizure compared to about 70% of those who were not given treatment.

Determining an Anti-Epileptic Drug (AED) Regimen

Most epileptic seizures can be controlled using a single-drug regimen. First-line AED drugs include phenytoin (Dilantin), carbamazepine (Tegretol, Carbatrol), and divalproex sodium (Depakote). Patients generally begin with low doses and build up until the seizures are controlled or a toxic reaction occurs. If a single drug fails to control seizures, then other drugs are added on. The specific drugs and whether more than one should be used are determined by various factors, including the patient's age and the seizure's type, frequency, and cause.

Treatment Success and Failure of AEDs

In a 2000 study that followed over 500 patients for 3 - 5 years, 63% of patients treated with AEDs become seizure-free. In the same study, drugs failed to control epilepsy in about 30% of patients. Those with the poorest chances of success were those who started AED treatment after more than 20 seizures, and those who failed to exhibit any benefit from their initial drug regimen. (In the latter case, subsequent drugs worked in only 11% of patients.)

Reasons for Failure. An AED's failure to reduce seizures can be attributed to factors such as:

• The wrong dose level
• Improper timing
• Introducing the medication too rapidly
• Not managing conditions that triggered the seizure
• Instability of the drugs. Many of the tablet forms disintegrate easily with moisture, so pills should be stored in a dry place, not in the bathroom, and kept away from heat.
• Toxicity. Some research indicates that over 40% of patients experience toxic effects from older AEDs, which often causes them to withdraw. Among the most distressing are sleepiness, problems in coordination, and weight gain.
• Some evidence suggests that about a quarter of patients who do not respond to AEDs actually have nonepileptic seizures that in many cases are caused by psychiatric conditions (panic attack, personality disorders).

The doctor should first address these issues. If the patient still does not respond, the doctor will usually try a different drug. If this fails, one or even two additional drugs at a time may be used. When seizures do not respond to the first two or three drugs, the odds of a fourth or fifth working diminish greatly, despite a number of new medications on the market. In such cases, the patient should ask about surgical alternatives.

Noncompliance. Failure to take medication as prescribed is a serious problem, particularly in young people. It is extremely important to take a drug exactly prescribed by the doctor as not doing so can lead to seizures. Studies have shown that uncontrolled epileptic attacks lead to changes in the neurons that may cause intractable epilepsy.

Healthy Behaviors. In young people, a positive attitude, continued support from family and health care providers, emotional well-being, and good treatment results can increase patient compliance. Unhealthful behaviors, such as smoking and alcohol use, can have a negative effect.

Monitoring Effects

During the first few months of therapy, the doctor will probably order blood tests once or twice to monitor drug levels and, if necessary, adjust dosages. Monitoring is used to check for AED complications, and to be sure the patient is complying with the regimen. Many experts feel, however, that these blood tests are a less reliable indicator of problems than the patient's own self-observations of his or her responses to the drug. For instance, blood tests may suggest that the dosage levels are insufficient according to general standards, yet the individual patient may be seizure-free and leading a normal life. It is very important that women have AED levels monitored during pregnancy.

General Information on Side Effects of AEDs

All anti-epileptic drugs have side effects, which vary depending on the drug. Increasingly, however, AEDs are being designed to specifically target mechanisms causing seizures, and should have fewer widespread effects. The complexity and potential severity of side effects are amplified when more than one drug is used. Seizures themselves can be a side effect of AEDs.

Some problems common to many of the AEDs include:

• Fatigue and sleepiness
• Changes in appetite and weight
• Loss of coordination
• Gastrointestinal problems
• Possible bone loss leading to osteoporosis, even in young people. The older medications, such as phenytoin, phenobarbital, carbamazepine, and primidone, have more severe effects than valproic acid and the newer drugs. Many of the latter drugs, however, also pose some risk. Patients should ask their doctors about taking calcium and vitamin D supplements, a bone-protecting exercise regimen, and monitoring with bone densitometry.
• Changes in skin and hair, including acne from phenytoin, excessive hair growth from phenytoin and carbamazepine, and hair loss from valproate
• Reproductive problems
• Severe allergic reactions (particularly from particularly phenytoin, carbamazepine, phenobarbital, and primidone). They can include severe skin rashes, fever, and occasionally even inflammation or swelling of the liver, kidneys, or lymph nodes.

Drug Interactions

AEDs interact with many other drugs, making them more or less potent, so it is very important that patients inform their doctor of everything they are taking, including over-the-counter medications and vitamins. Some specific interactions are covered later in discussions of individual drugs. Many of the AEDs have some common effects on other medications; several reduce the effectiveness of oral contraception, for example. Erythromycin and some drugs used to treat asthma, ulcers, and heart disease can interact with AEDs.

Discontinuing Drug Therapy

An estimated 60% of all patients treated effectively can stop taking AEDs within 5 - 10 years. Evidence in 2002 suggests that medications in children should not be halted for at least 2 years after the last seizure, particularly if they have partial seizures and abnormal EEGs. It is not clear whether children who have been free of generalized seizures need to wait more than 2 years or if they can withdraw earlier. There is also no clear evidence on whether adults who are free of any seizure type can safely withdraw from their medications within 2 years of their last seizure of if they should wait.

In any case, attempts to halt drugs should be done during periods when seizures will cause the least harm. For instance, the best time to test the effects of drug withdrawal in teenagers might be about a year before they are eligible to drive.

Indications for Surgery

Surgery is an option for appropriate patients who do not respond to medications and have epilepsy in the temporal lobe (where most complex partial seizures occur). Younger people are preferred candidates for surgery because older people have more difficulty with rehabilitation.

In general, about 75% of appropriate patients can expect at least partial remission at experienced centers, with some centers reporting even better results. Temporal lobe surgery may even improve quality of life, prolong survival, and help prevent sudden deaths associated with epilepsy. Yet despite these benefits, and the significant chance for failure after trying four or five drugs, doctors now wait an average of 15 - 19 years before they consider a surgical alternative.

Treatment for Special Population Groups

Treatment of Specific Seizure Syndromes in Infants and Small Children.

• Lennox-Gastaut. The newer drugs, felbamate, lamotrigine, and topiramate, are useful in treating this syndrome in children 2 years and older. (Note: Serious rash is more common in young children with lamotrigine than it is in adults.)
• Infantile spasms. Infantile spasms are treated with vigabatrin, adrenocorticotropic hormone (ACTH), or valproate. Some experts recommend that vigabatrin be given first and ACTH administered 10 - 14 days later. In one small study, no infants who were given this combination relapsed after 4 months. Newer drugs may also be effective for this problem, but their effects on small children are not yet wholly known.
• Acute tonic-clonic convulsions and convulsive status epilepticus. Intravenous diazepam, a drug known as a benzodiazepine, is the first choice. Rectal administration of benzodiazepines, either diazepam or lorazepam, may also be beneficial. Some evidence suggests that rectal administration of lorazepam is safer and more effective than diazepam, but more research is needed.
• Prolonged febrile seizures. Prolonged febrile seizures in infants and small children may be treated with intravenous benzodiazepines, usually diazepam. Other drugs under investigation include nasally administered midazolam (a newer benzodiazepine). In one study, it was effective for managing febrile seizures in children. It is absorbed quickly and is as safe as diazepam. With the proper instruction, it can also be administered by caregivers at home.

Treatment of Adults with Symptomatic Myoclonus . Myoclonus is sudden, jerky contractions that can be a symptom of epilepsy. Symptomatic, or secondary, myoclonus is usually caused by metabolic disorders or drugs. In 2005, brivaracetam was approved for treatment of symptomatic myoclonus. The drug is also being studied for epilepsy treatment

Treatment of the Elderly. Anti-epileptic drugs interact with many other drugs, and may cause special problems in older patients who use multiple medications for other health problems. Elderly patients should have liver and kidney function tests performed before starting antiseizure medication. Standard drugs are usually effective, while safe, newer ones (including gabapentin, lamotrigine, oxcarbazepine, and gamma-vinyl-GABA) may sometimes prove to be useful as a sole therapy. These newer drugs also increase patient compliance because they tend to have fewer side effects than the older ones.

Treatment of Women. Hormonal fluctuations affect epilepsy in about a third to a half of female patients. Estrogen appears to increase activity, and progesterone reduces it. The effect of pregnancy on women with epilepsy is complex. The following treatments may help or affect women with epilepsy:

• Hormonal Drugs that Suppress Ovulation. When seizures in women are worsened by hormonal changes, such as during the menstrual cycle, suppressing ovulation may be recommended using drugs called gonadotropin-releasing hormone agonists.
• Hysterectomy. Women with epilepsy who no longer wish to bear children may consider hysterectomy (surgical removal of the uterus) or oophorectomy (surgical removal of the ovaries). Each of these treatments must be accompanied by estrogen replacement therapy.
• Oral contraceptives. Antiseizure medications affect many oral contraceptives (OCs). Carbamazepine, phenytoin, phenobarbital, primidone, oxcarbazepine, and topiramate reduce the effects of OCs. Valproate does not, and may even increase hormonal levels. Gabapentin, lamotrigine, tiagabine, and vigabatrin may also prove to be safe with OCs, but more research is needed. Progestins may be the best contraceptive drugs for women with epilepsy at this time. Injected progestins may actually help prevent seizures in some cases.

More information on epilepsy and pregnancy can be found in this report under "Outlook and Effects."

• Review Date: 11/15/2006
• Reviewed By: Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital

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