Epilepsy and Seizures Treatment & Management

The goal of treatment is to achieve a seizure-free status without adverse effects. This goal is accomplished in more than 60% of patients who require treatment with anticonvulsants. However, many people have adverse effects, and some have seizures that are refractory to medical therapy. Monotherapy is important, because it decreases the likelihood of adverse effects and avoids drug interactions. In addition, monotherapy may be cheaper than polytherapy, as many of the anticonvulsant agents have hepatic enzyme–inducing properties that decrease the serum level of the concomitant drug, increasing the required dose of the concomitant drug.

People with seizures experience psychosocial adjustments after their diagnosis; therefore, social and/or vocational rehabilitation may be needed. Many physicians underestimate the consequences that epilepsy may have on patients. For instance, patients with epilepsy may live in fear of experiencing the next seizure, and they may be unable to drive or work at heights.

The mainstay of therapy for people with recurrent unprovoked seizures is an anticonvulsant. If a patient has had more than 1 seizure, administration of an anticonvulsant is recommended. However, standard of care for a single, unprovoked seizure is avoidance of typical precipitants (eg, alcohol, sleep deprivation); no anticonvulsants are recommended unless the patient has risk factors for recurrence.

The risk of recurrence in the 2 years after a first unprovoked seizure is 15-70% depending on several factors, mainly an abnormal brain magnetic resonance image (MRI), an abnormal sleep-deprived electroencephalogram (EEG), and a partial-onset seizure.

The abnormal brain MRI finding refers to a possible substrate for an epileptogenic zone; therefore, it most often suggests that the brain injury that led to epilepsy is in the cortical and limbic regions. Diffuse abnormalities, such as hydrocephalus, might increase the risk by injuring the cerebral cortex.

An abnormal sleep-deprived EEG can include any or several abnormalities: epileptiform discharges, focal slowing, diffuse background slowing, and intermittent diffuse intermixed slowing. Epileptiform abnormalities and focal slowing are associated with an increased risk of seizure recurrence compared with the other findings. Nevertheless, the risk of recurrence in a person with 1 generalized tonic-clonic seizure, a normal EEG, a normal brain MRI, and no evidence of focal onset is about 15%; the patient is not treated. If a patient has all risk factors, the risk is approximately 80%, and the patient is treated.

The major unresolved question is how to treat patients with 1 abnormality with a recurrence risk of 30-50%. With such a patient, some authors discuss the possibilities with the individual, including the risk of seizure recurrence, the risk of toxic effects from taking the anticonvulsant, and the benefits of avoiding another seizure. The authors also discuss seizure precautions, including not driving for a specific time. Treatment with anticonvulsants does not alter the natural history of seizure recurrence; it only masks the risk for the duration of treatment.

The First Seizure Trial Group randomly selected 397 patients with an unprovoked, generalized tonic-clonic first seizure to take a conventional anticonvulsant (ie, carbamazepine, phenobarbital, phenytoin, valproic acid) or no treatment and reported that about 18% of treated patients had seizure recurrence in 1 year, compared with 39% of untreated patients.^[19] Therefore, patients must be told that anticonvulsants reduce the risk of their having another seizure but that anticonvulsants do not totally stop seizures from recurring.

The mainstay of treatment is anticonvulsant medication, and the drug of choice depends on an accurate diagnosis of the epileptic syndrome, probably owing to the different pathophysiologic mechanisms in the types of seizure and the specific epileptic syndromes.

Some anticonvulsants (eg, lamotrigine, topiramate, valproic acid, zonisamide) have multiple mechanisms of action, and some (eg, phenytoin, carbamazepine, ethosuximide) have only one known mechanism of action. Anticonvulsants can be divided into large groups based on their mechanisms, as follows:

• Blockers of repetitive activation of the sodium channel – Phenytoin, carbamazepine, oxcarbazepine, lamotrigine, topiramate
• Enhancer of slow inactivation of the sodium channel – Lacosamide, rufinamide
• Gamma aminobutyric acid (GABA)–A receptor enhancers – Phenobarbital, benzodiazepines
• Glutamate modulators – Topiramate, lamotrigine, felbamate
• T-calcium channel blockers – Ethosuximide, valproate
• N- and L-calcium channel blockers – Lamotrigine, topiramate, zonisamide, valproate
• H-current modulators – Gabapentin, lamotrigine
• Blockers of unique binding sites – Gabapentin, levetiracetam
• Carbonic anhydrase inhibitors – Topiramate, zonisamide
• Neuronal potassium channel (KCNQ [Kv7]) opener - Ezogabine

For more information, see Antiepileptic Drugs.

This section discusses the use of anticonvulsant agents for absence, tonic or atonic, myoclonic, and tonic-clonic seizures. A discussion of treatment focal-onset seizures, including refractory cases, also follows, with some findings from the Veterans Administration (VA) Cooperative Studies and Standard and New Antiepileptic Drugs (SANAD) trial.

Absence seizures

If only absence seizures are present, most neurologists treat them with ethosuximide. If absence seizures are present with other types (eg, generalized tonic-clonic seizures, myoclonic seizures), the choices are valproic acid, lamotrigine, or topiramate. Do not use carbamazepine, gabapentin or tiagabine, because these drugs may exacerbate absence seizures. Whether pregabalin, a medication related to gabapentin, might also exacerbate this type of seizure is uncertain.

A single, double-blind randomized controlled trial compared the efficacy, tolerability, and neuropsychologic effects of ethosuximide, valproic acid, and lamotrigine in children with newly diagnosed childhood absence epilepsy and concluded that ethosuximide was the drug of choice for newly diagnosed childhood absence epilepsy.^[20] Valproate was equally as effective ethosuximide, but it was associated with more adverse effects.

Tonic or atonic, myoclonic, and tonic-clonic seizures

Tonic or atonic seizures typically indicate clinically significant brain injury. The Lennox-Gastaut syndrome is one common example of tonic seizures, and it is best treated with broad-spectrum drugs (eg, valproic acid, lamotrigine, topiramate) or felbamate as a last resort. Other modalities include the use of vagal nerve stimulation (VNS). The US Food and Drug Administration (FDA) has approved several new agents, rufinamide (Banzel) in 2008 and clobazam (ONFI)^[21] in 2011, as adjunctive therapy for seizures associated with Lennox-Gastaut syndrome.

Myoclonic seizure has a bimodal distribution. Infants with myoclonic epilepsies usually have a poor prognosis; however, in late childhood and adolescence, the syndrome of juvenile myoclonic epilepsy (JME) is often the cause of myoclonic seizures. This condition is typically a benign process that is treated easily, but JME has a high recurrence rate of approximately 80-90% after discontinuation of anticonvulsants. The best medications for JME and myoclonic seizures are valproic acid, lamotrigine, and topiramate. Levetiracetam has been approved by the FDA for adjunctive therapy of JME; this is the first medication approved for this syndrome. Anecdotal evidence suggests that zonisamide might be helpful in JME.

Primary generalized tonic-clonic seizures respond to valproic acid, topiramate, or lamotrigine. Levetiracetam gained FDA approval in 2007 as adjunctive therapy.

Generalized and unclassified epilepsies

The generalized seizures arm of the SANAD trial demonstrated that "Valproate is better tolerated than topiramate and more efficacious than lamotrigine, and should remain the drug of first choice for many patients with generalized and unclassified epilepsies. However, because of known potential adverse effects of valproate during pregnancy, the benefits for seizure control in women of childbearing years should be considered."^[22] Levetiracetam and zonisamide were not included in this trial, which only tested lamotrigine, topiramate and valproate.

Focal-onset seizures – First-line and adjunctive therapy

In focal-onset seizures, carbamazepine is considered first-line therapy. However, in special populations, lamotrigine, oxcarbazepine, and topiramate might be better choices. Adjunctive therapy with levetiracetam, tiagabine, gabapentin, or pregabalin might be a choice if the first or second monotherapy trial with first-line treatments failed.

The VA Cooperative Study I clearly demonstrated similar efficacies for carbamazepine, phenytoin, primidone, and phenobarbital.^[23] However, carbamazepine and phenytoin were tolerated better by men than women. The VA Cooperative Study II findings showed that carbamazepine and valproic acid had similar efficacies.^[24] However, in subset analysis for complex focal seizures, it suggested that carbamazepine might be a better choice than valproate.

In the VA Cooperative Study of the treatment of seizures in the elderly (patients aged 60 y or older), the investigators compared carbamazepine, lamotrigine, and gabapentin and found that lamotrigine and gabapentin were not only better tolerated than carbamazepine, but they were also similarly effective.^[25] However, gabapentin caused more adverse effects than lamotrigine. The results led to the recommendation of lamotrigine as first-line monotherapy in elderly patients.^[25]

The focal seizures arm of the SANAD trial demonstrated that although carbamazepine is the standard drug treatment, lamotrigine is clinically better for time to treatment failure outcomes.^[26] This study also determined lamotrigine is a cost-effective alternative to carbamazepine for patients with focal-onset seizures. Carbamazepine, gabapentin, lamotrigine, oxcarbazepine, and topiramate were included for comparison.^[26]

All new medications have been tested as adjunctive therapy, and head-to-head comparisons between new drugs and carbamazepine have been conducted in Europe. In general, the new drugs have similar statistical efficacies but fewer adverse effects than carbamazepine.

Of the new anticonvulsants, lamotrigine and topiramate appear to have broad spectrum of action in many seizure types.^{[27, 28]} The American Academy of Neurology and the American Epilepsy Society assembled a task force that reviewed the literature and provided evidence-based recommendations for monotherapy, adjunctive therapy, treatment of primary generalized seizures, treatment in children, and treatment of subgroups of new-onset and refractory epilepsy.^{[27, 28]}

If carbamazepine fails to control the seizures, lamotrigine, topiramate, tiagabine, gabapentin, levetiracetam, oxcarbazepine, pregabalin and zonisamide are considered for second- or third-line therapy. Several new anticonvulsants, including lamotrigine, topiramate, and oxcarbazepine, are indicated as monotherapy. Although the new anticonvulsants are considered second- or third-line therapy, they can be used as first-line therapy in some patients.

Discussing the adverse-effect profiles of anticonvulsants with patients is important, because the efficacies of anticonvulsants appear to be similar.

Looking ahead

Future advancements will involve antiepileptic drugs that alter the natural history of epilepsy. Evidence in animal models of epilepsy suggests that at least 2 of the current anticonvulsants, topiramate and levetiracetam, have neuroprotective effects and that they might slow the natural history of epilepsy. However, the applicability of animal data to human patients is unknown.

The use of anticonvulsants is slightly different in several populations of patients, including neonates, children, elderly patients, pregnant women, and patients with hepatic or renal insufficiency.

Children, neonates, and elderly patients

Children and neonates tend to require similar loading doses per kilogram of body weight, but they tend to metabolize the drugs faster than adults. This younger population also has rapid increases in the total volume of distribution.

Elderly patients present the opposite problem to that of neonates and children, in which there is a need for lowered initial and maintenance doses, owing to a slowed hepatic metabolism, decreased renal clearance, and decreased volumes of distribution, which are normal features of the aging process.

Women on contraception

Enzyme-inducing anticonvulsants, such as carbamazepine, phenytoin, phenobarbital, primidone, felbamate, lamotrigine, topiramate, and oxcarbazepine, decrease the efficacy of birth control pills. Some anticonvulsants cause this drug interaction in a dose-dependent manner, with a negligible effect at low doses. Some obstetricians use a high-dose estrogen-progesterone pill. An alternative and possibly preferred approach is to use a second method of contraception.

Women of childbearing age and pregnant women

In 2009, the American Academy of Neurology and American Epilepsy Society issued new guidelines for the management of antiepileptic drugs (AEDs) during pregnancy.^{[29, 30, 31]}

Woman of childbearing age should take folic acid at least 1 mg/d to decrease the rate of neural-tube malformations in the fetus. In addition, evidence strongly suggests that, during pregnancy, women should take the medication that best controls their epilepsy. Switching medications during pregnancy is not recommended because of the risk of losing seizure control. Furthermore, women should be treated with only 1 anticonvulsant rather than polytherapy. Data from Japan show an exponential risk of birth defects as anticonvulsants are added in polytherapy.

Drug serum levels should be obtained frequently because of the many physiologic changes that take place during pregnancy, including changes in volume of distribution, protein binding, and hepatic metabolism and erratic absorption. In particular, decreased serum concentration of lamotrigine in the third trimester is well documented.

The performance of amniocentesis is a personal decision between the woman and her obstetrician. The most important point is to have a clear idea about how the information obtained will be useful for clinical decision making.

Patients with hepatic and renal insufficiency

Gabapentin and levetiracetam are excreted mostly by means of renal clearance. Their doses could be adjusted for renal insufficiency. These agents are useful in patients with hepatic failure, especially when a drug-induced etiology is suspected. Lamotrigine, which is metabolized by means of glucuronidation, a phase II reaction, is also used in some patients with hepatic insufficiency.

Considerable data are available on the use of phenytoin in both hepatic and renal insufficiency. However, phenytoin is not a preferred medication because of its nonlinear kinetics, hepatic autoinduction, numerous drug interactions, and high degree of protein binding. Among all anticonvulsants, phenytoin, valproic acid, and felbamate have been associated with acute hepatic injury.

After a person has been seizure free for typically 2-5 years, physicians consider discontinuing the medication. Many patients outgrow many epileptic syndromes of childhood and need not take anticonvulsants. However, the recurrence rate during adulthood for patients with juvenile myoclonic epilepsy (JME) is about 80-90% in 2 years, despite many years of being seizure free with low doses of appropriate anticonvulsants. The relapse rate for adults is about 40-50%; for children, it is about 25%. This difference is probably due to the different epileptic syndromes that are prevalent in the 2 populations.

Risk of seizure recurrence

Many neurologists use the risk factors for new-onset seizures to assess patients for discontinuation of anticonvulsants. A normal sleep-deprived electroencephalogram (EEG) and normal brain magnetic resonance image (MRI) lower the risk of relapse after discontinuation, whereas epileptiform or focal abnormalities on a sleep-deprived EEG and/or focal cortical abnormalities on a brain MRI significantly increase the risk.

Other factors associated with an increased risk of seizure recurrence after discontinuation include the following:

• Abnormal EEG (worse if epileptiform discharges or focal abnormalities are present)
• Abnormal brain MRI (especially injury in cortical and limbic regions)
• Several seizure types (worse if tonic or atonic seizures are present)
• High number and frequency of seizures
• Long duration of epilepsy before the seizures are controlled
• Short duration of seizure freedom

Seizure relapse

About 75% of relapses after discontinuation occur in the first year, and at least 50% of patients who have another seizure do so in the first 3 months. Therefore, advise the patients to observe strict seizure precautions (including not driving) during tapering and for at least 3 months after discontinuation, depending on state laws. Driving is an impediment in some patients, who may opt to continue therapy.

Some authors recommend that all anticonvulsants, except primidone, phenobarbital, and benzodiazepines, be gradually discontinued over 6-10 weeks, if they were used for a long period. Discontinue primidone, phenobarbital, and benzodiazepines over 10-16 weeks.

A ketogenic diet and vagal nerve stimulation are 2 nonpharmacologic methods in managing patients with seizures.

Ketogenic diet

The ketogenic diet, which relies heavily on Crisco (shortening product), has a role in children with severe epilepsy. However, this diet is difficult to maintain, although it is unquestionably effective in some refractory cases. One major problem is that despite television programs and a movie supporting its use, less than 10% of patients continue the diet after a year. Furthermore, any small carbohydrate intake (eg, lollypop, piece of candy) resets ketone metabolism for 2 weeks, eliminating antiseizure efficacy. Some authors do not consider this treatment in teenagers or adults unless all of their intake is being delivered by means of a gastric tube.

Thus, although ketogenic diet is an effective tool to improve seizure control in very select cases, it is very difficult to follow, as it requires achieving a ketotic state. Fewer than 1 in 20 patients who started this diet will be following it 1 year later.

Anecdotal data has been published about improvement of seizure frequency following the Atkins diet and taking fewer than 10 g of carbohydrates, but the data are only preliminary.^[32]

Vagal nerve stimulation

Vagal nerve stimulation (VNS) is a palliative device approved to treat medically refractory focal-onset epilepsy in adults. Some studies demonstrate its efficacy in focal-onset seizures and in a small number of patients with primary generalized epilepsy. Randomized studies showed modest efficacy at 3 months, but postmarketing experience shows delayed improvement in another group of patients.

According to the manufacturer's registry, efficacy of the device at 18 months is 40-50%, where efficacy is defined as a reduction in seizures of 50% or more. Many patients report improvement in seizure intensity and general mood. However, seizure-free rates for pharmacologically intractable focal-onset epilepsy are less than 10%.

The 2 major kinds of brain surgery for epilepsy are palliative and potentially curative.

A few years ago, the most common palliative surgery was anterior callosotomy, which was indicated for patients with intractable atonic seizures, who often have facial and neck injuries due to a fall. This surgery is still performed but rarely. The use of a vagal nerve stimulator (VNS) in such patients has reduced the need for anterior callosotomy.

Several curative surgeries are possible, including lobectomy and lesionectomy. In general, the epileptogenic zone must be mapped by using video-electroencephalographic (EEG) monitoring with intracranial electrodes unless the patient clearly has a unilateral temporal-lobe onset.

Outcomes of temporal-lobe surgeries are better than those for surgeries in other areas. If a patient has unilateral temporal-lobe seizures (as observed on video-EEG) and unilateral hippocampal sclerosis (as observed on brain magnetic resonance imaging [MRI]), the likelihood of a class I outcome (no seizures or only auras) at 2 years is 85%.

In a single, randomized controlled trial, patients with temporal lobe epilepsy, at 1 year, the group randomized to anterior temporal lobe resective surgery had 58% of patients who were free from seizures impairing awareness as compared with 8% in the group that received anticonvulsant treatment.^[33]

If another anticonvulsant is attempted in the same patient with medically refractory epilepsy, the likelihood of a class I outcome is less than 5% at 2 years. A patient with medically refractory epilepsy is one in whom 3 anticonvulsants with adequate serum concentrations fail because of lack of efficacy and not because of adverse effects. After 3 anticonvulsants fail, patients with focal-onset seizures should be referred to an epileptologist.

For more information on surgical management, see Identification of Potential Epilepsy Surgery Candidates, Outcome of Epilepsy Surgery, and Presurgical Evaluation of Medically Refractory Epilepsy.

The major problem for patients with seizures is the unpredictability of the next seizure.

Clinicians should discuss 5 types of seizure precautions with patients who have epileptic seizures and other spells of sudden-onset seizures: driving, ascending heights, working with fire or cooking, using power tools, taking unsupervised baths, and swimming. These lifestyle precautions are clearly more applicable to some patients than others. Document on the patient's chart that driving and occupational hazards for people with seizures were discussed.

Safety must be balanced with the risk for seizures. A patient with many poorly controlled, diurnal seizures may exercise more caution than a patient who has only nocturnal seizures. Encourage the use of helmets to prevent head trauma while the patient is biking, skiing, riding a motorcycle, or participating in other activities.

The restrictions differ for each patient because of the individual features of the seizures; the degree of seizure control; and, in the United States, state laws. Other countries have more permissive or more restrictive laws regarding driving.

Physicians should be aware of the state regulations regarding driving, which vary considerably among states and nations.

Driving motorized vehicles

Recommendations vary depending on state laws and on whether the patient has seizures that occur exclusively during sleep. Consult current state and federal laws and regulations. For example, to resume commercial driving across state lines, a patient must have a 5-year seizure-free period. The recommendation for driving cars and trucks extends to the operation of other motorized vehicles, such as boats, motorcycles, and others. Aircraft pilots are typically no longer permitted to fly.

Water precautions

Common sense dictates that patients should not swim alone, and patients with seizures should be particularly aware being in the presence of an adult lifeguard who can pull them out of the water if needed. Wearing a life jacket in a boat is important. Activities as simple as taking a bath may be risky, because a patient can drown with as little as an inch of water during the flaccid postictal phase. Patients who might have a seizure, for example, while waiting for the water to warm up, may suffer hot-water burns.

Heights, fire, and power tools

Patients with seizures might experience an episode in situations such as while trying to fix a roof or during another activity at considerable height from floor. In addition, burns from injuries related to cooking are not uncommon, and injuries can occur with the use of power tools. Caution, in particular, supervision, is advised when power tools are used and the use of safety devices, such as automatic shutoff switches, is recommended.

Refer patients with intractable spells to a neurologist or an epileptologist for further workup, including video-electroencephalographic (EEG) monitoring, to characterize the etiology of their seizures. A neurosurgical consult is recommended when the possibility of surgical management is considered.