Epilepsy

EPILEPSY

Treatment of epilepsy (professional aspect)

Therapy for a patient with a seizure disorder is almost always multimodal and includes treatment of underlying conditions that cause or contribute to the seizures, avoidance of precipitating factors, suppression of recurrent seizures by prophylactic therapy with antiepileptic medications or surgery, and addressing a variety of psychological and social issues. Treatment plans must be individualized, given the many different types and causes of seizures as well as the differences in efficacy and toxicity of antiepileptic medications for each patient. In almost all cases a neurologist with experience in the treatment of epilepsy should design and oversee implementation of the treatment strategy. Furthermore, patients with refractory epilepsy or those who require polypharmacy with antiepileptic drugs should remain under the regular care of a neurologist.

Treatment of Underlying Conditions If the sole cause of a seizure is a metabolic disturbance such as an abnormality of serum electrolytes or glucose, then treatment is aimed at reversing the metabolic problem and preventing its recurrence. Therapy with antiepileptic drugs is usually unnecessary unless the metabolic disorder cannot be corrected promptly and the patient is at risk of having further seizures. If the apparent cause of a seizure was a medication (e.g., theophylline) or illicit drug use (e.g., cocaine), then appropriate therapy is avoidance of the drug and there is usually no need for antiepileptic medications unless subsequent seizures occur in the absence of these precipitants.

Seizures caused by a structural CNS lesion such as a brain tumor, vascular malformation, or brain abscess may not recur after appropriate treatment of the underlying lesion. However, despite removal of the structural lesion, there is a risk that the seizure focus will remain in the surrounding tissue or develop de novo as a result of gliosis and other processes induced by surgery, radiation, or other therapies. Most patients are therefore maintained on an antiepileptic medication for at least 1 year, and an attempt is made to withdraw medications only if the patient has been completely seizure-free. If the seizures are refractory to medication, the patient may benefit from surgical removal of the epileptic brain region (see "Surgical Treatment of Refractory Epilepsy").

Avoidance of Precipitating Factors Unfortunately, little is known about the specific factors that determine precisely when a seizure will occur in a patient with epilepsy. Some patients can identify particular situations that appear to lower their seizure threshold; these situations should be avoided. For example, a patient who has seizures in the setting of sleep deprivation should obviously be advised to maintain a normal sleep schedule. Many patients note an association between alcohol intake and seizures, and they should be encouraged to modify their drinking habits accordingly. There are also relatively rare cases of patients with seizures that are induced by highly specific stimuli such as a video game monitor, music, or an individual's voice ("reflex epilepsy"). If there is an association between stress and seizures, stress reduction techniques such as physical exercise, meditation, or counseling may be helpful.

Antiepileptic Drug Therapy Antiepileptic drug therapy is the mainstay of treatment for most patients with epilepsy. The overall goal is to completely prevent seizures without causing any untoward side effects, preferably with a single medication and a dosing schedule that is easy for the patient to follow. Seizure classification is an important element in designing the treatment plan, since some antiepileptic drugs have different activities against various seizure types. However, there is considerable overlap between many antiepileptic drugs, such that the choice of therapy is often determined more by specific needs of the patient, especially the patient's assessment of side effects.

When to Initiate Antiepileptic Drug Therapy Antiepileptic drug therapy should be started in any patient with recurrent seizures of unknown etiology or a known cause that cannot be reversed. Whether to initiate therapy in a patient with a single seizure is controversial. Patients with a single seizure due to an identified lesion such as a CNS tumor, infection, or trauma, in which there is strong evidence that the lesion is epileptogenic, should be treated. The risk of seizure recurrence in a patient with an apparently unprovoked or idiopathic seizure is uncertain, with estimates ranging from 31 to 71% in the first 12 months after the initial seizure. This uncertainty arises from differences in the underlying seizure types and etiologies in various published epidemiologic studies. Generally accepted risk factors associated with recurrent seizures include the following: (1) an abnormal neurologic examination, (2) seizures presenting as status epilepticus, (3) postictal Todd's paralysis, (4) a strong family history of seizures, or (5) an abnormal EEG. Most patients with one or more of these risk factors should be treated. Issues such as employment or driving may influence the decision whether or not to start medications as well. For example, a patient with a single, idiopathic seizure and whose job depends on driving may prefer taking antiepileptic drugs rather than risking a seizure recurrence and the potential loss of driving privileges.

Older medications such as phenytoin, valproic acid, carbamazepine, and ethosuximide are generally used as first-line therapy for most seizure disorders since, overall, they are as effective as recently marketed drugs and significantly less expensive. Of the new drugs that have become available in the United States in the past decade, most are currently being used as add-on or alternative therapy.

In addition to efficacy, other factors influencing the specific choice of an initial medication for a patient include the relative convenience of dosing schedule (e.g., once daily versus three or four times daily) and potential side effects. Almost all of the commonly used antiepileptic drugs can cause similar, dose-related side effects such as sedation, ataxia, and diplopia. Close follow-up is required to ensure these are promptly recognized and reversed. Most of the drugs may also cause idiosyncratic toxicity such as rash, bone marrow suppression, or hepatotoxicity. Although rare, these side effects need to be carefully considered during drug selection, and patients require laboratory tests (e.g., complete blood count and liver function tests) prior to the institution of a drug (to establish baseline values) and during initial dosing and titration of the agent.

ANTIEPILEPTIC DRUG SELECTION FOR PARTIAL SEIZURES Carbamazepine or phenytoin is currently the initial drug of choice for the treatment of partial seizures, including those that secondarily generalize. Overall they have very similar efficacy, but differences in pharmacokinetics and toxicity are the main determinants for use in a given patient. Phenytoin has a relatively long half-life and offers the advantage of once or twice daily dosing compared to two or three times daily dosing for carbamazepine (although a more expensive, extended-release form of carbamazepine is now available). An advantage of carbamazepine is that its metabolism follows first-order pharmacokinetics, and the relationship between drug dose, serum levels, and toxicity is linear. By contrast, phenytoin shows properties of saturation kinetics, such that small increases in phenytoin doses above a standard maintenance dose can precipitate marked side effects. This is one of the main causes of acute phenytoin toxicity. Long-term use of phenytoin is associated with untoward cosmetic effects (e.g., hirsutism, coarsening of facial features, and gingival hypertrophy), so it is often avoided in young patients who are likely to require the drug for many years. Carbamazepine can cause leukopenia, aplastic anemia, or hepatotoxicity and would therefore be contraindicated in patients with predispositions to these problems.

Valproic acid is an effective alternative for some patients with partial seizures, especially when the seizures secondarily generalize. Gastrointestinal side effects are fewer when using the valproate semisodium formulation (Depakote). Valproic acid also rarely causes reversible bone marrow suppression and hepatotoxicity, and laboratory testing is required to monitor toxicity. This drug should generally be avoided in patients with preexisting bone marrow or liver disease. Irreversible, fatal hepatic failure appearing as an idiosyncratic rather than dose-related side effect is a relatively rare complication; its risk is highest in children <2 years old, especially those taking other antiepileptic drugs or with inborn errors of metabolism. Valproic acid therapy should therefore only be used in infants and young children when the benefits clearly exceed this risk.

Lamotrigine, gabapentin, topiramate, tiagabine, and phenobarbital are additional drugs currently used for the treatment of partial seizures with or without secondary generalization. Lamotrigine appears to have an overall efficacy profile similar to the more standard drugs and is now being used as monotherapy. All patients, particularly children, need to be monitored closely for a lamotrigine-induced rash during the initiation of therapy. Also, lamotrigine must be started very slowly when used as add-on therapy with valproic acid, since valproic acid can inhibit its metabolism, thereby substantially prolonging its half-life. Gabapentin is unique in not having any significant drug interactions. This makes it potentially useful as add-on therapy, especially in patients who are particularly susceptible to side effects of other medications. Until recently, phenobarbital and other barbiturate compounds were commonly used as first-line therapy for many forms of epilepsy. However, the barbiturates frequently cause sedation in adults, hyperactivity in children, and other more subtle cognitive changes; thus, their use should be limited to situations in which no other suitable treatment alternatives exist.

ANTIEPILEPTIC DRUG SELECTION FOR GENERALIZED SEIZURES Valproic acid is currently considered the best initial choice for the treatment of primarily generalized, tonic-clonic seizures and lamotrigine, followed by carbamazepine and phenytoin, are suitable alternatives. Valproic acid is also particularly effective in absence, myoclonic, and atonic seizures and is therefore the drug of choice in patients with generalized epilepsy syndromes having mixed seizure types. Ethosuximide remains the preferred drug for the treatment of uncomplicated absence seizures, but it is not effective against tonic-clonic or partial seizures. Ethosuximide rarely causes bone marrow suppression, so that periodic monitoring of blood cell counts is required. Although approved for use in partial seizure disorders, lamotrigine appears to be effective in epilepsy syndromes with mixed, generalized seizure types such as JME and Lennox-Gastaut syndrome.

Initiation and Monitoring of Therapy Because the response to any antiepileptic drug is unpredictable, patients should be carefully educated about the approach to therapy. Patients need to understand that the goal is to prevent seizures and minimize the side effects of therapy; determination of the optimal dose is often a matter of trial and error. This process may take months or longer if the baseline seizure frequency is low. Most anticonvulsant drugs need to be introduced relatively slowly to minimize side effects, and patients should expect that minor side effects such as mild sedation, slight changes in cognition, or imbalance will typically resolve within a few days. Subsequent increases should be made only after achieving a steady state with the previous dose (i.e., after an interval of five or more half-lives).

Monitoring of serum antiepileptic drug levels can be very useful for establishing the initial dosing schedule. However, the published therapeutic ranges of serum drug concentrations are only an approximate guide for determining the proper dose for a given patient. The key determinants are the clinical measures of seizure frequency and presence of side effects, not the laboratory values. Conventional assays of serum drug levels measure the total drug (i.e., both free and protein-bound), yet it is the concentration of free drug that reflects extracellular levels in the brain and correlates best with efficacy. Thus, patients with decreased levels of serum proteins (e.g., decreased serum albumin due to impaired liver or renal function) may have an increased ratio of free to bound drug, yet the concentration of free drug may be adequate for seizure control. These patients may have a "subtherapeutic" drug level, but the dose should be changed only if seizures remain uncontrolled, not just to achieve a "therapeutic" level. It is also useful to monitor free drug levels in such patients. In practice, other than during the initiation or modification of therapy, monitoring of antiepileptic drug levels is most useful for documenting compliance.

If seizures continue despite gradual increases to the maximum tolerated dose and documented compliance, then it becomes necessary to switch to another antiepileptic drug. This is usually done by maintaining the patient on the first drug while a second drug is added. The dose of the second drug should be adjusted to decrease seizure frequency without causing toxicity. Once this is achieved, the first drug can be gradually withdrawn (usually over weeks unless there is significant toxicity). The dose of the second drug is then further optimized based on seizure response and side effects.

When to Discontinue Therapy Overall, about 70% of children and 60% of adults who have their seizures completely controlled with antiepileptic drugs can eventually discontinue therapy. Clinical studies suggest that the following patient profile yields the greatest chance of remaining seizure-free after drug withdrawal: (1) complete medical control of seizures for 1 to 5 years; (2) single seizure type, either partial or generalized; (3) normal neurologic examination, including intelligence; and (4) normal EEG. The appropriate seizure-free interval is unknown and undoubtedly varies for different forms of epilepsy. However, it seems reasonable to attempt withdrawal of therapy after 2 years in a patient who meets all of the above criteria, is motivated to discontinue the medication, and clearly understands the potential risks and benefits. In most cases it is preferable to reduce the dose of the drug gradually over 2 to 3 months. Most recurrences occur in the first 3 months after discontinuing therapy, and patients should be advised to avoid potentially dangerous situations such as driving or swimming during this period.

Treatment of Refractory Epilepsy Approximately one-third of patients with epilepsy do not respond to treatment with a single antiepileptic drug, and it becomes necessary to try a combination of drugs to control seizures. Patients who have focal epilepsy related to an underlying structural lesion or those with multiple seizure types and developmental delay are particularly likely to require multiple drugs. There are currently no clear guidelines for rational polypharmacy, but in most cases the initial combination therapy combines first-line drugs, i.e., carbamazepine, phenytoin, valproic acid, and lamotrigine. If these drugs are unsuccessful, then the addition of a newer drug such as topiramate or gabapentin is indicated. Patients with myoclonic seizures resistant to valproic acid may benefit from the addition of clonazepam, and those with absence seizures may respond to a combination of valproic acid and ethosuximide. The same principles concerning the monitoring of therapeutic response, toxicity, and serum levels for monotherapy apply to polypharmacy, and potential drug interactions need to be recognized. If there is no improvement, a third drug can be added while the first two are maintained. If there is a response, the least effective of the first two drugs should be gradually withdrawn.

Surgical Treatment of Refractory Epilepsy Approximately 20% of patients with epilepsy are resistant to medical therapy despite efforts to find an effective combination of antiepileptic drugs. For some, surgery can be extremely effective in substantially reducing seizure frequency and even providing complete seizure control. Understanding the potential value of surgery is especially important when, at the time of diagnosis, a patient has an epilepsy syndrome that is considered likely to be drug-resistant. Rather than submitting the patient to years of unsuccessful medical therapy and the associated psychosocial trauma of ongoing seizures, the patient should have an efficient but relatively brief attempt at medical therapy and then be referred for surgical evaluation.

The most common surgical procedure for patients with temporal lobe epilepsy involves resection of the anteromedial temporal lobe (temporal lobectomy) or a more limited removal of the underlying hippocampus and amygdala. Focal seizures arising from extratemporal regions may be suppressed by a focal neocortical resection or precise removal of an identified lesion (lesionectomy). When the cortical region cannot be removed, multiple subpial transection, which disrupts intracortical connections, is sometimes used to prevent seizure spread. Hemispherectomy or multilobar resection is useful for some patients with severe seizures due to hemispheric abnormalities such as hemimegaloencephaly or other dysplastic abnormalities, and corpus callosotomy has been shown to be effective for disabling tonic or atonic seizures, usually when they are part of a mixed-seizure syndrome (e.g., Lennox-Gastaut syndrome).

Presurgical evaluation is designed to identify the functional and structural basis of the patient's seizure disorder. Inpatient video-EEG monitoring is used to define the anatomic location of the seizure focus and to correlate the abnormal electrophysiologic activity with behavioral manifestations of the seizure. Routine scalp or scalp-sphenoidal recordings are usually sufficient for localization, and advances in neuroimaging have made the use of invasive electrophysiologic monitoring such as implanted depth electrodes or subdural electrodes much less common. A high-resolution MRI scan is routinely used to identify structural lesions. Functional imaging studies such as SPECT and PET are adjunctive tests that may help verify the localization of an apparent epileptogenic region with an anatomic abnormality. Once the presumed location of the seizure onset is identified, additional studies, including neuropsychological testing and the intracarotid amobarbital test (Wada test) may be used to assess language and memory localization and to determine the possible functional consequences of surgical removal of the epileptogenic region. In some cases, the exact extent of the resection to be undertaken is determined by performing cortical mapping at the time of the surgical procedure. This involves electrophysiologic recordings and cortical stimulation in the awake patient to identify the extent of epileptiform disturbances and the function of cortical regions in question.

Advances in presurgical evaluation and microsurgical techniques have led to a steady increase in the success of epilepsy surgery. Clinically significant complications of surgery are <5%, and the use of functional mapping procedures has markedly reduced the neurologic sequelae due to removal or sectioning of brain tissue. For example, about 70% of patients treated with temporal lobectomy will become seizure-free, and another 15 to 25% will have at least a 90% reduction in seizure frequency. Marked improvement is also usually seen in patients treated with hemispherectomy for catastrophic seizure disorders due to large hemispheric abnormalities. Postoperatively, patients generally need to remain on antiepileptic drug therapy, but the marked reduction of seizures following surgery can have a very beneficial effect on their quality of life.

Vagus Nerve Stimulation (VNS) VNS is a new treatment option for patients with medically refractory epilepsy who are not candidates for resective brain surgery. The procedure involves placement of a bipolar electrode on the midcervical portion of the left vagus nerve. The electrode is connected to a small, subcutaneous generator located in the infraclavicular region, and the generator is programmed to deliver intermittent electrical pulses to the vagus nerve. The precise mechanism of action of VNS is unknown, although experimental studies have shown that stimulation of vagal nuclei leads to widespread activation of cortical and subcortical pathways and an associated increased seizure threshold. In practice, the efficacy of VNS appears to be no greater than recently introduced anticonvulsant medications. Adverse effects of the surgery are rare, and stimulation-induced side effects, including transient hoarseness, cough, and dyspnea, are usually mild and well tolerated

[PakMed Homepage] [Disclaimer/Privacy Policy] [Contact]

© Copyrights PakMed Biomedical Solutions

Optimized for Java-script enabled Microsoft Internet Explorer 6, at screen resolution of 800 by 600 pixels.