Epilepsy

Description

Medications

According to a 2000 survey, the anti-epilepsy drug arsenal has nearly doubled in size since 1993. As a result, physicians 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 agents). If they fail or if the patient becomes tolerant to the primary AEDs, then newer so-called 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 agents 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 agent 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 are reporting 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preceded by hearing loss in people who have taken it for more than a year, but they were reversible when the drug was withdrawn.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.

• 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.)
• The drug poses a significant risk for birth defects.
• Valproate and divalproex sodium are not usually recommended for young children because of an unusual, but potentially fatal, toxic effect on the liver. It should be noted that this very rare effect is most likely to affect children under two years of age who have birth defects and are taking more than one antiseizure drug. Some physicians recommend monitoring of blood levels for liver function once before administering valproate or divalproex sodium, monthly during the first six 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 (liver or pancreas).
• Nausea or vomiting (liver or pancreas).
• Loss of appetite (liver or pancreas).
• 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 now available that allows twice-daily dosing rather than three 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 the following:

• Skin reactions develop that are so severe that the drug has to be discontinued 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 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 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 (e.g., Stevens-Johnson syndrome).

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 agent 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 agents, 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 authorities even believe that primidone has no advantage over the other drug.

Ethosuximide and Similar Agents

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 Agents

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 agents that fail to control seizures, many physicians are now prescribing them as single agents. Specific choices usually depend on the individual's particular condition and the specific side effects of the AED. None as yet has emerged as being superior to either standard or newer agents. All appear to offer some benefits, but as with standard antiseizure drugs, they also have troublesome side effects.

Lamotrigine. Lamotrigine (Lamictal) is effective as add-on therapy and is well tolerated in treating partial and generalized seizures. It has now been approved as monotherapy for partial seizures in adults who have not responded to standard agents and as add-on therapy for children with partial seizures and Lennox-Gastaut syndrome. Studies overseas have suggested that it is as effective as carbamazepine and phenytoin and patients tolerate it better. Lamotrigine may be a good alternative for people who experience weight gain or other hormone-related side effects from valproate. Lamotrigine may not have the adverse effects on sexual function in men as some other antiseizure agents have. The drug also appears to improve cholesterol levels.

A rash occurs in 5% of patients; it may disappear in some patients who continue taking the drug, but in rare cases it can become very severe. The risk of the rash increases if the drug is started at too high a dose or if the patient is also taking valproic acid. (Serious rash is more common in young children who take the drug than it is in adults.) Other side effects may include nausea, dizziness, blurred vision, headache, and sleepiness. Some patients report severe insomnia. A rare but serious side effect is anticonvulsant hypersensitivity syndrome, which is characterized by fever, skin eruptions, abnormal lymph nodes, and liver damage.

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.

Topiramate. Topiramate (Topamax) is similar to phenytoin and carbamazepine and is effective and safe for a wide variety of seizures in adults and children as young as two, including partial and generalized tonic-clonic epilepsies. Studies are showing a 34% to 87% reduction in seizure frequency with some patients becoming seizure-free. It may even help some children who have Lennox-Gastaut syndrome. A 2000 study reported that it was safe even in infants with severe myoclonic epilepsy, and in half of these patients seizure frequency fell by more than 50%, with 22% of them experiencing a reduction greater than 75%. 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. Reported side effects include mood swings and behavioral problems, dizziness, fatigue, visual disturbances, tremor, impaired concentration and thinking, weight loss and diarrhea, and a higher risk for kidney stones. Reduced sweating can be a significant adverse effect, particularly in children, since it can increase body temperature. Recent reports have associated a few cases of an uncommon form of glaucoma called angle-closure glaucoma with topiramate. Symptoms can occur suddenly and include blurred vision, headache, vision loss, and nausea. Immediate treatment is required.

Oxcarbazepine. Oxcarbazepine (Trileptal) is similar to phenytoin and carbamazepine but has fewer side effects. It has been approved as monotherapy for partial seizures in adults and as add-on treatments for children. Oxcarbazepine, for example, appears to have few interactions with other drugs and may be particularly useful for elderly patients, who often require additional medication.

Zonisamide. Zonisamide (Zonegran) is a unique agent 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 agent and has been approved for partial onset seizures. Nootropics enhance mental function under conditions of low-oxygen levels. Some experts believe that levetiracetam represents a significant advance and will prove to be an important first-line agent. Some evidence suggests that it improves mental function and quality of life, which persist over the long term.One advantage of levetiracetam is that the initial dose is often effective for maintenance, simplifying the regimen. It has fewer drug interactions than other anti-epileptic agents 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, and 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. And, one study suggested that it has more adverse effects than lamotrigine and is not as well tolerated.

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-vinylGABA. 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 US 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% and 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 Agents

GABA Enhancers.Retigabine and pregabalin are investigative GABA enhancers that may prove to be more effective than the current AEDs with similar actions (vigabatrin, tiagabine, gabapentin and topiramate).

Other Investigative Anti-Epilepsy Agents.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.

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

Other anti-seizure agents being investigated include carabersat, fluorofelbamate, harkoseride, safinamide, and valrocemid.

Cannabinoids. Cannabinoids are compounds in marijuana (cannabis), which may have properties that protect nerve cells. In one 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 agent except as part of a clinical trial. Of note, in some studies, melatonin has been found to cause seizures in children who have existing neurologic problems.