For patients with epilepsy, medication is prescribed with the goal of preventing further attacks and is usually continued until there have been no seizures for at least 2 years. Epileptic patients should be advised to avoid situations that could be dangerous or life-threatening if further seizures should occur. Legislation may require clinicians to report to the state authorities any patients with seizures or other episodic disturbances of consciousness; driving cessation for 6 months or as legislated is appropriate following an unprovoked seizure.
Medication selection depends on seizure type (Table 24–2). The dose of the selected anticonvulsant is gradually increased until seizures are controlled or side effects prevent further increases. If seizures continue despite treatment at the maximal tolerated dose, a second medication is added and the dose increased depending on tolerance; the first medication is then gradually withdrawn. In most patients with seizures of a single type, satisfactory control can be achieved with a single anticonvulsant. Treatment with two medications may further reduce seizure frequency or severity but usually only at the cost of greater toxicity. Treatment with more than two medications is almost always unhelpful unless the patient is having seizures of different types. Other factors to consider in selecting an anticonvulsant include likely side effects, teratogenicity, interactions with other medications and oral contraceptives, and route of metabolism.
All antiepileptics are potentially teratogenic, although the teratogenicity of the newer antiseizure medications is less clear. Nevertheless, antiepileptic medication must be given to pregnant women with epilepsy to prevent seizures, which can pose serious risk to the fetus from trauma, hypoxia, or other factors.
Individual differences in drug metabolism cause a given dose of a medication to produce different blood concentrations in different patients, and this will affect the therapeutic response. In general, the dose of an antiepileptic agent is increased, depending on tolerance, to achieve the desired clinical response regardless of the serum drug level. When a dose is reached that either controls seizures or is the maximum tolerated, then a steady-state trough drug level may be obtained for future reference; rechecking this level may be appropriate during pregnancy, if a breakthrough seizure occurs, a dose change occurs, or another (potentially interacting) medication is added to the regimen. A laboratory’s therapeutic range for a medication is only a guide; many patients achieve good seizure control with no adverse effect at serum levels that exceed the stipulated range, and in these cases no dose adjustment is needed. The most common cause of a lower concentration of medication than expected for the prescribed dose is suboptimal patient adherence. Adherence can be improved by limiting to a minimum the number of daily doses. Recurrent seizures or status epilepticus may result if medications are taken erratically, and in some circumstances nonadherent patients may be better off without any medication. All anticonvulsants have side effects, and many require baseline and regular laboratory monitoring (Table 24–2).
3. Discontinuance of medication
Only when adult patients have been seizure-free for 2 years should withdrawal of medication be considered. Unfortunately, there is no way of predicting which patients can be managed successfully without treatment, although seizure recurrence is more likely in (1) patients with a longer duration of epilepsy prior to remission, (2) those with a shorter duration of remission, (3) those who initially did not respond to therapy, (4) those with seizures having focal features or of multiple types, (5) those with onset during adulthood, and (6) those with continuing electroencephalographic abnormalities. Dose reduction should be gradual (over weeks or months), and medications should be withdrawn one at a time. If seizures recur, treatment is reinstituted with the previously effective regimen.
Patients with seizures refractory to two or more medications may be candidates for operative treatment. Surgical resection is most efficacious when there is a single well-defined seizure focus, particularly in the temporal lobe. Among well-chosen patients, up to 70% remain seizure-free after extended follow-up. Deep brain or cortical stimulation for medically refractory focal-onset seizures may be of benefit.
5. Vagal nerve stimulation
Treatment by chronic vagal nerve stimulation for adults and adolescents with medically refractory focal seizures is approved in the United States and provides an alternative approach for patients who are not optimal candidates for surgical treatment. The mechanism of therapeutic action is unknown. Adverse effects consist mainly of transient hoarseness during stimulus delivery.
In patients who have had only one seizure or a flurry of seizures over a brief period of several hours, investigation as outlined earlier should exclude an underlying cause requiring specific treatment. An electroencephalogram should be obtained, preferably within 24 hours after the seizure. Prophylactic anticonvulsant treatment is generally not required unless further attacks occur or investigations reveal underlying pathology. The risk of seizure recurrence varies in different series between about 30% and 70%, with higher risk of recurrence in patients with structural brain lesions or abnormalities on electroencephalogram. Epilepsy should not be diagnosed on the basis of a solitary seizure. If seizures occur in the context of transient, nonrecurrent systemic disorders such as hyponatremia or hypoglycemia, the diagnosis of epilepsy is inaccurate, and long-term prophylactic anticonvulsant treatment is unnecessary.
2. Alcohol withdrawal seizures
The characteristic alcohol withdrawal seizure pattern is one or more generalized tonic-clonic seizures that may occur within 48 hours or so of withdrawal from alcohol after a period of high or prolonged intake. If the seizures have consistently focal features, the possibility of an associated structural abnormality, often traumatic in origin, must be considered. Treatment with anticonvulsants is generally not required for alcohol withdrawal seizures, since they are self-limited. Benzodiazepines are effective and safe for preventing further seizures. Status epilepticus may complicate alcohol withdrawal and is managed along conventional lines. Further attacks will not occur if the patient abstains from alcohol.
3. Tonic-clonic status epilepticus
Poor adherence to the anticonvulsant regimen is the most common cause; however, any disorder that can cause a single seizure may be responsible. The mortality rate may be as high as 20%, and among survivors the incidence of neurologic and cognitive sequelae is high. The prognosis relates to the underlying cause as well as the length of time between onset of status epilepticus and the start of effective treatment.
Status epilepticus is a medical emergency. Initial management includes maintenance of the airway and 50% dextrose (25–50 mL) intravenously in case hypoglycemia is responsible. If seizures continue, an intravenous bolus of lorazepam, 4 mg, is given at a rate of 2 mg/min and repeated once after 10 minutes if necessary; alternatively, 10 mg of midazolam is given intramuscularly, and again after 10 minutes if necessary. Diazepam can also be given rectally as a gel (0.2 mg/kg). These measures are usually effective in halting seizures for a brief period. Respiratory depression and hypotension may complicate the treatment and are treated as in other circumstances, including intubation and mechanical ventilation and admission to an intensive care unit.
Regardless of the response to lorazepam or midazolam, fosphenytoin or phenytoin should be administered intravenously. Fosphenytoin (18–20 mg phenytoin equivalents [PE]/kg) is rapidly and completely converted to phenytoin following intravenous administration and is preferred because it is less likely to cause reactions at the infusion site, can be given with all common intravenous solutions, and may be administered at a faster rate (150 mg PE/min). When fosphenytoin is not available, phenytoin (18–20 mg/kg) is given intravenously at a rate of 50 mg/min. Phenytoin is best injected directly but can also be given in saline; it precipitates, however, if injected into glucose-containing solutions. Because arrhythmias may develop during rapid administration of fosphenytoin or phenytoin, electrocardiographic monitoring is prudent. Hypotension may occur, especially if diazepam has also been given. Alternatively or additionally, intravenous valproate (loading dose 20–40 mg/kg over 15 min, maximum dose 3000 mg) or levetiracetam (loading dose 60 mg/kg over 15 min, maximum dose 4500 mg) is used for status epilepticus. Although neither is approved by the FDA for this indication, both were equivalent to fosphenytoin in a randomized trial. Due to the teratogenicity of valproate, it should be avoided in women who may be pregnant.
If seizures continue, phenobarbital is then given in a loading dose of 10–20 mg/kg intravenously by slow or intermittent injection (50 mg/min). Respiratory depression and hypotension are especially common with this therapy.
If these measures fail, general anesthesia with ventilatory assistance may be required; some experts recommend proceeding directly to general anesthesia if convulsions do not cease after the initial 18–20 PE/kg fosphenytoin load. Intravenous midazolam may provide control of refractory status epilepticus; the suggested loading dose is 0.2 mg/kg, followed by 0.05–0.2 mg/kg/h. Propofol (1–2 mg/kg as an intravenous bolus, followed by infusion at 2–15 mg/kg/h depending on response) may also be used, as may pentobarbital (5–15 mg/kg intravenously, followed by 0.5–4 mg/kg/h).
After status epilepticus is controlled, an oral medication program for the long-term management of seizures is started, and investigations into the cause of the disorder are pursued.
4. Nonconvulsive status epilepticus
In some cases, status epilepticus presents not with convulsions, but with a fluctuating abnormal mental status, confusion, impaired responsiveness, and automatism. Electroencephalography establishes the diagnosis. The treatment approach outlined above applies to any type of status epilepticus, although intravenous anesthesia is usually not necessary. The prognosis is a reflection of the underlying cause rather than of continuing seizures.