• Highlights
• Introduction
• Causes
• Outlook and Effects
• Diagnosis
• Treatment
• Long-Term Treatment
• Medications
• Surgery
• Lifestyle Changes
• Resources
• References

Epilepsy

Description

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

Medications

According to a 2000 survey, the anti-epilepsy drug (AED) arsenal has nearly doubled in size since 1993. As a result, doctors have been able to offer many of their patients drugs with improved effectiveness, tolerability, and safety. Depending on the seizure type, certain standard AEDs are usually used first (called first-line drugs). If they fail, or if the patient becomes tolerant to the primary AEDs, then newer add-on or second-line AEDs are tried, usually in combination with the standard drugs. The lines are beginning to blur, however, as studies on the newer second-line drugs add to the evidence of their effectiveness and tolerability.

Valproate and Divalproex Sodium

Valproate (Depakene, valproic acid) and its delayed release form, divalproex sodium (Depakote), are anticonvulsants. Valproate is the most widely prescribed anti-epileptic drug worldwide. It is the first choice for patients with generalized seizures and is used to prevent nearly all other major seizures as well.

General Side Effects. These drugs have a number of side effects that vary depending on dosage and duration. Most side effects occur early in therapy and then subside. General side effects include:

• Stomach and intestinal problems, which are experienced by nearly half of patients after starting the drugs and may still occur after several years of use. Divalproex sodium (Depakote) has a lower risk for these side effects than valproate (Depakene).
• Increased appetite with significant weight gain often becomes a problem and can be a major reason for noncompliance, particularly in young people.
• Hand tremors, irritability, and hyperactivity in children are fairly common.
• Temporary hair thinning and hair loss have occurred. Taking zinc and selenium supplements may help reduce the effect.
• Young girls may develop secondary male characteristics, and premenopausal women are at increased risk for menstrual irregularities and polycystic ovaries, due to elevated male hormones. The effects are reversible. (These side effects also appear in women using other anti-epileptic drugs, but the risk from valproate appears to be higher.)
• Studies have reported symptoms of Parkinson's disease preceded by hearing loss in people who have taken it for more than a year, but they were reversible when the drug was withdrawn.

Toxic Side Effects.

• Valproate poses a higher risk for serious birth defects than many other AEDs. These birth defects include skull and limb deformities, and brain, heart, and lung problems. Experts recommend that women of child-bearing age use a different type of anti-epilepsy drug than valproate. If valproate is used, it should be prescribed at the lowest possible dose.
• Cases of pancreatitis, a serious and even life-threatening inflammation in the pancreas, have been reported in children and adults taking valproate. (It is still very rare, however.)
• Valproate and divalproex sodium are not usually recommended for young children because of an unusual, but potentially fatal, toxic effect on the liver. This very rare effect is most likely to affect children under 2 years of age who have birth defects and are taking more than one antiseizure drug. Some doctors recommend monitoring of blood levels for liver function once before administering valproate or divalproex sodium, monthly during the first 6 months, and then periodically after that.
• Children with epilepsy who take valproic acid may eventually develop some problems in the kidney, although, according to a 2001 study, they are generally not significant.

Symptoms of Toxic Side Effects in Liver or Pancreas.

• Abdominal pain
• Nausea or vomiting
• Loss of appetite
• Lethargy
• Acute confusion
• Water retention
• Easy bruising
• Yellowish skin coloring

Carbamazepine

Carbamazepine (Tegretol, Carbatrol) is an effective anticonvulsant and specific analgesic when used alone or with other drugs. Carbamazepine also has the added benefit of relieving depression and improving alertness. An extended release form is available that allows twice-daily dosing rather than 3 times a day. It is the standard treatment for partial epilepsies in children, and a chewable form makes it easier for them to take it.

This drug is used to prevent the following seizures or epilepsy syndromes:

• Patients with partial seizures tend to tolerate this drug better than others, although responses differ among individuals.
• Grand mal seizures
• Combinations of grand mal and partial seizures
• Autosomal dominant nocturnal frontal lobe epilepsy (an inherited disorder)

This drug is not useful for the following seizures:

• Petit mal seizures
• Myoclonic seizures
• Atonic seizures

Side Effects. Different side effects may develop or resolve at different points in the treatment duration. Initial side effects may include:

• Double vision, headache, sleepiness, dizziness, and stomach upset. These usually subside after a week and can be greatly reduced by starting with a small dose and building up gradually.
• Some people experience visual disturbances, ringing in the ears, agitation, or odd movements when drug levels are at their peak. The extended-release form of carbamazepine (Carbatrol) may help reduce these symptoms.

Serious side effects are less common but can include:

• Carbamazepine may increase the risk for birth defects, especially if it is taken during the first trimester of pregnancy.
• Skin reactions that are so severe that the drug has to be discontinued develop in about 6% of patients.
• Water retention can be a problem in older people.
• Hormonal changes, particularly higher levels of male hormones in both men and women, pose some risk for sexual dysfunction over time.
• A decrease in white blood cells occurs in about 10% of those taking the drug. This is generally not serious unless infection accompanies it.
• Other blood conditions can arise that are also potentially serious. Patients should be sure to inform the doctor if they have any sign of irregular heartbeats, sore throat, fever, easy bruising, or unusual bleeding.
• Long-term therapy can cause bone loss (osteoporosis) in women, who should take preventive calcium and vitamin D supplements.
• Children are at higher risk for behavioral problems.

Note : Citrus fruit, especially grapefruit, can increase carbamazepine's adverse effects and should be avoided by those taking this drug.

Phenytoin

Phenytoin (Dilantin) is effective for adults who have the following seizures or conditions:

• Grand mal seizures
• Partial seizures
• Status epilepticus
• Can be effective for people with head injuries who are at high risk for seizures

This drug is not useful for the following seizures:

• Petit mal seizures
• Myoclonic seizures
• Atonic seizures

Side Effects. Side effects are sometimes difficult to control. Some people may develop a toxic response to normal doses, while others, such as those with alcoholism, may require higher doses to achieve benefits. As with any drug, side effects generally rely on dosage and duration. Using phenytoin in combination with newer add-on drugs can allow lower doses and may reduce some of the risks. Side effects may include:

• Excess body hair, eruptions and coarsening of the skin, and weight loss
• Gum disease
• Staggering, lethargy, nausea, depression, eye-muscle problems, anemia, and an increase in seizures can occur as a result of high doses.
• The part of the brain that affects muscular stability can be damaged as a result of taking this drug in very high amounts or for long periods of time.
• Liver damage may develop in rare cases.
• Long-term therapy can cause bone loss. Patients should take preventive calcium and vitamin D supplements and exercise regularly to improve bone mass.
• Severe and even rare life-threatening skin reactions (Stevens-Johnson syndrome)
• This drug may increase the risk for birth defects.

Barbiturates (Phenobarbital and Primidone)

Phenobarbital. Phenobarbital (Luminal), also called phenobaritone, is a barbiturate anticonvulsant and is often the initial drug prescribed for newborns and young children. It is a relatively inexpensive drug and is used to also prevent grand mal (tonic-clonic) seizures or partial seizures, particularly in economically disadvantaged areas. Phenobarbital has fewer toxic effects on other parts of the body than most anti-epileptic drugs, and drug dependence is unusual, given the low doses used for patients with epilepsy. Nevertheless, withdrawal is common because of side effects, and therefore it is less likely to be used over time than other drugs, including phenytoin, another relatively inexpensive but effective drug.

Side Effects. Patients sometimes describe their state as "zombie-like." The most common and troublesome side effects are:

• Drowsiness
• Memory problems
• Problems with tasks requiring sustained performance
• Problems with motor skills
• Hyperactivity in some patients, particularly in children and the elderly
• Depression in some adults
• Some controversy has arisen over studies indicating that children taking phenobarbital score lower on intelligence tests, even for some months after going off the drug.

Primidone. Primidone (Mysoline) is converted in the body to phenobarbital, and so has the same benefits and adverse effects. It is reported that primidone is not as well-tolerated as phenobarbital. Some experts believe that primidone has no advantage over the other drug.

Ethosuximide and Similar Drugs

Ethosuximide (Zarontin) is used for petit mal (absence) in children and adults when the patient has experienced no other type of seizures. Ethosuximide succeeds in abolishing petit mal seizures in 60% of patients and controls them in up to 90%. Use of this drug can cause stomach problems, dizziness, loss of coordination, and lethargy. In rare cases, it has caused severe and even fatal blood abnormalities. Periodic blood counts are recommended for patients taking this drug.

Methsuximide (Celontin), a drug similar to ethosuximide, may be suitable as an add-on treatment for intractable epilepsy in children without causing serious or permanent side effects.

Clonazepam and Similar Drugs

Clonazepam (Klonopin) is recommended for myoclonic and atonic seizures that cannot be controlled by other drugs and for Lennox-Gastaut (absence variant). It may be useful in newborns in whom other drugs are ineffective. Although clonazepam can prevent generalized or partial seizures, patients generally develop tolerance to the drug, and then seizures recur.

Side Effects. People who have had liver disease or acute angle glaucoma should not take clonazepam, and people with lung problems should approach the drug with caution. Clonazepam can be addictive and abrupt withdrawal has been known to trigger status epilepticus. Side effects include the following: drowsiness, imbalance and staggering, irritability, aggression, hyperactivity in children, weight gain, eye muscle problems, slurred speech, tremors, skin problems, and stomach problems.

Add-Ons or Secondary AEDs

Many newer AEDs are now available and are usually better tolerated than the older, standard AEDs. They often cause less sedation and require less monitoring. Although they are generally approved for use as add-ons to standard drugs that fail to control seizures, many doctors are now prescribing them as single drugs. Specific choices usually depend on the individual's particular condition and the specific side effects of the AED. None has yet has emerged as being superior to either standard or newer drugs. All appear to offer some benefits, but, as with standard antiseizure drugs, they also have troublesome side effects.

Lamotrigine. Lamotrigine (Lamictal) is approved as add-on (adjunctive) therapy for partial seizures, and generalized seizures associated with Lennox-Gastaut syndrome, in children aged 2 years and older and in adults. In 2006, lamotrigine was approved as add-on therapy for treatment of primary generalized tonic-clonic (PGTC) seizures, also known as “grand mal” seizures, in children aged 2 years and older and adults. Lamotrigine can be used as a single drug treatment (monotherapy) for adults with partial seizures who have not responded to monotherapy with carbamazepine, phenytoin, phenobarbital, primidone, or valproate.

Common side effects include dizziness, headache, blurred or double vision, lack of coordination, sleepiness, nausea, vomiting, insomnia, and rash. Although most cases of rash are mild, in rare cases the rash can become very severe. The risk of rash increases if the drug is started at too high a dose or if the patient is also taking valproate. (Serious rash is more common in young children who take the drug than it is in adults.) Rash is most likely to develop within the first 8 weeks of treatment. Be sure to immediately notify your doctor if you develop a rash, even if it is mild.

Studies suggest that lamotrigine may cause fewer problems with sexual function in men than other antiseizure drugs. A 2006 study indicated that lamotrigine may cause fewer cognitive problems (such as confusion and difficulty concentrating) than topiramate.

Gabapentin. Gabapentin (Neurontin) is an effective add-on drug for controlling complex partial seizures and secondarily generalized partial seizures and is approved for adults and children with these seizures. In a 2002 analysis of current evidence, it achieved response rates in patients with resistant partial epilepsy that were as high as 28% at high doses. It is not at all useful for generalized petit mal seizures.

Its toxicity is low and side effects include sleepiness, headache, fatigue, and dizziness. Some weight gain has been reported. Gabapentin has no significant interactive effects when taken with other drugs. It has the added advantage of improving mood, which is independent from its effect on seizure control. Children may experience hyperactivity or aggressive behavior. Long-term adverse effects are still unknown.

Pregabalin . Pregabalin (Lyrica) is similar to gabapentin. In 2005, it was approved as add-on therapy to treat partial-onset seizures in adults with epilepsy. In clinical trials, half of the patients who received pregabalin experienced a 50% reduction in seizure frequency. Side effects may include dizziness, sleepiness, dry mouth, swelling in hands and feet, blurred vision, weight gain, and trouble concentrating

Topiramate. Topiramate (Topamax, generic) is similar to phenytoin and carbamazepine and is effective and safe for a wide variety of seizures in adults and children. It is approved as add-on therapy for patients 2 years and older with generalized tonic-clonic seizures, partial-onset seizures, or seizures associated with Lennox-Gastaut syndrome. It is also approved as single therapy for patients 10 years and older with tonic-clonic seizures or partial-onset seizures. Studies have shown a 34 - 87% reduction in seizure frequency with some patients becoming seizure-free. Topiramate may have fewer interactions with oral contraceptives than other AEDs.

Most side effects are mild-to-moderate and can be reduced or even prevented by beginning at low doses and increasing dosage gradually. Serious side effects may include glaucoma, decreased sweating, increased body temperature, kidney stones, sleepiness, dizziness, confusion, and trouble concentrating. Patients should immediately tell their doctor if they have blurred vision or eye pain.

Oxcarbazepine. Oxcarbazepine (Trileptal) is similar to phenytoin and carbamazepine but generally has fewer side effects. It is approved as single therapy or add-on therapy for partial seizures in adults and for children aged 4 - 16 years. Serious side effects, while rare, include Stevens-Johnson syndrome and toxic epidermal necrolysis. These skin reactions cause a severe rash that can be life-threatening. Rash and fever may also be a sign of multi-organ hypersensitivity, another serious side effect associated with this drug. Oxcarbazepine can also reduce sodium levels (hyponatremia). Your doctor may want to monitor the sodium level in your blood. This drug can also reduce the effectiveness of birth control pills. Women who take oxcarbazepine may need to use a different type of contraceptive.

Zonisamide. Zonisamide (Zonegran) is a unique drug that blocks sodium and calcium channels and may have nerve-protecting properties. It is approved as add-on therapy for adults with partial seizures and studies indicate it is often effective against infantile spasms (West's syndrome) and myoclonic seizures. Zonisamide increases the risk for kidney stones, which can be reduced with increased fluid intake and citrate. It has also been associated with reduced sweating and a sudden rise in body temperature, especially in hot weather. Children are especially at risk for this side effect, which can be serious. (The drug has not been approved for children.) Other side effects tend to decrease over time and include dizziness, forgetfulness, headache, weight loss, and nausea.

Levetiracetam. Levetiracetam (Keppra) is known as a nootropic drug. It is approved both in oral and intravenous forms as add-on therapy for partial onset seizures in adults and children aged 4 years and older. It is also approved as add-on therapy for treatment of myoclonic seizures in adults and adolescents 12 years of age and older who have juvenile myoclonic epilepsy. Some experts believe that levetiracetam represents a significant advance and will prove to be an important first-line drug. Levetiracetam appears to have fewer drug interactions than other anti-epileptic drugs and may be particularly useful for older patients.

Side effects occur mostly in the first month. They include sleepiness and fatigue, muscle weakness and coordination difficulties, headache, flu symptoms, dizziness, behavioral abnormalities, possible risk of a reduced white blood cell count, and a higher rate of infections. Caution is advised for patients with kidney dysfunction. There have been some reports of adverse effects on mood (irritability, depression, anxiety), but recent studies have found fewer such effects than with other AEDs. Epilepsy, rather than the drug, is likely to be the cause of these mood changes. About 1% of patients report considerable weight loss.

Tiagabine. Tiagabine (Gabitril) has properties similar to phenytoin and carbamazepine, and is also showing promise. Evidence has reported some significant side effects with its use, including dizziness, fatigue, agitation, and tremor. At least one study suggested that it has more adverse effects than lamotrigine and is not as well tolerated. In February 2005, the FDA issued a warning advising that tiagabine may cause seizures in patients without epilepsy. Tiagabine is only approved for use with other anti-epilepsy medicines to treat partial seizures in adults and children 12 years and older.

Less Commonly Used AEDs

Felbamate. Felbamate (Felbatol) is an effective antiseizure drug. However, after reports of deaths from a serious blood condition known as aplastic anemia or from liver failure, felbamate is only recommended under certain circumstances. They include severe epilepsy, such as Lennox-Gastaut syndrome or as monotherapy for partial seizures in adults when other drugs fail.

Vigabatrin. Vigabatrin (Sabril) is a chemical called gamma-vinyl GABA. It was designed to increase the brain levels of gamma aminobutyric acid (GABA), the enzyme that inhibits seizure activity. It has serious side effects, however, and is generally prescribed in the U.S. in only certain cases, such as in low doses for patients with Lennox-Gastaut syndrome. Overseas it is also used for partial seizures and as first line therapy in children with infantile spasms (West syndrome). Between 10 - 30% of people on long-term treatment have developed irreversible visual disturbances, including reductions in acuity and color vision. Men are at higher risk for this side effect than are women. Further studies are needed to determine the extent and severity of this complication, particularly in children. There is a slight risk for depression or psychosis when vigabatrin is used as add-on therapy, and particularly if the drug is administered too quickly. These risks are far lower if the drug is used as sole therapy.

Older Drugs. Some older but less effective drugs may still play a role against epilepsy:

• Acetazolamide (Diamox) is sometimes used against common types of seizures, but patients quickly develop a tolerance for it. Some experts suggest it still may be useful when drug interactions are a problem, when a rapid effect is required, or when an additional drug is needed for a short time.
• Trimethadione (Tridione) is effective for petit mal seizures, but has very serious side effects, and its use is severely limited.

Investigative Drugs

GABA Enhancers. Retigabine is an investigative GABA enhancer that may prove to be more effective than current AEDs with similar actions (vigabatrin, tiagabine, gabapentin and topiramate). It is currently in phase III trials for treatment of partial-onset seizures.

Other Investigative Anti-Epilepsy Drugs. Losigamone is a unique AED whose exact mechanism is unclear. In a well-conducted 2003 study, the drug appeared to be effective and safe for adults with partial epilepsy. Most side effects occurred within the first month and then subsided.

Drugs known as AMPA receptor antagonists, for example, have anti-seizure properties and are under investigation. Talampanel is one such potentially effective AED and is currently in early trials.

Other anti-seizure drugs being investigated include fluorofelbamate, safinamide, brivaracetam, and seletracetam.

Cannabinoids. Cannabinoids are compounds in marijuana (cannabis) that may have properties that protect nerve cells. In a 2003 report, people with epilepsy were twice as likely to use marijuana as the general public, with two thirds of them taking it because they believed it reduced their seizures. Other active users of marijuana reported no effect on seizures. No one has reported worse seizures from the drug. Animal studies further support some protection from cannabinoids against seizures. Clinical studies using humans have not been conducted.

Melatonin. Melatonin is a hormone found in the brain that is best known for its role in sleep. Some researchers believe that it might have properties that could benefit patients with epilepsy. Melatonin is a powerful hormone that can have major effects on all parts of the body. No one with epilepsy should experiment with this supplement except as part of a clinical trial. In some studies, melatonin has been found to cause seizures in children who have existing neurologic problems.

• 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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