Suicide Risk and Antiepileptic Drugs
In 2008, the U.S. Food and Drug Administration (FDA) announced that it will require warnings about suicidal risks to be added to the prescribing labels of all antiepileptic drugs. The FDA based its decision on clinical trials that showed that patients who took antiepileptic drugs had twice the risk of suicidal behavior or thoughts compared to patients who received placebo. The FDA recommends that patients who receive these drugs should be closely observed for signs of suicidality.
Antiepileptic drugs include:
- Carbamazepine (Carbatrol, Equetro, Tegretol)
- Valproate (Depakene)
- Divalproex sodium (Depakote)
- Ethosuximide (Zarontin)
- Clonazepam (Klonopin)
- Lamotrigine (Lamictal)
- Gabapentin (Neurontin)
- Pregabalin (Lyrica)
- Topiramate (Topamax)
- Oxcarbazepine (Trileptal)
- Zonisamide (Zonegran)
- Levetiracetam (Keppra)
Febrile Seizures and Epilepsy
Febrile seizures are caused by high fever and are common in young children. This type of seizure usually has no long-term effects. Although children who have simple febrile seizures have a slightly higher risk of developing epilepsy than children who do not have febrile seizures, the overall risk is still low. According to 2008 guidelines from the American Academy of Pediatrics, there is no evidence that preventive treatment of simple febrile seizures reduces the risk of epilepsy. Furthermore, due to the low risks of febrile seizures compared to the risks of anticonvulsant drugs, the AAP does not recommend anticonvulsant drug therapy to prevent febrile seizure recurrence.
Epilepsy is a neurological disorder characterized by unprovoked, recurring seizures that disrupt the nervous system and can cause mental and physical dysfunction. In the U.S., about 2.5 million people are affected by epilepsy and seizures. About 10% of the American population will experience at least one seizure during their lifetime.
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. Epilepsy types are generally put into two categories, which are based on the specific biologic mechanisms involved in the seizure and the anatomical location of the seizure. The 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.
Doctors 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.
New classification systems better define specific epilepsies. Some professional groups now suggest that epilepsies be classified in the following five ways:
- Type of seizure (partial or generalized)
- Description of the seizure onset and evolution
- Specific syndromes that are associated with one or more seizure types (however, not all seizures will be part of a syndrome)
- Specific causes of the seizures, if known
- Degree of impairment
Partial Seizures (also called Focal Seizures)
These seizures are 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 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. 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 2 minutes. They may occur 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 are caused by nerve cell disturbances that occur in more widespread 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 - 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 1 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 2 - 3 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 - 30 seconds. Physical movement and loss of attention may stop for only a moment. Such seizures may pass unnoticed by others. Young 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. [For more informaiton, see In-Depth Report #30: Attention deficit hyperactivity disorder.] In petit mal, however, a person may experience attacks as often as 50 - 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.
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.
Epilepsy is also grouped according to a set of common characteristics, including:
- Patient age
- Type of seizure or seizures
- Whether a cause is known or not (idiopathic)
A few syndromes and inherited epilepsies are listed as follows. They do not represent all epilepsies.
West Syndrome (Infantile Spasms). West syndrome, also called infantile spasms, is a disorder that involves spasms and developmental delay in children within the first year, usually in infants ages 4 - 8 months.
Benign Familial Neonatal Convulsions. Benign familial neonatal convulsions (BFNC) are a rare, inherited form of generalized seizures that occur in infancy. BFNC appears to be caused by genetic defects that affect ion channels in nerve cells that carry potassium.
Juvenile Myoclonic Epilepsy (Impulsive Petit Mal). Juvenile myoclonic epilepsy, also called impulsive petit mal epilepsy, is characterized by generalized seizures, usually tonic-clonic marked by jerky movements (called myoclonic jerks), and sometimes absence seizures. This accounts for 7% of epilepsies, and usually occurs in individuals ages 8 - 20.
Adult Myoclonic Epilepsy. Some research suggests that adult myoclonic epilepsy may be a previously un-described and distinct syndrome. It involves the development of generalized epilepsy of unknown causes in middle-aged adults.
Lennox-Gastaut Syndrome. Lennox-Gastaut syndrome is a severe form of epilepsy in young children that causes multiple seizures and some developmental retardation. It usually involves absence, tonic, and partial seizures.
Myoclonic-Astatic Epilepsy. Myoclonic-astatic epilepsy (MAE) is a combination of myoclonic seizures and astasia (a decrease or loss of muscular coordination), often resulting in the inability to sit or stand without aid.
Progressive Myoclonic Epilepsy. Progressive myoclonic epilepsy is an inherited disorder occurring in children ages 6 - 15. It usually involves tonic-clonic seizures and marked sensitivity to light flashes. Although the disease was previously considered to be progressive throughout life, current therapies have significantly improved its outlook.
Autosomal Dominant Nocturnal Frontal Lobe Epilepsy. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a rare, inherited syndrome that usually occurs during childhood, typically around age 11. However, onset varies widely within families. Seizures can be dystonic (twisting contractions) or tonic (muscle contractions), or involve thrashing. They are brief, frequent, and occur in clusters during the night. The seizures often subside with age. ADNFLE appears to be caused by an alteration in the brain receptor neuronal nicotinic acetylcholine,
Landau-Kleffner Syndrome. Landau-Kleffner syndrome is an epileptic condition that results in the inability to communicate either with speech or by writing (aphasia).
Contactin-Associated Protein-Like 2 (CASPR2) Epilepsy. CASPR2 is associated with a childhood epilepsy and autism disorder found in closely related relatives in Amish communities.
Status epilepticus (SE) is a serious, potentially life-threatening, condition that can lead to chronic epilepsy. It occurs in 100,000 - 150,000 people in the U.S. each year, over half of whom are children. Permanent brain damage or death can result if the seizure is not treated effectively.
The condition is defined as recurrent convulsions that last for more than 20 minutes and are interrupted by only brief periods of partial relief. 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 (accounts for about a third of status epilepticus events)
- Abrupt withdrawal of certain anti-epileptic drugs, particularly barbiturates and benzodiazepines
- High fever
- Electrolyte imbalances (imbalance in calcium, sodium, and potassium)
- Cardiac arrest
- Low blood sugar in people with diabetes
- Central nervous system infection
- Brain tumor
- Alcohol withdrawal
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.
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.
- Serotonin's role in epilepsy is also being studied. Serotonin is a brain chemical that is important for well-being and associated behaviors (such as eating, relaxation, and sleep). Imbalances in serotonin are also associated with depression.
- Acetylcholine is a neurotransmitter that is important for learning and memory.
Dozens of genetic syndromes representing a variety of seizure patterns may account for the different forms epilepsy.
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.)
Febrile Seizures and Vaccination-Related Seizures
Febrile seizures are caused by high fever and occur in 2 - 5% of children ages 6 months to 5 years. They usually have no long-lasting effect. There are two types of febrile seizures: simple and complex. Simple febrile seizures last for less than 15 minutes and occur once in a 24-hour period. Complex febrile seizures last longer than 15 minutes and occur more than once in 24 hours. Most children who experience simple febrile seizures have a low risk of developing epilepsy.
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 research suggests 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 2 or 3 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. Also, a newer version of the DTP vaccine reduces the risk of any seizure.
Abnormalities in the Structure or Anatomy of the Brain
Brain Tumors. Both cancerous and noncancerous brain tumors can cause seizures in all patients.
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 cause them. The shunt is a device that drains the excess fluid from the brain. Up to half of children who receive shunts may experience epileptic seizures, particularly if the shunt is placed before 2 years of age. 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.
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.
Cavernous Angiomas. Cavernous angiomas are blood vessels that grow abnormally and, like a tumor, can put pressure on nerve tissue.
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 2 days after the last drink, and the time between the first and last seizure is usually 6 hours or less. [For more information, see In-Depth Report #56: Alcoholism.]
Sudden withdrawal from certain antianxiety or antidepressant drugs such as benzodiazepines, barbiturates, and tricyclic antidepressants can also contribute to seizures.
Injuries to the Brain
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, but only very rarely. People with mild head injuries, which involve loss of consciousness for fewer than 30 minutes, have only a slight risk that lasts up to 5 years after the injury.
Head Injuries in Infants and Children. Infants are at high risk for head trauma, and the severity of injury may be difficult to determine. The risk of even one seizure is generally only a concern after severe head trauma. Most children who have had a minor or not very serious head injury do not need to have medications to prevent seizures, especially when an evaluation in the emergency department was unnecessary.
Stroke. Seizure is one possible symptom of a major stroke. Even injury to the brain from small strokes may cause seizures. Patients who have had a severe stroke are 5 times more likely to develop epilepsy than patients who have had a mild stroke.
Other Causes in Adults
Seizures in adults can also be caused by:
- Low blood sugar (hypoglycemia), a complication of diabetes in both children and adults.
- Medications such as theophylline, meperidine, tricyclic antidepressants, phenothiazines, lidocaine, quinolones, penicillins, selective serotonin re-uptake inhibitors, isoniazid, antihistamines, cyclosporine, interferons, cocaine, lithium, amphetamines, and alcohol (withdrawal).
- Occupational exposure to environmental triggers. High exposure to certain chemicals has been linked with seizures.
- Alzheimer's or other degenerative brain diseases in the elderly.
- Infections of the brain and central nervous system such encephalitis and meningitis.
Between 20 - 45% of cases of untreatable seizures have a psychologic rather than physical origin. In this form of epilepsy, known as psychogenic seizures, 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. Psychogenic seizures can usually be distinguished from true epilepsy by using an electroencephalogram (EEG), which measures brain waves. The cause of psychogenic seizures is unknown.
Epilepsy and seizure disorders affect over 3 million Americans and 45 million people worldwide.
Epilepsy affects all age groups. The incidence is highest in children under the age of 2 and older adults over age 65. In recent years, epilepsy has been decreasing in children while increasing in the elderly, probably because of mild strokes and cardiac arrest.
In children age 10 and younger, generalized seizures are more common; in older children, partial seizures are more common.
Males have a slightly higher risk than females of developing epilepsy.
Race and Ethnicity
African-Americans and other racial minorities are at higher risk than Caucasians.
Individuals with the following medical conditions have a higher than average risk of developing epilepsy:
- Children with mental retardation, cerebral palsy, or both
- Adults with Alzheimers disease
- Patients who have suffered a stroke
General Outlook for Patients with Epilepsy
Most patients can control their seizures with a single drug and stop drug treatment completely after 2 years without seizures. In fact, patients who respond well to an anti-epileptic drug (AED), have a better chance for remaining seizure-free in the future. In general, patients who do not have good control with medications are more likely to have difficulty with epilepsy treatment.
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.
Household Accidents. Household environments, such as the kitchen and bathroom can be dangerous places for children with epilepsy. Parents should take precautions to prevent burning accidents from stoves and other heat sources. Children with epilepsy should never be left alone when bathing.
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 a fourth of drivers with uncontrolled epilepsy had a seizure-related accident at some time. Many of these accidents resulted in injuries to the patient or others.
Certain factors can help predict who may safely drive:
- A long duration between seizures (seizure-free for 6 months or more)
- Having few seizure-related accidents
- Having a reliable pre-seizure warning sign, such as an aura
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 swim with a knowledgeable, competent, and experienced companion or have a supervisor on site.
Epileptic patients who are cured have a normal lifespan. Their long-term survival rates are lower than average 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, doctors suspect heart arrhythmias in many cases.
Effects of Epilepsy in Children
Long-Term General Effects. In general, the long-term effects of seizures vary widely depending on the seizure's cause. The long-term outlook for children with idiopathic epilepsy (epilepsy of unknown causes) is very favorable. One study reported that 68 - 92% of these patients were seizure-free after 20 years. Another 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.
Effect on Memory and Learning. The studies on the effects of seizures on memory and learning vary widely and depend on many factors. 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. Learning and language problems, and emotional and behavioral disorders, occur in a significant number of children with several of the partial epilepsy syndromes. These children perform worse on behavioral tests than do other children. Whether these problems are caused by the seizure disorder and anti-seizure medications or are simply part of the seizure disorder remains unclear.
Effects of Epilepsy in Adults
Effect on Mental Functioning in Adults. The effects of adult epilepsy on mental functioning are not clear. More research is needed in this area, as results have been contradictory.
Psychological Health. About 25 - 75% of adults with epilepsy show signs of depression. People with epilepsy have a high risk for suicide, particularly in the first 6 months following diagnosis. The risk for suicide is highest among people who have epilepsy and an accompanying psychiatric condition such as depression, anxiety disorder, schizophrenia, or chronic alcohol use. Antiepileptic drugs (such as carbamazepine, gabapentin,topiramate,valproate, and many others) can increase the risk of suicidal thoughts and behavior. [For more information, see Medications section in this report.]
Overall Health. Many patients with epilepsy describe their overall health as "fair" or "poor," compared to those who do 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 as osteoporosis and weight changes.
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 erectile dysfunction in men. Causes of these problems may be emotional, medication induced, or a result of changes in hormone levels:
- 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.
Epilepsy and Pregnancy
Studies have been conflicting on the effects of fertility from epilepsy, but most suggest that fertility rates among women with epilepsy are lower than among women in the general population. A number of factors, including anti-epileptic drugs (AEDs) or social factors such as marriage at an older age, may contribute to this lower rate. Certain AEDs, particularly valproate, disrupt ovulation and menstruation by increasing male hormone levels and weight and causing polycystic ovaries.
Preparing to Become Pregnant. A woman should visit her doctor at least 3 months before becoming pregnant to talk about risks of medications and the possibility of making any changes.
- A woman who has been seizure-free for 2 or more years may attempt to discontinue drugs under her doctors supervision.
- If she has not been seizure-free, she should continue medications but try to reduce them to a single drug, if possible. (Again, under a doctors supervision.)
- If a woman taking antiseizure medications has an unplanned pregnancy, there may be no point in switching medications right away, since the effects of the drugs last for 10 weeks. However, she should notify her doctor immediately.
- Folic acid is recommended for all pregnant women, and women with epilepsy should talk with their doctor about taking folic acid supplements at least 3 months before conception as well as during the pregnancy.
Effect of Pregnancy on Seizure Frequency. The frequency and intensity of seizures vary widely in women with epilepsy. About 25% of pregnant women with epilepsy face an increase in events, and the risk is highest in those who have more than one seizure per month prior to becoming pregnant. In most cases, however, there is no change at all. Some pregnant women even have a decrease in seizures. The risk is lower in women who experience less than one seizure in the 9 months prior to becoming pregnant.
The following conditions may contribute to an increase in seizures during pregnancy:
- Nausea and vomiting (vitamin B6 and antihistamines may help with nausea)
- Fluid retention
- Higher estrogen levels
- Psychological and emotional stress
- Medication noncompliance from fear of side effects
- Problems with sleeping
- Changes in absorption of anticonvulsants
Anti-epileptic drug levels are monitored at least three times during the pregnancy, more often if seizures are occurring or levels are not normal. Dosage levels should be adjusted accordingly.
Effects of Epilepsy on the Pregnant Patient and the Fetus. Women who become pregnant have a risk for uncontrolled seizures and birth defects from antiseizure medications. In studies of women who were carefully monitored, however, 95% of pregnancies (which is close to normal) had favorable outcomes.
Isolated seizures do not appear to pose any adverse effects to the mother or the unborn child, but repeated seizures and status epilepticus can lead to great dangers. In one study, the effect of epilepsy on complications during pregnancy was the same as in non-epileptic women except for a higher rate of premature deliveries (8.2% in the women with epilepsy).
Drugs Used During Pregnancy. Some types of anti-epileptic drugs (AEDs) can increase the risks for birth defects, especially when taken during the first trimester of pregnancy. Expert guidelines advise that pregnant women use the most effective medication for their type of epilepsy at the lowest dose possible to control seizures. They should also have their doctors take blood tests during pregnancy to monitor their drug levels.
The fetus should be carefully monitored with ultrasonic evaluation and sometimes amniocentesis (visual tests and examination of the fluid in the womb for birth defects and other fetal problems).
In general, research indicates that 90% of women who take AEDs will give birth to healthy children. Still, doctors recommend that women of child-bearing age use a drug other than valproate if possible.
The risk for malformation is higher when more medications are used. For example, there is a 3% risk of birth defects with women who use one anticonvulsant. The risk increases to 20% when four drugs are used.
Birth Defects Associated with Medication. The most common birth defects related to anti-epileptic drugs are:
- Cleft lip or palate (risks from lamotrigine, phenobarbital, phenytoin, valproate especially when taken during the first trimester).
- Genital or urinary abnormalities (risk from most standard drugs).
- Neural tube defects (NTD) in the skull or spinal column (risk of 2% with valproate and 1% with carbamazepine). These complications are most often due to lower folic acid levels caused by both pregnancy itself and antiseizure drugs. Folic acid supplements can help prevent this problem.
- Mental impairment (known risk with phenytoin and valproate; inconclusive in carbamazepine and phenobarbital).
- Heart defects (risk from phenobarbital, phenytoin, valproate).
Many antiseizure drugs also cause a deficiency in vitamin K clotting factors that increases the risk for hemorrhage in the newborn. Treatment with vitamin K during the last month of pregnancy and a single dose given to the newborn is recommended.
Labor and Delivery. Seizures occur during labor and after delivery in a small percentage of women with epilepsy. The following labor complications are more common among pregnant women with epilepsy: Vaginal bleeding, anemia, and preeclampsia (extremely high blood pressure in the third trimester). If seizures occur during labor, they are generally treated intravenously with benzodiazepines or phenytoin. If tonic-clonic seizures, absence seizures, or status epilepticus occur, a cesarean section may be appropriate.
Monitoring the Infant. The infant should be thoroughly examined for any birth defects. Also, if the mother was given phenobarbital or primidone while pregnant, the infant should be monitored for up to 8 months to see if withdrawal symptoms develop. Drug dosages will also need to be adjusted for the mother after delivery.
Breast-feeding. Women on most AEDs typically can nurse their babies, since usually only a small amount of the drug enters the breast milk. The lowest levels are with phenytoin and valproate. (Ethosuximide and possibly levetiracetam are exceptions and should be avoided when a woman is breast-feeding. Women taking phenobarbital are also usually advised not to nurse.) A mother should watch for signs of lethargy or extreme sleepiness in her infant, which could be caused by her medication.
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.
Conditions that cause similar symptoms to epilepsy include:
- Syncope. Syncope, a brief lapse of consciousness in which blood flow is reduced to the brain, can mimic epilepsy. It is often misdiagnosed as epilepsy. Patients with syncope do not have the rhythmic contracting and then relaxing of the body's muscles.
- 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 to encompass one side of the head.
- Panic Attacks. In some patients, partial seizures may resemble 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.
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 or a recording during sleep. 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. Repeated EEGs are often needed to confirm a diagnosis, particularly for certain partial seizures that often produce an initially normal EEG reading.
Video Electroencephalography (Video EEG). For this task, patients are admitted to a special part of the hospital where they are monitored both by EEG and are also watched by a video camera. Patients may need this for a variety of reasons including withdrawal or addition of medications in a patient with difficult-to treat-epilepsy, before epilepsy surgery for some patients, and also when psychogenic nonepileptic seizures are suspected.
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.
Magnetic Resonance Imaging (MRI). Doctors strongly recommend MRIs for children with first seizures in certain cases, such as children under 1 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 are emerging as important tools for epilepsy researchers. By detecting abnormalities, such as changes in brain activity, positron emission tomography (PET) may help locate damaged or scarred locations in the brain where partial seizures are triggered. These findings may help determine which patients with severe epilepsy are good candidates for surgery. Single-photon emission computer tomography (SPECT) may also be used to decide if the surgery should be performed and what part of the brain needs to be removed. Both of these imaging techniques are generally only needed when an MRI of the brain has not been helpful.
What To Do When Someone Has a Seizure
You cannot stop a seizure, but you can help the patient prevent serious injury.
Remain calm, and do 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 when:
- A first-time seizure occurs
- Any seizure lasts beyond 2 - 3 minutes
- The patient has been injured
- The patient is pregnant
- The patient is diabetic
- Parents, caregivers, or bystanders are at all uncertain
Not all patients with chronic epilepsy need to go to the hospital after a seizure. Hospitalization 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.
Treatment after a First Seizure
Most children who have a febrile seizure do not have a seizure disorder and generally do not require drug treatment to preventive more seizures. 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.
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. (If there was either a long period of time between seizures or the seizure was provoked by an injury or other specific causes, your doctor may wait before starting AEDs. 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 (EEG or MRI) reveal any brain injury, or if specific neurologic, develolpmental, or epilepsy 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 doctors do not recommend treating adult patients after a single seizure if they have a normal neurologic examination, EEG, and imaging studies.
Determining an Anti-Epileptic Drug (AED) Regimen
Most epileptic seizures can be controlled using a single-drug regimen. First-line AED drugs include phenytoin (Dilantin), carbamazepine (Tegretol, Carbatrol), and divalproex sodium (Depakote). Patients generally begin with low doses and build up until the seizures are controlled or a toxic reaction occurs. If a single drug fails to control seizures, 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 If Seizures Still Occur
Drugs fail to control epilepsy in about 30% of patients. For patients who have little or no benefit from their initial drug regimen the likelihood of good or complete control from different medications or multidrug regimens is not very high.
Reasons for Failure. An AED may fail to reduce seizures due to such factors 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.
- Patients not taking medication as prescribed. Over 40% of patients experience toxic or bothersome effects from older AEDs, which often cause them to stop medications. 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 (such as panic attack or personality disorders).
The doctor should first address these issues. If the patient still does not respond, the doctor will usually try a different drug. If this fails, one or even two additional drugs at a time may be used. When seizures do not respond to the first two or three drugs, the odds of a fourth or fifth working diminish greatly, despite a number of new medications on the market. In such cases, the patient should ask about surgical alternatives.
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.
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. These blood tests may be, however, a less reliable indicator of problems than the patient's own self-observations of his or her responses to the drug. For instance, blood tests may suggest that the dosage levels are insufficient according to general standards, yet the individual patient may be seizure-free and leading a normal life. It is very important that women have AED levels monitored during pregnancy.
Discontinuing Drug Therapy
Over half of all patients treated effectively can stop taking AEDs within 5 - 10 years. Evidence suggests that medications in children should not be halted for at least 2 years after the last seizure, particularly if they have partial seizures and abnormal EEGs. It is not clear whether children who have been free of generalized seizures need to wait more than 2 years or if they can withdraw earlier.
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
There is also no clear evidence on whether adults who are free of any seizure type can safely withdraw from their medications within 2 years of their last seizure of if they should wait.
In any case, attempts to halt drugs should be done during periods when seizures will cause the least harm. For instance, the best time to test the effects of drug withdrawal in teenagers might be about a year before they are eligible to drive.
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 newer ones (including gabapentin, lamotrigine, oxcarbazepine, and gamma-vinyl-GABA) may sometimes prove to be useful as a sole therapy. These newer drugs also increase patient compliance because they tend to have fewer side effects than the older ones.
Treatment of Women
Hormonal fluctuations affect epilepsy in about a third to a half of female patients. Estrogen appears to increase activity, and progesterone reduces it. The effect of pregnancy on women with epilepsy is complex. The following treatments may help or affect women with epilepsy:
- Hormonal drugs that suppress ovulation. When seizures in women are worsened by hormonal changes, such as during the menstrual cycle, suppressing ovulation may be recommended using drugs called gonadotropin-releasing hormone agonists.
- Oral contraceptives. Antiseizure medications affect many oral contraceptives (OCs). Carbamazepine, phenytoin, phenobarbital, primidone, oxcarbazepine, and topiramate reduce the effects of OCs. Valproate does not, and may even increase hormonal levels. Gabapentin, lamotrigine, tiagabine, and vigabatrin may also prove to be safe with OCs, but more research is needed. Progestins may be the best contraceptive drugs for women with epilepsy at this time. Injected progestins may actually help prevent seizures in some cases.
(For more information, see the Prognosis section of this report.)
Many newer anti-epilepsy drugs (AEDs) are 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, they are often prescribed as single drugs. Specific choices usually depend on the individual's particular condition and the specific side effects of the AED. None 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.
All antiepileptic drugs can increase the risks of suicidal thoughts and behavior. Research has shown that the highest risk of suicide can occur as soon as 1 week after beginning drug treatment and can continue for at least 24 weeks. Patients who take these drugs should be monitored for signs of suicidality.
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.
Uses. Valproate is the first choice for patients with generalized seizures and is used to prevent nearly all other major seizures as well.
General Side Effects. These drugs have a number of side effects that vary depending on dosage and duration. Most side effects occur early in therapy and then subside. General side effects include:
- Stomach and intestinal problems, which are experienced by nearly half of patients after starting the drugs and may still occur after several years of use. Divalproex sodium (Depakote) has a lower risk for these side effects than valproate (Depakene).
- Increased appetite with significant weight gain often becomes a problem and can be a major reason for noncompliance, particularly in young people.
- Hand tremors, irritability, and hyperactivity in children are fairly common.
- Temporary hair thinning and hair loss have occurred. Taking zinc and selenium supplements may help reduce the effect.
- Young girls may develop secondary male characteristics, and premenopausal women are at increased risk for menstrual irregularities and polycystic ovaries, due to elevated male hormones. The effects are reversible. (These side effects also appear in women using other anti-epileptic drugs, but the risk from valproate appears to be higher.)
- Studies have reported symptoms of Parkinson's disease preceded by hearing loss in people who have taken it for more than a year, but they were reversible when the drug was withdrawn.
- Valproate poses a higher risk for serious birth defects than many other AEDs. These birth defects include skull and limb deformities, and brain, heart, and lung problems. Women of child-bearing age should use a different type of anti-epilepsy drug than valproate. If valproate is used, it should be prescribed at the lowest possible dose.
- Cases of pancreatitis, a serious and even life-threatening inflammation in the pancreas, have been reported in children and adults taking valproate. (It is still very rare, however.)
- Valproate and divalproex sodium are not usually recommended for young children because of an unusual, but potentially fatal, toxic effect on the liver. This very rare effect is most likely to affect children under 2 years of age who have birth defects and are taking more than one antiseizure drug. Some doctors recommend monitoring blood levels for liver function once prior to administering valproate or divalproex sodium, monthly during the first 6 months, and then periodically after that.
- Children with epilepsy who take valproic acid may eventually develop some problems in the kidney, although they are generally not significant.
Symptoms of Toxic Side Effects in Liver or Pancreas.
- Abdominal pain
- Nausea or vomiting
- Loss of appetite
- Acute confusion
- Water retention
- Easy bruising
- Yellowish skin coloring
Carbamazepine (Tegretol, Equetro, Carbatrol) is an effective anticonvulsant and specific analgesic when used alone or with other drugs. Carbamazepine also has the added benefit of relieving depression and improving alertness. An extended release form is available that allows twice-daily dosing rather than 3 times a day. A chewable form makes it easier for children to take.
Uses. This drug is used to prevent the following seizures or epilepsy syndromes:
- Partial seizures. Patients 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).
Side Effects. Different side effects may develop or resolve at different points in the treatment duration. Initial side effects may include:
- Double vision, headache, sleepiness, dizziness, and stomach upset. These usually subside after a week and can be greatly reduced by starting with a small dose and building up gradually.
- Some people experience visual disturbances, ringing in the ears, agitation, or odd movements when drug levels are at their peak. The extended-release form of carbamazepine (Carbatrol) may help reduce these symptoms.
Serious side effects are less common but can include:
- Carbamazepine may increase the risk for birth defects, especially if it is taken during the first trimester of pregnancy.
- Skin reactions, including toxic epidermal necrolysis and Stevens-Johnson syndrome, so severe the drug has to be discontinued develop in about 6% of patients. These skin reactions cause skin lesions, blisters, fever, itching, and other symptoms. People of Asian ancestry have a 10 times greater risk for skin reactions than other ethnicities. The FDA recommends that patients of Asian ancestry get a blood test prior to starting the drug to determine if they have the gene variant that increases this risk.
- Water retention can be a problem in older people.
- Hormonal changes, particularly higher levels of male hormones in both men and women, pose some risk for sexual dysfunction over time.
- A decrease in white blood cells occurs in about 10% of those taking the drug. This is generally not serious unless infection accompanies it.
- Other blood conditions can arise that are also potentially serious. Patients should be sure to inform the doctor if they have any sign of irregular heartbeats, sore throat, fever, easy bruising, or unusual bleeding.
- Long-term therapy can cause bone loss (osteoporosis) in women, who should take preventive calcium and vitamin D supplements.
- Children are at higher risk for behavioral problems.
Note: Citrus fruit, especially grapefruit, can increase carbamazepine's adverse effects and should be avoided by those taking this drug.
Uses. Phenytoin (Dilantin) is effective for adults who have the following seizures or conditions:
- Grand mal seizures
- Partial seizures
- Status epilepticus
- Can be effective for people with head injuries who are at high risk for seizures
This drug is not useful for the following seizures:
- Petit mal seizures
- Myoclonic seizures
- Atonic seizures
Side Effects. Side effects are sometimes difficult to control. Some people may develop a toxic response to normal doses, while others, such as those with alcoholism, may require higher doses to achieve benefits. As with any drug, side effects generally rely on dosage and duration. Using phenytoin in combination with newer add-on drugs can allow lower doses and may reduce some of the risks. Side effects may include:
- Excess body hair, eruptions and coarsening of the skin, and weight loss
- Gum disease
- Staggering, lethargy, nausea, depression, eye-muscle problems, anemia, and an increase in seizures can occur as a result of high doses.
- Liver damage may develop in rare cases.
- Bone loss from long-term therapy. Patients should take preventive calcium and vitamin D supplements and exercise regularly to improve bone mass.
- Severe and even rare life-threatening skin reactions (Stevens-Johnson syndrome, toxic epidemral necrosis)
- An increased risk for birth defects
Barbiturates (Phenobarbital and Primidone)
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. Primidone (Mysoline) is converted in the body to phenobarbital, and has the same benefits and adverse effects. It is reported that primidone is not as well-tolerated as phenobarbital. Some doctors believe that primidone has no advantage over the other drug.
Uses. Barbiturates are used to also prevent grand mal (tonic-clonic) seizures or partial seizures. They are no longer typically used as a first-line drug.
Side Effects. 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.
Patients sometimes describe their state as "zombie-like." The most common and troublesome side effects are:
- 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.
Ethosuximide and Similar Drugs
Uses. 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%. 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.
Side Effects. 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.
Clonazepam and Similar Drugs
Uses. 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 when 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.
Uses. Lamotrigine (Lamictal) is approved as add-on (adjunctive) therapy for partial seizures, and generalized seizures associated with Lennox-Gastaut syndrome, in children aged 2 years and older and in adults. Lamotrigine is also approved as add-on therapy for treatment of primary generalized tonic-clonic (PGTC) seizures, also known as grand mal seizures, in children aged 2 years and older and adults. Lamotrigine can be used as a single drug treatment (monotherapy) for adults with partial seizures. Birth control pills lower blood levels of lamotrigine.
Side Effects. Common side effects include dizziness, headache, blurred or double vision, lack of coordination, sleepiness, nausea, vomiting, insomnia, and rash. Although most cases of rash are mild, in rare cases the rash can become very severe. The risk of rash increases if the drug is started at too high a dose or if the patient is also taking valproate. (Serious rash is more common in young children who take the drug than it is in adults.) Rash is most likely to develop within the first 8 weeks of treatment. Be sure to immediately notify your doctor if you develop a rash, even if it is mild.
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. It has achieved response rates in patients with resistant partial epilepsy. It is not useful for generalized petit mal seizures.
Side Effects. 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. Children may experience hyperactivity or aggressive behavior. Long-term adverse effects are still unknown.
Pregabalin (Lyrica) is similar to gabapentin.
Uses. 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. These may include dizziness, sleepiness, dry mouth, swelling in hands and feet, blurred vision, weight gain, and trouble concentrating
Uses. Topiramate (Topamax, generic) is similar to phenytoin and carbamazepine and is effective and safe for a wide variety of seizures in adults and children. It is approved as add-on therapy for patients 2 years and older with generalized tonic-clonic seizures, partial-onset seizures, or seizures associated with Lennox-Gastaut syndrome. It is also approved as single drug therapy.
Side Effects. 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. Topiramate may have fewer interactions with oral contraceptives than other AEDs.
Oxcarbazepine (Trileptal, generic) is similar to phenytoin and carbamazepine but generally has fewer side effects.
Uses. Approved as single therapy or add-on therapy for partial seizures in adults and for children ages 4 years and older.
Side Effects. 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 (Zonegran) is a unique drug that blocks sodium and calcium channels and may have nerve-protecting properties.
Uses. It is approved as add-on therapy for adults with partial seizures, and studies indicate it is often effective against infantile spasms (West syndrome) and myoclonic seizures.
Side Effects. 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 (Keppra) is known as a nootropic drug.
Uses. This drug is approved both in oral and intravenous forms as add-on therapy for:
- Partial onset seizures in adults and children ages 4 years and older
- Myoclonic seizures in adults and adolescents ages 12 years and older who have juvenile myoclonic epilepsy
- Primary generalized tonic-clonic seizures in adults and children ages 6 years and older who have idiopathic generalized epilepsy
Levetiracetam appears to have fewer drug interactions than other anti-epileptic drugs and may be particularly useful for older patients.
Side Effects. These tend to occur mostly in the first month. They include sleepiness and fatigue, muscle weakness and coordination difficulties, headache, flu symptoms, dizziness, behavioral abnormalities, possible risk of a reduced white blood cell count, and a higher rate of infections. Caution is advised for patients with kidney dysfunction. There have been some reports of adverse effects on mood (irritability, depression, and 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 (Gabitril) has properties similar to phenytoin and carbamazepine, and is also showing promise.
Side Effects. 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 recommended only under certain circumstances. They include severe epilepsy, such as Lennox-Gastaut syndrome or as monotherapy for partial seizures in adults when other drugs fail.
Vigabatrin. Vigabatrin (Sabril) is a chemical called gamma-vinyl GABA. It was designed to increase the brain levels of gamma aminobutyric acid (GABA), the enzyme that inhibits seizure activity. It has serious side effects, however, and is generally prescribed in the U.S. only in certain cases, such as in low doses for patients with Lennox-Gastaut syndrome. Overseas it is also used for partial seizures and as first-line therapy in children with infantile spasms (West syndrome).
Between 10 - 30% of people on long-term treatment have developed irreversible visual disturbances, including reductions in acuity and color vision. Men are at higher risk for this side effect than are women. Further studies are needed to determine the extent and severity of this complication, particularly in children. There is a slight risk for depression or psychosis when vigabatrin is used as add-on therapy, and particularly if the drug is administered too quickly. These risks are far lower if the drug is used as sole therapy.
Older Drugs. Some older but less effective drugs may still play a role against epilepsy:
- Acetazolamide (Diamox) is sometimes used against common types of seizures, but patients quickly develop a tolerance for it. 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.
Treatment of Infantile Spasms
Infantile spasms are treated with vigabatrin, adrenocorticotropic hormone (ACTH), or valproate. This condition can be very difficult to treat.
New AEDs. Retigabine is an investigational GABA enhancer that works in a different way from existing AEDs. It is currently in phase III trials for treatment of partial-onset seizures in patients who are receiving other AEDs. Talampanel is another new type of drug, known as an AMAP receptor antagonist, that is currently in early trials. Other drugs under investigation are related to existing AEDs. For example, brivaracetam and seletracetam are similar to levetiraceptam, fluorofelbamate is similar to felbamate, and eslicarbazepine is similar to oxcarbazepine.
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:
- MRI of the brain is performed on all patients with epilepsy during the course of their illness. It often may identify an abnormality in brain tissue that is causing poorly controlled seizures.
- Many patients now have long-term EEG monitoring. This may involve wearing an EEG while taking part in everyday life or undergoing video EEG. These tests are done to help locate the exact brain tissue that is triggering the epileptic event
- Advanced imaging techniques can sometimes provide valuable additional information. They include functional magnetic resonance imaging (fMRI), 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, 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 most common surgical procedure for epilepsy is temporal lobectomy, which is performed when epilepsy are beginning in an area of 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.
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. Studies have shown that many patients remain seizure-free after temporal lobectomy. When a well-described area in the temporal lobes is identified as the source of the seizures, around 60% of patients became free of disabling seizures after surgery versus only 8% of patients treated with medications. In general, around 60 - 80% of patients are seizure free 1 - 2 years after surgery.
Patients may still need to take medications after surgery, 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 typically temporary and resolves within a few months.
Successful temporal lobe surgery improves quality of life and can help relieve depression and anxiety.
Effects on Mental Functioning. Although surgery on the left temporal lobe does not impair intelligence to any significant degree, some studies suggest negative effects of mental functioning and behavior. A risk of impairment of verbal memory is also present.
In general, surgical effects on mental functioning and behavior depend on the extent and location of the surgical area.
Lesionectomy is a procedure that removes abnormal tissues in certain conditions, such as:
- Cavernous angiomas (abnormal clusters of blood vessels)
- Low-grade brain tumors
- Cortical dysplasias (these are abnormalities 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.
Vagus Nerve Stimulation (VNS)
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:
- 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 - 30% of patients.)
- The batteries wear out after 3 - 5 years and need to be removed and replaced by a simple surgical procedure.
Candidates. The American Academy of Neurology recommends VNS for:
- 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 4 months by up to 50% and even more in many patients. Studies report that it has been effective for longer than 7 years.
Complications. Vagus nerve stimulation does not eliminate seizures in most patients and is still somewhat invasive. VNS 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. (However, VNS may also be helpful for treating status epilepticus in some patients.)
Deep Brain Stimulation. An investigational neurostimulation approach called deep brain stimulation (DBS) targets the thalamus, the part of the brain that produces most epileptic seizures. Early results have shown some benefit. Researchers are also studying other implanted brain and nerve stimulation devices such as the responsive neurostimulator system (RNS), which detects seizures and stops them by sending electrical stimulation to the brain. A third investigational approach, trigeminal nerve stimulation (TNS), stimulates a nerve involved in inhibiting seizures.
Stereotactic Radio Surgery. Focused beams of radiation are able to destroy lesions deep in the brain without the need for open surgery. Sometimes used for brain tumors, stereotactic radio surgery is also under investigation for temporal lobe epilepsy and for seizures due to cavernous malformations. It may be used for patients when an open surgical approach is not possible because the location of the abnormal area is surrounded by delicate brain tissue.
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 (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. Food allergies may provoke 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 U.S.).
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 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 is a problem with some 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, if patients are concerned they should discuss this issue with their doctors.
Some small studies have reported significant benefits from the practice of yoga, which employs weight bearing and balancing postures. Well-controlled studies are needed to confirm these benefits.
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. 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.
The Ketogenic Diet
The ketogenic diet, which is very high in fat (90%), very low in carbohydrates, and low in protein, has been studied and debated for decades. It has proven to be helpful for many children with severe epilepsy that does not respond to AEDs. It is not clear why it works. The standard theory is that burning fat instead of carbohydrates causes an increase in ketones. Excess ketones (called ketosis) appears to alter certain amino acids in the brain and to increase levels of the neurotransmitter gamma aminobutyric acid (GABA), which helps prevent nerve cells from over-firing.
Benefits. Studies report that about 10 - 15% of children who use the diet are seizure free after 1 year, while 30% are nearly seizure free. Some parents report that the diet helps improve their childrens alertness, even if seizures continue. Many children who try the ketogenic diet are able to stop or at least reduce their medications.
Candidates. The ketogenic diet seems to be most helpful for children who have difficult-to-control seizures, in particular:
- Generalized and partial seizures (the diet does not appear to be as helpful for children with partial-onset seizures)
- Myoclonic-atastic epilepsy
- Infantile spasm
Typical Ketogenic Diet. (This diet must be professionally monitored! Parents can endanger their children if they try the program on their own without consulting a doctor or trained health expert.) The child fasts for the first 1 - 2 days, then the diet is gradually introduced. The regimen uses small amounts of carbohydrates and large amounts of fats (up to 90%), with very few proteins and no sugar. Children generally consume 75% of their usual daily calorie requirements.
A typical dinner may include a chicken cutlet or piece of fish, broccoli with cheese, lettuce with mayonnaise, and a whipped cream sundae. Vegetables may include celery, cucumbers, or asparagus, cauliflower, and spinach. Breakfast might consist of an omelet, bacon, and cocoa with cream. (Artificial sweeteners are used for any desserts.)
The diet is difficult, as a slight deviation from the diet can provoke a seizure. Children cannot take medications that contain sugar (which is common in many drugs produced for children). Some sunscreens and lotions contain sorbitol, a carbohydrate that can be absorbed through skin. About 40 - 50% of patients find the diet too difficult or ineffective and stop it after 6 months.
Researchers are also investigating the Atkins diet, a popular weight-loss diet that has similar effects but is less restrictive than the ketogenic diet. Early results indicate that it might be helpful for some young people. Another alternative is a low glycemic index diet, which contains even fewer carbohydrates than the Atkins diet. Still, parents should not put their children on these diets without support from a doctor.
Side Effects and Complications. To prevent serious side effects, children need regular monitoring by a doctor, especially when the diet is first initiated.
Side effects or complications that may occur at the start of the diet include:
- Acidosis, a build-up of acid in the blood and body
- Low blood sugar (hypoglycemia)
- Stomach upset
Side effects that may occur later on include:
- Unhealthy cholesterol and lipid levels
- Kidney stones, which may be a complication of acidosis, occur in about 5% of children on the diet. Patients should drink plenty of fluids. Oral potassium citrate (Polycitra K) may be protective.
- Slowing of growth (tends to occur more in younger children than older children
- Decreased bone density
Because most patients remain on the diet for only 2 years, the risks for potential long-term damage appear minimal.
Emotional and Psychologic Support
Many patients with epilepsy and parents whose children have epilepsy can benefit from support associations. These services are usually free and available in most cities.
Tips for Helping Children. Some of the following tips may help the child with epilepsy:
- Children should be treated as normally as possible by parents and siblings.
- Children should be assured that they will not die from epilepsy.
- Often children can be given the hope that they will outgrow the disorder.
- Most children will not have seizures triggered by sports or by any other ordinary activities that are enjoyable and healthy.
- As soon as they are old enough, children should be active participants in maintaining their drug regimens, which should be presented in as positive a light as possible.
Therapies for Children and Adults. Because of the risks for serious emotional consequences, psychological therapy may be beneficial and even necessary for some adults and children. In one study, cognitive behavioral therapy was helpful in lowering seizure rates in young people with juvenile myoclonic epilepsy. This approach offers a structured counseling program that helps people change behaviors that can reduce seizure risk factors such as anxiety and insomnia.
- www.epilepsyfoundation.org -- Epilepsy Foundation
- www.aesnet.org -- American Epilepsy Society
- www.aan.com -- American Academy of Neurology
- www.ninds.nih.gov -- National Institute of Neurological Disorders and Stroke
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Reviewed By: Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc.