Epilepsy In-Depth

Introduction

Epilepsy is characterized by unprovoked, recurring seizures that disrupt the nervous system and can cause mental and physical dysfunction. In the US, about two and a half million people are affected by epilepsy and seizures. About 10% of the American population will experience at least one seizure during their lifetime.

The structures of the brain include: the brainstem, consisting of the spinal cord, the medulla oblongata, the pons and the midbrain; the cerebellum; the cerebrum (one half, or hemisphere shown), and the diencephalon .

Epilepsy affects all age groups. Males have a slightly higher risk than females. The incidence is highest in children with another, but lesser, peak occurring after age 60. According to one estimate, 14% of epilepsy patients are under 15 years old and approximately a quarter are over age 64.

Every year between 25,000 and 40,000 American children have a first seizure that is unrelated to a fever. Epilepsy is decreasing in childhood but increasing in the elderly, probably because of mild strokes and cardiac arrest.

Criteria for Classifying Epilepsies and Seizures

Epilepsy is not a single disorder but rather a wide spectrum of problems. What all types of epilepsy share are recurrent, unprovoked seizures caused by an uncontrolled electrical discharge from nerve cells in the cerebral cortex. This part of the brain controls higher mental functions, general movement, and the functions of the internal organs in the abdominal cavity, perception, and behavioral reactions.

Seizures are a symptom of epilepsy. At this time, epilepsy types are generally into two categories, which are based on the specific biologic mechanisms involved in the seizure and the anatomical location of the seizure. They two types are:

• Partial (also called focal or localized) seizures. These seizures are more common than generalized seizures and occur in one or more specific locations in the brain. In some cases, partial seizures can spread to wide regions of the brain. They are likely to develop from specific injuries, but in most cases the exact origins are unknown.
• Generalized seizures. These seizures typically occur in both sides of the brain. Many forms of these seizures are genetically based. There is usually normal neurologic function.

Experts are finding, however, that these categories do not actually reflect what is now known about the brain's anatomy. For example, the words "partial" and "generalized" suggest that seizures either involve only part of the brain or are widespread. However, a number of events in the brain occur with either type, muddying these distinctions. Researchers are now in the process of making clearer definitions and terms that reflect what actually is happening in the brain.

Improved definitions of terms and new diagnostic technologies, including advanced imaging and genetic testing, have spawned new classification systems that better define specific epilepsies. The evolving methods may help researchers more accurately focus on specific epilepsies and allow doctors to make more appropriate therapeutic decisions. For example, some professional groups now suggest that epilepsies be classified in the following five ways:

• Type of seizure (partial or generalized). Currently these categories are undergoing change.
• Description of the seizure onset and evolution.
• Specific syndromes that are associated with one or more seizure types. (Not all seizures will be part of a syndrome.)
• Specific causes of the seizures, if known.
• The degree of impairment.

Partial Seizures (also called Focal Seizures)

Partial, or focal, seizure is the more common type of epilepsy, and is generally defined as a disorder of neurons that starts on one side of the brain. The seizures are currently subcategorized as "simple" or "complex partial."

• Simple Partial Seizures. A person with a simple partial seizure (sometimes known as Jacksonian epilepsy) does not lose consciousness, but may experience confusion, jerking movements, tingling, or odd mental and emotional events. Such events may include deja vu, mild hallucinations, or extreme responses to smell and taste. After the seizure, the patient usually has temporary weakness in certain muscles.
• Complex Partial Seizures. Slightly over half of the seizures in adults are complex partial type. About 80% of these seizures originate in the temporal lobe, the part of the brain located close to the ear. Disturbances there can result in loss of judgment, involuntary or uncontrolled behavior, or even loss of consciousness. About 20% of these patients have seizures that start in the brain's frontal lobes. Prior to the actual seizure, people sometimes experience a warning sign, known as an aura, which can be a visual or auditory hallucination, an odd odor or a feeling of warmth. They may lose consciousness briefly and appear to others as motionless with a vacant stare. Emotions can be exaggerated; some sufferers even appear to be drunk. After a few seconds, a patient may begin to perform repetitive movements, such as chewing or smacking of lips. Episodes usually last no more than two minutes. People can have them infrequently, or as often as every day. A throbbing headache may follow a complex partial seizure.

In some cases, simple or complex partial seizures evolve into what are known as secondarily generalized seizures. The progress may be so rapid that the partial stage is not even noticed.

While the term "partial" implies the seizures affect only small or specific brain locations, in reality, they almost always involve diffuse and even widespread areas. In the future, the term "focal seizures" will most likely replace the term "partial seizures," and its subcategories. Until new classifications are more widely in use, this report will continue to use the term "partial seizures" and its subcategories.

Generalized Seizures

Generalized seizures are caused by nerve cell disturbances that occur in more diffuse areas of the brain than do partial seizures. Therefore, they have a more serious effect on the patient. They are further subcategorized as tonic-clonic (or grand mal) or absence (petit mal) seizures.

• Tonic-Clonic (Grand Mal) Seizures. The first stage of a grand mal seizure is called the tonic phase, in which the muscles suddenly contract, causing the patient to fall and lie stiffly for about 10 to 30 seconds. Some people experience a premonition or aura before a grand mal seizure; most, however, lose consciousness without warning. If the throat or larynx is affected, there may be a high-pitched musical sound (stridor) when the patient inhales. Spasms occur for about 30 seconds to a minute, then the seizure enters the second phase, called the clonic phase. The muscles begin to alternate between relaxation and rigidity. After this phase, the patient may lose bowel or urinary control. The seizure usually lasts a total of two to three minutes, after which the patient remains unconscious for a while and then awakens to confusion and extreme fatigue. A severe throbbing headache similar to migraine may also follow the tonic-clonic phases.
• Absence (Petit Mal) Seizures. Absence or petit mal seizures are brief losses of consciousness that occur for 3 to 30 seconds. Physical movement and loss of attention may stop for only a moment. Such seizures may pass unnoticed by others. Small children may simply appear to be staring or walking distractedly. Petit mal may be confused with simple or complex partial seizures, or even with attention deficit disorder. [See In-Depth Report #30: Attention deficit hyperactivity disorder.] In petit mal, however, a person may experience attacks as often as 50 to 100 times a day. About 25% of patients with petit mal develop grand mal seizures. An electroencephalogram (EEG) test that shows a specific brain wave pattern can usually identify these patients.

Click the icon to see a depiction of a tonic-clonic seizure.

Other Seizures

Atonic (Akinetic) Seizures. A person who has an atonic (or akinetic) seizure loses muscle tone. Sometimes it may affect only one part of the body so that, for instance, the jaw slackens and the head drops. At other times, the whole body may lose muscle tone, and the person can suddenly fall. A brief atonic episode is known as a drop attack.

Simply Tonic or Clonic Seizures. Seizures can also be simply tonic or clonic. In tonic seizures, the muscles contract and consciousness is altered for about 10 seconds, but the seizures do not progress to the clonic or jerking phase. Clonic seizures, which are very rare, occur primarily in young children, who experience spasms of the muscles but not tonic rigidity.

Myoclonic. Myoclonic seizures are a series of brief jerky contractions of specific muscle groups, such as the face or trunk.

Causes

The cause of a seizure is determined in about 28% of partial epilepsy patients. In the rest, however, epilepsy is deemed idiopathic, which means that the cause is unknown. The age of seizure onset can sometimes offer a clue. Idiopathic epilepsy is rare in children and young adults.

General Biologic Mechanisms Involved with Seizures

Epileptic seizures are triggered by abnormalities in the brain that cause a group of nerve cells in the cerebral cortex to become activated simultaneously, emitting sudden and excessive bursts of electrical energy. A seizure's effect depends on the location in the brain where this electrical hyperactivity occurs. Effects range from brief moments of confusion to minor spasms to loss of consciousness.

Click the icon to see an animation about the nervous system.

Ion Channels. Sodium, potassium, and calcium act as ions in the brain. They produce electric charges that must fire regularly in order for a steady current to pass from one nerve cell in the brain to another. If the ion channels that carry them are genetically damaged, a chemical imbalance occurs. This can cause nerve signals to misfire, leading to seizures. Abnormalities in the ion channels are believed to be responsible for absence and many other generalized seizures.

Neurotransmitters. Abnormalities may occur in neurotransmitters, the chemicals that act as messengers between nerve cells. Three neurotransmitters are of particular interest:

• Gamma aminobutyric acid (GABA), which helps prevent nerve cells from over-firing. GABA deficiencies are of particular interest to researchers in epilepsy. Researchers have recently discovered epilepsy-related genetic factors that regulate the GABA signaling system. The discovery is emphasizing the GABA's importance in the disease process.
• Serotonin's role in epilepsy is also being studied. Serotonin is a brain chemical that is important for well-being and associated behaviors (eating, relaxation, sleep). Imbalances in serotonin are also associated with depression. A 2005 study indicated that depression may be risk factor for epilepsy and that the two conditions may share common chemical pathways in the brain.
• Acetylcholine is a neurotransmitter that is important for learning and memory.

Hippocampal Sclerosis. Hardened tissue (sclerosis) in the brain's hippocampus is the most commonly identified abnormality in patients with partial epilepsy. Such abnormal brain tissue leads to structural reorganization, and both the loss and regeneration of nerve cells.

Genetic Factors

Dozens of genetic syndromes representing a variety of seizure patterns may account for the different forms epilepsy. The following epilepsy syndromes are known to be caused by single genetic defects:

• Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). ADNFLE is now believed to be caused by an alteration in the brain receptor neuronal nicotinic acetylcholine.
• Benign familial neonatal convulsions (BFNC). BFNC appears to be caused by genetic defects that affect ion channels in nerve cells that carry potassium.

A genetic cause has been identified for at least some cases of juvenile myoclonic epilepsy, which represents 10% of all epilepsy cases. (Such research and other studies have pointed to the GABA signaling system as an important player in many cases of epilepsy.)

Causes of Childhood Seizures

Febrile Seizures. Febrile seizures are caused by high fever. They usually occur in children age three months to five years. Between 10% and 15% of children with epilepsy have a history of febrile seizures before they develop the disease. It should be strongly noted, however, that febrile seizures are quite common and occur in about 3% of all children under five years old. Nearly all are brief and have no long-lasting effect.

Vaccinations. In young children, high fever from a vaccination can, in rare instances, trigger seizures. These seizures are almost always temporary and have no serious consequences. Some controversy arose a few years ago over the possibility that the DTP (diphtheria-tetanus-pertussis) vaccine might trigger epilepsy or other neurologic diseases. Some experts suggest that children who have neurologic events following their DTP shot already have a preexisting impairment such as epilepsy, which is revealed, but not caused by, the vaccine. Children with existing epilepsy may be at risk for seizures two or three days after the vaccination. Infants with suspected neurologic problems may have their vaccinations delayed until their neurologic situation is clarified, but not beyond their first birthday.

Head Injuries in Infants and Children. Infants are at high risk for head trauma. In fact, one study suggested that any infant who had a scalp fracture with a hematoma may be at risk for brain injury. A hematoma is a swelling caused by a broken blood vessel, which creates a large purplish hue like a bruise. It should be noted that hematoma is quite common after childbirth, but typically causes no problems.

Childhood Viral Infections. A 2001 study of 22 children with status epilepticus (sustained periods of convulsions) revealed that presence of several pediatric viruses. Human herpesvirus 6 was particularly associated with severe seizures. Herpesvirus 6 is common in children and causes roseola infantum, an acute, but usually benign, illness that can lead to high fever and skin rash.

Hydrocephalus and Shunts. Hydrocephalus occurs when cerebrospinal fluid (CSF) accumulates in the brain, leading to excessive swelling of the brain ventricles. The resulting pressure can damage the brain's tissue. Hydrocephalus itself is not commonly known to cause seizures, but its treatment, which involves insertion of a shunt, may be. The shunt is a device that drains the excess fluid from the brain. One 2001 study noted that up to half of children who receive shunts may experience epileptic seizures, particularly if the shunt is placed before age two. More research on its relationship to epileptic seizures is needed.

Focal Cortical Dysplasia. This is an abnormality in fetal development in which the normal migration of nerve cells is altered. It can cause very severe epilepsy that is difficult to treat.

Other Causes of Seizures in Children. Seizures in infants and children may be due to birth defects, difficulties during delivery, or poisoning.

Causes of Adult-Onset Seizures

Alcohol Abuse. Alcohol abuse is one of the most common causes of adolescent- and adult-onset seizures. Seizures, nearly always generalized tonic-clonic, occur in about 10% of adults during withdrawal. Multiple seizures happen in about 60% of these patients. The first seizure occurs 7 hours to two days after the last drink, and the time between the first and last seizure is usually six hours or less. [For more information, see In-Depth Report #56: Alcoholism.]

Head Injuries in Adults. Head injuries to adults can cause seizures, with the risk highest in severe head trauma. A first seizure related to the injury can occur years later. People with mild head injuries, which involve loss of consciousness for less than 30 minutes, have only a slight risk that lasts up to five years after the injury.

Sleep Disorders. Some sleep disorders, such as obstructive sleep apnea or narcolepsy, have been associated with seizures, although a causal relationship is unclear. Sleep apnea and hereditary nocturnal frontal lobe epilepsy have very similar symptoms (feeling of choking, abnormal motor activity during sleep, and excessive sleepiness during the day). A 2000 study reported that one-third of patients with epilepsy who did not respond to medications were later diagnosed with obstructive sleep apnea. Other studies have found that when sleep apnea is treated in patients with both epilepsy and the sleep disorder, seizure activity decreases. More research is needed.

Stroke. Seizure is a symptom of a major stroke. In some cases, injury to the brain from small strokes may cause seizures. Studies report that between 15 - 23% of stroke patients consequently have seizures. A 2005 study found that 3% of patients who have had a stroke go on to develop epilepsy. Patients who had a severe stroke were 5 times more likely to develop epilepsy than patients who had a mild stroke.

Other Causes in Adults. Other known or possible causes of epilepsy in teenage or adult years include:

• Drug abuse or withdrawal from drugs.
• Sudden withdrawal from certain antianxiety or antidepressant drugs.
• Occupational exposure to environmental triggers. High exposure to certain chemicals has been linked with seizures. A 2000 study of utility company employees in Denmark revealed an association between high exposure to electromagnetic fields (EMF) and an increased risk of epilepsy and neurologic diseases that affected motor control.
• Alzheimer's or other degenerative brain diseases in the elderly.
• Nervous system infection by tapeworm larvae is an important cause of epilepsy in developing nations.

Causes of Seizures That Can Occur at Any Age

Infections of the Brain and Central Nervous System (CNS). Acute infections of the brain and the CNS can cause seizures. Some cases are complicated by brain damage that can lead to recurrent seizures afterward. The most common central nervous system infections are encephalitis and meningitis. Researchers have also found an association between epileptic seizures and CNS-occurring herpes simplex virus infections. More research is needed before any causative role can be proved.

The organs of the central nervous system (brain and spinal cord) are covered by three connective tissue layers called the meninges. They consist of the pia mater (closest to the CNS structures), the arachnoid and the dura mater (farthest from the CNS). The meninges help support blood vessels and contain cerebrospinal fluid. The structures are involved in meningitis, an inflammation of the meninges, which, if severe, may become encephalitis, an inflammation of the brain.

Hypoglycemia. Seizures can be caused by low blood sugar (hypoglycemia), a complication of diabetes in both children and adults.

Brain Tumors. Both cancerous and noncancerous brain tumors can cause seizures in all patients.

Cavernous Angiomas. Cavernous angiomas are blood vessels that grow abnormally and, like a tumor, can put pressure on nerve tissue.

Pseudoepilepsy. Between 20% and 45% of cases of untreatable seizures have a psychologic rather than physical origin. In this form of epilepsy, known as pseudoepilepsy or psychogenic epilepsy, the patient has no conscious intent of forcing a seizure and does not show unusual emotional behavior or signs of hysteria. It is very difficult to treat and can be very disabling. Pseudoepilepsy can usually be distinguished from true epilepsy using an electroencephalogram (EEG), which measures brain waves. The cause of pseudoepilepsy is unknown.

Outlook and Effects

General Outlook for Patients with Epilepsy

Most patients can control their seizures with a single drug and stop drug treatment completely after two seizureless years. In fact, the sooner patients achieve remission using an anti-epileptic drug (AED), the better their chances for remaining seizure-free in the future. If epilepsy is not effectively treated, and if the patient has continuing seizures, changes in the neurons may eventually cause intractable, or refractive, epilepsy. This type of epilepsy is hard to control. Early treatment is extremely important.

Effects of Epileptic Seizures on the Brain. Some studies have reported changes in brain structures in epileptic patients, but it is unclear if such changes are a cause or result of seizures. A reassuring 2003 study found no indication that seizures cause any progressive abnormalities in the brain. However, a 2005 study suggested that people with a history of epilepsy have a higher risk of later developing schizophrenia or schizophrenia-like psychosis.

Acute Repetitive Seizures. Some patients occasionally experience seizures called acute repetitive, serial, or cluster seizures; these are two or more seizures occurring over minutes to hours separated by periods of consciousness. Left untreated, they can develop into status epilepticus, a very serious condition.

Status Epilepticus. Status epilepticus is a serious, potentially life-threatening condition that can lead to chronic epilepsy. It occurs in 100,000 to 150,000 people in the US each year, over half of whom are children. Permanent brain damage or death can result if the seizure is not treated effectively; the longer the seizure lasts, the greater the danger. Mortality rates from this condition are about 10%. (This high mortality rate is most likely due to a high incidence of myoclonic SEs in elderly adults after cardiac arrest. One study reported much lower mortality rates from SE when cardiac arrest in elderly epilepsy patients is excluded.)

The condition is often defined as recurrent convulsions that last for more than 20 minutes and are interrupted by only brief periods of partial relief. Some experts believe these criteria are too strict, and that the condition should be diagnosed if seizures last at least five minutes or more, or when the patient does not fully recover consciousness between two or more seizures. Although any type of seizure can be sustained or recurrent, the most serious form of status epilepticus is the generalized convulsive or tonic-clonic type. In more than a third of cases, status epilepticus occurs with the first seizure. The trigger is often unknown, but can include the following:

• Failure to take anti-epileptic medications (makes up about a third of status epilepticus events).
• Abrupt withdrawal of certain anti-epileptic drugs, particularly barbiturates and benzodiazepines.
• High fever.
• Poisoning.
• Electrolyte imbalances (imbalance in calcium, sodium, and potassium).
• Cardiac arrest.
• Stroke. In one study, about 9% of stroke patients with seizures had status epilepticus, which resulted in higher disability after the stroke, particularly if these severe seizures occurred within a week of the stroke.
• Low blood sugar in people with diabetes.

Survival Rates

Epileptic patients who are cured have a normal lifespan. Their long-term survival rates are lower than average, however, if medications or surgery fail to stop the seizures. The lower survival rate is partly due to a higher-than-average risk for death due to accidents and suicide. The specific cause of the seizure may also contribute to fatalities.

There is a very low risk for sudden death in patients with epilepsy. Although the causes of such events are not fully known, experts suspect heart arrhythmias in many cases. There is some evidence, in fact, that a malfunction in the autonomic nervous system (which controls heart rate) may be responsible for some of these deaths. Some researchers believe that temporal lobe surgery in appropriate patients may reduce the risk. Drugs that block arrhythmias may also be helpful in reducing this risk.

Effects of Epilepsy in Children

Chance for Recurrence After a First Seizure. According to one 2000 study, about 64% children with one seizure unrelated to fevers have another one, and nearly two-thirds who have a history of more than one seizure are likely to have more seizures. Researchers are trying to find ways of predicting which children have the best chances to become seizure free, and which ones will not. Studies suggest that the frequency of early seizures, not their total number or type, determines whether a child will develop intractable epilepsy.

Long-Term General Effects. In general, the long-term effects of seizures vary widely depending on the seizure's cause. Children with febrile seizures rarely have any long-term effects. In very rare cases, children experience severe fever-related seizures known as complex febrile convulsions. In such cases, there is a risk for brain injury that may lead to temporal lobe epilepsy, but this is very small. Such seizures last over 15 minutes, occur more than once within 24 hours, and may affect only one side of the body.

The long-term outlook for children with idiopathic epilepsy (epilepsy of unknown causes) is very favorable. One study reported that between 68% and 92% of such individuals were seizure-free after 20 years. In addition, a 2000 study reported that they had a survival rate no different from children without these seizures.

Children whose epilepsy is a result of a specific condition (for example, a head injury or neurologic disorder) have higher mortality rates than the normal population, but their lower survival rates are most often due to the underlying condition not the epilepsy itself.

Side Effects of Medications and Withdrawal from Them. The drugs used for epilepsy can have distressing short- and long-term effects. Eventually, many children with epilepsy can go off medication. Children who tend to relapse after withdrawal from treatment usually have the following conditions or situations:

• A family history of epilepsy.
• Require multiple medications to control seizures.
• Abnormal EEG readings after treatment has started.
• Partial seizures.

Effect on Memory and Learning. The studies on the effects of seizures on memory and learning vary widely and depend on many factors. Some results include the following:

• A 2001 study reported greater mental flexibility and memory capacity in some children with a history of febrile seizures compared to peers who did not have these seizures. Children with a history of febrile seizures before age one, however, were at higher risk for some learning deficits.
• A number of studies have demonstrated no diminished intelligence in patients with epilepsy that occurs in the left temporal lobe (the left side of the brain where most complex partial types occur). A 2000 study suggested, however, that it may affect long-term memory. Patients with seizures originating on the left side of the brain may also have less well-developed language skills than those with right-side epilepsy.
• A 2001 study suggested that children with generalized epilepsy who have petit mal (absence) seizures tend to retain their language skills and verbal memory, but some may have poorer testing scores, problems with nonverbal memory, and a slower recall of events.

In general, the earlier a child has seizures and the more extensive the area of the brain affected, the poorer the outcome. Children with seizures that are not well-controlled are at higher risk for intellectual decline.

Social and Behavioral Consequences. Studies have noted that children with epilepsy perform worse on behavioral tests than do other children. In a well-conducted 2000 study, girls with severe epilepsy had the highest rate of behavioral problems (and they worsened over time) compared to boys and girls with mild or moderate epilepsy and all children with asthma, another chronic illness. In another study, although there were no differences in intelligence, adults with previous epilepsy (even if they no longer had seizures) were less likely to attain higher-education degrees. They were slightly more likely to be unemployed, unmarried, and childless compared to the general population.

Effects of Epilepsy in Adults

Chance for Recurrence. Adults whose first episode occurs when they are over 59 years of age have a higher risk for recurring seizures than do younger adults. Some studies have indicated that recurrence is least likely in adults with the following combination of factors:

• A primary generalized seizure.
• A seizure-free period of between two and five years.
• A normal EEG reading.
• A single-drug treatment.

In one study of adult-onset epilepsy, it was discovered that after one year of treatment, 70% of patients experienced complete control of their seizures, 14% had occasional seizures, and 16% were unable to control the seizures.

Effect on Mental Functioning in Adults. The effects of adult epilepsy on mental functioning are not clear. One study found that IQ scores increased in adults with recurrent seizures during the trial period. A previous study yielded the opposite result, reporting that intelligence scores start declining with long duration of adult epilepsy. More research is needed in this area, as results have been contradictory.

Overall Physical Effects. In a major 2000 survey, 46% of the respondents with epilepsy described their overall health as "fair" or "poor," compared to 18.5% of those who did not have epilepsy. People with epilepsy also report a higher frequency of pain, depression, anxiety, and sleep problems. In fact, their overall health state is comparable to people with other chronic diseases, including arthritis, heart problems, diabetes, and cancer. Treatments can cause considerable physical effects, such osteoporosis and weight changes.

Emotional Consequence. About 25% to 75% of adults with epilepsy show signs of depression. They also have a higher than average risk for suicide. The most common emotional responses are the following:

• Fear of the unexpected seizure.
• Acute humiliation after a seizure, particularly if incontinence occurs.
• Feelings of alienation at work and in social situations.

Emotional difficulties increase if epilepsy becomes chronic. In one study, the intensity of the negative emotional response was directly related to the intensity and frequency of the attacks.

Effect on Sexual and Reproductive Health

Effects on Sexual Function. There have been studies suggesting that up to two-thirds of patients with epilepsy experience sexual disturbances, including impotence in men. There are various reasons for this:

• Epilepsy in childhood may cause disturbances in hormones regulating puberty.
• Persistent seizures in adults may be associated with other hormonal and neurologic changes that contribute to sexual dysfunction.
• Negative emotions due to epilepsy can reduce sexual drive.
• Medications may be responsible for many of these cases, although newer drugs may reduce this problem.

Effects on Female Fertility and Pregnancy. Epilepsy and its treatments can have adverse effects on female fertility and pregnancy.

Injuries and Accidents

Injuries from Falls. Because many people with seizures fall, injuries are common. Although such injuries are usually minor, people with epilepsy have a higher incidence of fractures than those without the disorder. Epilepsy patients who take the drug phenytoin have an even higher risk, since the drug can cause osteoporosis.

Driving and the Risk for Accidents. Being unable to drive is an extremely distressing and severe component of epilepsy. Drivers with well-controlled epilepsy are not at a high or unacceptable risk for automobile accidents. Uncontrolled epilepsy, however, poses a high risk. Needless to say, seizures can be very dangerous if they occur while a person is driving. Studies have reported that more than one-fourth of drivers with uncontrolled epilepsy had an seizure-related accident at some time. One particular study found that over half of these accidents resulted in injuries to the patient or others. In spite of these events, 30% of the patients had driven within the past year, and most drove at least once a week.

Four factors help predict who may safely drive:

• A long duration between seizures. In one 1999 study, being seizure-free for six months reduced the risk for accidents by 85%, and being seizure-free for a year lowered the risk by 93%. State laws restricting driving in people with seizures vary from requiring seizure-free periods of three months (which is too short for protection) to 18 months.
• Having few seizure-related accidents.
• Having a reliable pre-seizure warning sign, such as an aura.
• Recently having reduced or changed medications.

Accidents while Swimming. Swimming poses another danger for people with epilepsy, particularly those with tonic seizures, which can cause the diaphragm to expel air quite suddenly. People with epilepsy who swim should avoid deep and cloudy water (a clear swimming pool is best), and always have with a knowledgeable, competent, and experienced companion or supervisor on site.

Diagnosis

An epilepsy diagnosis is often made during an emergency visit for a seizure. If a person seeks medical help for a previous or suspected seizure, the doctor will ask about the patient's medical history, including seizure events.

One interesting study suggested that a doctor might be able to identify the location in the brain where the seizure is originating by watching the patient wipe his or her nose. A runny nose is common after a temporal lobe seizure, but not after seizures in other locations. Furthermore, the hand with which the patient wipes the nose coincides with the side of the brain in which the seizure occurs.

Ruling Out Serious Causes & Similar Conditions

Health- or life-threatening causes of seizures should first be ruled out. (See Causes in this report.)

The doctor will also rule out conditions that cause similar symptoms, including:

• Syncope. Syncope, a brief lapse of consciousness in which blood flow is reduced to the brain, can mimic epilepsy. It often misdiagnosed as epilepsy. Research continues to suggest that taking the patient's history and giving a physical exam, rather than administering an assortment of cardiac tests, is the most effective way to diagnose syncope.
• Migraines. Migraine headaches, particularly migraine with auras, may sometimes be confused with epilepsy. With epileptic seizure, the preceding aura is often seen as multiple, brightly colored, circular spots, while migraine sufferers tend to see black, white, or colorless lined or zigzag flickering patterns. Typically the migraine pain expands gradually over minutes toward one side.
• Panic Attacks. One study found that, in some patients, partial seizures resembled a panic disorder. Symptoms of panic disorder include palpitations, sweating, trembling, sensation of breathlessness, chest pain, feeling of choking, nausea, faintness, chills or flushes, fear of losing control, and fear of dying.
• Narcolepsy. Narcolepsy, a sleep disorder that causes a sudden loss of muscle tone and excessive daytime sleepiness, can be confused with epilepsy.

Diagnostic Tools

Electroencephalogram (EEG). The most important diagnostic tool for epilepsy is an EEG, which measures brain waves. Ideally, it should be performed within 24 hours of a seizure. An EEG recording session may last for less than an hour, but in some cases the doctor will want a day-long recording. Long-term monitoring may be necessary in some cases when patients do not respond to medications. Portable EEG units are available in some places, which can be used to monitor patients throughout normal activities. EEGs are not foolproof; in one study half of people who had experienced an epileptic seizure showed a normal EEG reading. Repeated EEGs are often needed to confirm a diagnosis, particularly for certain partial seizures that often produce an initially normal EEG reading.

Computerized Tomography (CT) Scans. Usually, the first brain imaging test ordered for most adults and children with first-time seizures is a CT scan. This imaging technique is sensitive enough for most purposes. In children, even if the scan is normal, the doctor will follow up to be sure other problems are not present.

A CT or CAT scan (computed tomography) is a much more sensitive imaging technique than X-ray, allowing high definition not only of the bony structures, but of the soft tissues. Clear images of organs such as the brain, muscles, joint structures, veins and arteries, as well as anomalies like tumors and hemorrhages may be obtained with or without the injection of contrasting dye.

Magnetic Resonance Imaging (MRI). Experts now strongly recommend MRIs for children with first seizures in certain cases, such as children under one year old and those with seizures that are associated with any unexplained significant mental or motor problems. These images may help to determine if the disorder can be treated with surgery, and may be used as a guide for surgeons.

Other Advanced Imaging Techniques. More advanced scanning techniques, particularly magnetic resonance spectroscopy (MRS), magnetoencephalography (MEG), positron emission tomography (PET), and single-photon emission computer tomography (SPECT), are emerging as important tools for epilepsy researchers. They are useful for detecting abnormalities, such as changes in brain activity, damaged or scarred locations in the brain where partial seizures are triggered, or tumors and other abnormalities that may be causing seizures. Some, such as MEG, may help determine which patients with severe epilepsy are good candidates for surgery.

Polysomnography

Some researchers recommend polysomnography for certain patients. This test is used to detect sleep disorders, such as obstructive sleep apnea, that are can be associated with epilepsy.

Investigative Diagnostic Procedures

Low brain levels of the neurotransmitter gamma aminobutyric acid (GABA) are associated with an increased risk of seizure recurrence. Some researchers suggest that measuring GABA levels, along with EEG recordings, could help better assess the risk of recurring seizures, and may identify which patients might benefit from GABA-stimulating drugs.

Treatment

Immediate Seizure Treatment

You can not stop a seizure, but you can help the patient prevent serious injury.

First, it is extremely important to remain calm and not panic. Then take the following actions:

• Wipe away any excess saliva to prevent obstruction of the airway. Do not put anything in the patient's mouth. It is an old wives' tale that people having seizures will swallow their tongues.
• Turn the victim gently on the side. Do not try to hold the patient down to prevent shaking.
• Rest the patient's head on something flat and soft to protect it from banging on the floor and to support the neck.
• Move sharp objects out of the way to prevent injury.

Do not leave the seizure victim alone. Anyone nearby should call 911. Patients should be taken to an emergency room if:

• Any seizure lasts beyond two or three minutes.
• The patient has been injured.
• The patient is pregnant.
• The patient is diabetic.
• Parents, caregivers, or bystanders are at all uncertain.

Children with seizures caused by fever rarely require any treatment other than taking precautions to prevent obstruction and reduce the fever. Research on adult patients has found that only 5.7% of adults with epilepsy who refused to go to the hospital following a seizure had a subsequent seizure during the study's three-day follow-up period. Hospitalization, then, may not be necessary in many patients whose seizure is not severe or repetitive, and who have no risk factors for complications. All patients or caregivers, however, should contact their doctor after a seizure occurs.

Drugs Used for Managing Acute Repetitive Seizures

The initial treatment for acute repetitive seizures (two or more seizures that occur over minutes to hours separated by periods of consciousness) are antianxiety drugs known as benzodiazepines. They include diazepam (Valium, Diastat) or lorazepam (Ativan). These drugs are available in the following forms:

• Tablets taken orally or under the tongue (sublingual). Oral tablets are difficult to give a patient who is convulsing, however.
• Rectal solutions, gels, or suppositories. Rectal administration is preferred. Solutions and gels work faster than suppositories. Diastat is rectal gel form of diazepam and, although more expensive than rectal solutions, it can be administered at home by a trained caregiver. The gel is safe and effective in reducing seizure frequency in both children and adults, and it may help prevent status epilepticus. Studies suggest that it significantly reduces the rate of hospitalization, and may even prove to be an alternative to drug therapy among children with prolonged or repetitive seizures.

Treatment of Status Epilepticus

The treatment goals of status epilepticus are the following:

• Stop the seizures.
• Prevent recurrence.
• Determine and prevent any factors that might have triggered it.
• Manage any complications.

Initial Management. The earlier a patient is treated, the better the results. In one study, seizures stopped in 80% of patients who were treated within 30 minutes. Only 40% of patients responded when they were treated after two hours. Initial management of status epilepticus consists of the following:

• Administer any seizure medications.
• Support systems to maintain or attain normal breathing, blood pressure, electrolyte balances, body temperature, and heart functions.
• Oxygen for patients who may need it.
• Attention by medical personnel trained to determine any treatable cause of status epilepticus, such as drug withdrawal, low blood sugar, infection, substance abuse (particularly cocaine), or eclampsia (elevated blood pressure induced by pregnancy).

Medications for Status Epilepticus. One or more of the following medications may be used initially:

• Benzodiazepine. An intravenously (IV) administered or injected benzodiazepine such as lorazepam (Ativan), diazepam (Valium), clonazepam, or midazolam (Versed) is usually used. Lorazepam or clonazepam is now preferred since they have a longer duration of action. Of note, midazolam is the only benzodiazepine available as a muscular injection. It may prove to be effective for children, as safe as other benzodiazepines, and safer than barbiturates. Intravenous diazepam is currently the first choice for children with status epilepticus. 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 in children, but more research is needed.
• Phenytoin or Fosphenytoin. Many doctors use phenytoin or fosphenytoin if seizures are not controlled by a benzodiazepine. These drugs must be prescribed with caution for patients who have liver and blood abnormalities or certain heart arrhythmias. Fosphenytoin works faster, and is safer than phenytoin.
• Phenobarbital. Although effective, barbiturates, such as phenobarbital (Barbita, Luminal), can reduce consciousness, blood pressure, and respiratory rate. They are generally used only when other drugs have failed.

Other medications or higher doses of the above-mentioned drugs may be used for status epilepticus patient who fail to respond to initial treatments. They include:

• Higher-dose barbiturates.
• Higher-dose intravenous benzodiazepines. In one study midazolam, the injected benzodiazepine, was as effective and possibly safer than propofol, an intravenous sedative also used for uncontrolled status epilepticus.
• Propofol (Diprivan), an intravenously administered sedative. A 2003 analysis of 22 studies suggested that this drug poses an increased risk of mortality. Experts recommended that this drug not be used routinely until better trials have been performed.

All of the medications mentioned carry a risk for hypotension, an abrupt and possibly dangerous drop in blood pressure, which may require treatment.

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. The first-line AED drugs include phenytoin (Dilantin), carbamazepine (Tegretol, Carbatrol), and divalproex sodium (Depakote). Nine other anti-epileptic drugs have become available since 1993. 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 one 2000 study that followed over 500 patients for three to five 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 (e.g., 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. It should be noted that, when seizures do not respond to the first two or three, 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; 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.

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 five to 10 years. Evidence in 2002 suggests that medications in children should not be halted for at least two 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 two 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 two 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 to 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 two 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 to 14 days later. In one small study, no infants who were given this combination relapsed after four 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 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. The best contraceptive drugs for women with epilepsy at time may be progestins. 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."

Medications

According to a 2000 survey, the anti-epilepsy drug 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 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 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 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 doctors 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 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 authorities even 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 as 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 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 drugs 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 drugs 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.

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) 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 to 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 and has been approved for partial onset seizures in adults and children aged 4 years and older. Some experts believe that levetiracetam represents a significant advance and will prove to be an important first-line drug. Some evidence suggests that it improves mental function and quality of life. Levitracetam 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. 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-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 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), 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 supplement 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.

Surgery

Surgical techniques to remove injured brain tissue may be appropriate for many patients with epilepsy. The surgeon's goal is to remove only the damaged tissue in order to prevent seizures and to avoid healthy brain tissue. Surgical techniques for reaching these goals have improved significantly over the past decades due to advances in imaging and monitoring, new surgical techniques, and a better understanding of the brain and epilepsy.

Tests to Determine if Surgery Is Indicated

A number of tests using imaging and electroencephalography (EEG) can determine if surgery is an option.

• The general approach is to first use long-term EEG monitoring to locate the brain tissue that triggers the epileptic event.
• Advanced imaging techniques can provide valuable additional information. They include functional magnetic resonance imaging (fMRI), magnetoencephalography (MEG), positron emission tomography (PET) or single-photon emission computer tomography (SPECT) scans.

If the imaging tests indicate that more than one site is involved or their results conflict, then more invasive monitoring of the brain may be required, although the newer imaging tests are proving to be very accurate tools. If such tests pinpoint a specific area in the brain as the location for seizures, then surgery is possible. MEG, for example, is now approved for imaging parts of the brain involved with motor control, sensation, and language function, and may become important in evaluating patients who are likely candidates for surgery. The doctor will also examine the test results to determine if the offending nerve cells perform vital functions and try to predict surgical outcome in certain cases.

The major areas of the brain have one or more specific functions.

Temporal Lobectomy

The most common surgical procedure for epilepsy is temporal lobectomy, which is performed when epilepsy occurs in the temporal lobe. (Surgery is not as successful in epilepsies that occur in the frontal lobe.) It involves removing small portions from the hippocampus. The hippocampus is a part of the brain that is involved in memory processing. It is part of the limbic system, which controls emotions.

Click the icon to see an image of the limbic system of the brain.

Candidates. Candidates for this surgery usually have a history of seizures. Anti-epileptic drugs have not helped them. Young children may be more difficult candidates because they often have injured areas outside the temporal lobes. Nevertheless, surgery can be very successful in many children, even if more than one area is involved.

Success Rates. New imaging techniques are dramatically improving the success rates of temporal lobe surgery. Studies have shown that many patients remain seizure-free after temporal lobectomy. A 2005 study of 48 patients who had temporal lobectomy found that half were seizure-free 30 years after the surgery. Patients still need to take medications, even if seizures are very infrequent. Cure is not always possible, and some patients may still experience some seizures. Double vision is very common after the operation, but it is nearly always temporary and resolves within a few months.

Studies are further indicating that temporal lobe surgery improves quality of life and may even prolong survival. Some experts theorize that surgery might stabilize parts of the brain that influence heart rate and may reduce the risk of sudden death, a rare complication of epilepsy.

Effects on Mental Functioning. Although surgery on the left temporal lobe does not impair intelligence to any significant degree, studies on the effects of mental functioning and behavior are unclear:

• One study reported that 10% of patients experienced significant decline in language abilities while another 9% reported significant improvement. In the study, about 16% reported improvement in nonverbal mental functions.
• In a study of children, surgery improved behavior in 31% of the patients and mental function in 25%. (Negative changes in personality, emotions, or behavior are uncommon following surgery.)
• A study of 50 children aged 3 to 7 reported that 66% of the children were seizure free within a year after surgery. Nearly all the children showed improvement in cognitive development, and a few children’s IQ scores improved by 15 points.

In general, surgical effects on mental functioning and behavior depend on the extent and location of the surgical area.

Lesionectomy

Lesionectomy is a procedure that removes specifically abnormal tissues in certain conditions, such as the following:

• Cavernous angiomas (abnormal clusters of blood vessels).
• Low-grade brain tumors.
• Cortical dysplasias. (This is an abnormality in fetal development in which the normal migration of nerve cells is altered for some reason.)

This local surgery, which can cure the patient's epilepsy, has become possible with the advent of advanced imaging techniques such as MRI.

Other Surgeries

Other surgical procedures called hemispherectomy and corpus callosotomy offer hope for specific patients. They include infants and young children with catastrophic seizures that occur in one or part of a hemisphere and for patients whose seizures are due to specific structural brain abnormalities or tumors.

Hemispherectomy. Hemispherectomy is the removal of half the brain, leaving the deep structures intact. Surgery can take 12 hours and there is always some paralysis on one side of the body. There is also a small risk for hydrocephalus, coma, or even death. Quality of life is almost always improved, however, and the surgery does not reduce intelligence.

Corpus Callosotomy. Corpus callosotomy involves cutting the nerve fibers that connect one side of the brain to another. It does not remove brain tissue. It may be done in two stages. In the first there is a partial separation. If seizures continue, then the surgeon may perform a complete separation. This surgery can reduce (although not entirely stop) uncontrolled tonic clonic seizures. The procedure has been used in patients with specific syndromes, such as Lennox-Gastaut syndrome. The procedure can have very severe complications, however.

Vagus Nerve Stimulation (VNS) and Other Neurostimulation Procedures

Electrical stimulation of areas in the brain that affect epilepsy is helping many patients with refractory epilepsy. Vagus nerve stimulation (VNS), an electrical stimulation of the vagus nerve, is now an accepted therapy for severe epilepsy that does not respond to AEDs. The two vagus nerves are the longest nerves in the body. They run along each side of the neck, then down the esophagus to the gastrointestinal tract. They affect swallowing, speech, and many other functions. They also appear to connect to parts of the brain that are involved with seizures. The procedure is as follows:

Click the icon to see a depiction of epilepsy treatment.

• A battery-powered device similar to a pacemaker is implanted under the skin in the upper left of the chest.
• A lead is then attached to the left vagus nerve in the lower part of the neck.
• The neurologist programs the device to deliver mild electrical stimulation to the vagus nerve. (Patients may also pass a magnet over the device to give it an extra dose if they sense a seizure coming on. This appears to help about 25% to 30% of patients.)
• The batteries wear out after three to five years and need to be removed and replaced by a simple surgical procedure.

An investigatory approach called deep brain stimulation targets the thalamus (which relays pain, temperature, and touch sensations to the brain). Early small studies are promising.

Candidates. The American Academy of Neurology now recommends VNS for the following:

• Patients who are over 12 years old, and
• Have partial seizures that do not respond to medication, and
• Are not appropriate candidates for surgery.

Evidence is accumulating, however, to indicate that VNS is effective and safe for many patients of all ages and for refractory epilepsy of many types.

Success Rates. Studies are reporting that the procedure reduces seizures within four months by up to 50% and even more in many patients. Studies report that it has been effective for longer than seven years. In one study that followed patients for a year, the benefits of VNS appeared to even increase over time.

Complications. It should be noted that vagus stimulation does not eliminate seizures in most patients and is still somewhat invasive. Vagus stimulation can cause shortness of breath, hoarseness, sore throat, coughing, ear and throat pain, or nausea and vomiting. These side effects can be reduced or eliminated by reducing the intensity of stimulation. Some studies suggest that the treatment causes adverse changes in breathing during sleep and may cause lung function deterioration in people with existing lung disease. People who have obstructive sleep apnea also should be cautious about this procedure. Turning off the VNS (for example before an MRI or surgery) may increase the risk for status epilepticus. (It should be noted that VNS may also be helpful for treating status epilepticus in some patients.)

Experimental Procedures

Gamma Knife Surgery. A device called a gamma knife delivers very focused beams of radiation. Typically used for brain tumors, it is now under investigation for temporal lobe epilepsy and for seizures due to cavernous malformations.

Lifestyle Changes

The best preventive measure is to comply strictly with the drug regimen as prescribed. Seizures cannot be prevented by lifestyle changes alone, but people can make behavioral changes that improve their lives and give them a sense of control.

Avoiding Epileptic Triggers

In most cases, there is no known cause for epileptic seizures, but specific events or conditions may trigger them and should be avoided.

Inadequate or Fragmented Sleep. Inadequate or fragmented sleep can set off seizures in many people. In one study, the lowest risk for seizures was during REM sleep (which is when dreams occur). The highest risk was during light non-REM stages of sleep. Using sleep hygiene or other methods to improve sleep may be helpful.

Food Allergies. One study indicated that food allergies might provoke some seizures in children who also have migraine headaches, hyperactive behavior, and abdominal pains. Parents should consult an allergist if they suspect foods or additives might be playing a role in such cases.

Alcohol and Smoking. Alcohol and smoking should be avoided, although light alcohol consumption does not appear to increase seizure activity in people who are not alcoholics or sensitive to alcohol.

Flashing Lights. Patients should avoid exposure to flashing or strobe lights. Video games have been known to trigger seizures in people with existing epilepsy, but apparently only if they are already sensitive to flashing lights. Seizures have been reported in Japan among people who watched cartoons with rapidly fluctuating colors and quick flashes. The frequency of flashes per second is measured in hertz (Hz). Screens that emit a lower hertz (such as 50 Hz screens sold in Europe) are more likely to cause seizures in people with epilepsy than a higher-hertz screen (such as 100 Hz screens sold in the US).

Relaxation Techniques

Relaxation methods include diaphragmatic rhythmic breathing, biofeedback, and meditation techniques. No strong evidence supports their value on reducing actual attacks (although some people have reported that they have), but they may be helpful in reducing anxiety in people who have positive experiences with them. There have been some reports that deep breathing (a common relaxation technique) triggers seizures in certain people.

Exercise

Exercise is important for many aspects of epilepsy, although it can be problematic. Weight-bearing exercise helps maintain bone density, which can be reduced by many of the medications, particularly the older ones. Exercise can also help to prevent weight gain, which may a problem with some of the drugs. There have been some reports that exercise may trigger seizures in some patients, but this is uncommon. A number of studies have found no significant association between physical activity and a higher incidence of seizures in patients with epilepsy. Nevertheless, some patients are concerned and they should discuss this issue with their doctor.

Some small studies have reported significant benefits from the practice of yoga, which employs weight bearing and balancing postures. In one study, a system of meditation called Sahaja yoga changed EEG readings of brain waves and reduced seizures. Other studies report a 50% reduction in seizures and an overall decline in the number of attacks per month. Still, well-controlled studies are needed to confirm these benefits.

Dietary Measures

All patients should maintain a healthy diet, including plenty of whole grains, fresh vegetables, and fruits. In addition, dairy foods may be important to maintain calcium levels. Fasting has been used to prevent seizures since ancient times. In the 1920s, a high-fat, no-sugar, low protein diet, known as a ketogenic diet, was used to prevent seizures. It lost popularity after the introduction of anti-epileptic drugs but is now proving to be effective with many children. Researchers are investigating whether the Atkins diet (high protein, low carbohydrate) may help people with epilepsy. Both the ketogenic diet and the Atkins diet can interfere with some anti-epileptic medications such as topiramate. Talk to your doctor before beginning any special diet or a weight loss program.