Epilepsy : Cause, Pathophysiology, and Treatment
Epilepsy implies a periodic recurrence of seizures with or without convulsions. A seizure results from an excessive discharge of cortical neurons and is characterized by changes in electrical activity as measured by the electroencephalogram (EEG). A convulsion implies violent, involuntary contraction(s) of the voluntary muscles.
- A seizure is traceable to an unstable cell membrane or its surrounding cells. Excess excitability spreads either locally (focal seizure) or more widely (generalized seizure).
- An abnormality of potassium conductance, a defect in the voltage-sensitive calcium channels, or a deficiency in the membrane adenosine triphosphatase (ATPase) linked to ion transport may result in neuronal membrane instability and a seizure.
- Normal neuronal activity depends on normal functioning of excitatory (e.g., glutamate, aspartate, acetylcholine, norepinephrine, histamine, corticotropin-releasing factor, purines, peptides, cytokines, and steroid hormones) and inhibitory (e.g., dopamine, Î³-aminobutyric acid [GABA]) neurotransmitters; an adequate supply of glucose, oxygen, sodium, potassium, chloride, calcium, and amino acids; normal pH; and normal receptor function.
- Prolonged seizures, continued exposure to glutamate, large numbers of generalized tonic-clonic (GTC) seizures (greater than 100), and multiple episodes of status epilepticus may be associated with neuronal damage.
In most cases, the health care provider will not be in a position to witness a seizure. Many patients (particularly those with complex partial or generalized tonic-clonic seizures) are amnestic to the actual seizure event. Obtaining an adequate history and description of the ictal event (including time course) from a third party (e.g., significant other, family member, or witness) is critically important.
- Symptoms of a specific seizure will depend on seizure type. While seizures can vary between patients, they tend to be stereotyped within an individual.
- Complex partial seizures may include somatosensory or focal motor features.
- Complex partial seizures are associated with altered conciousness.
- Absence seizures may appear relatively bland, with only very brief (seconds) periods of altered conciousness.
- Generalized tonic-clonic seizures are major convulsive episodes and are always associated with a loss of conciousness.
Interictally (between seizure episodes), there are typically no objective, pathognomonic signs of epilepsy.
There are currently no diagnostic laboratory tests for epilepsy. In some cases, particularly following generalized tonic-clonic (or perhaps complex partial) seizures, serum prolactin levels may be transiently elevated. Laboratory tests may be done to rule out treatable causes of seizures (e.g., hypoglycemia, altered electrolyte concentrations, infections, etc.) that do not represent epilepsy.
OTHER DIAGNOSTIC TESTS
- EEG is very useful in the diagnosis of various seizure disorders.
- The EEG may be normal in some patients who still have the clinical diagnosis of epilepsy.
- While MRI is very useful (especially imaging of the temporal lobes), CT scan typically is not helpful except in the initial evaluation for a brain tumor or cerebral bleeding.
- The International Classification of Epileptic Seizures (Table 50-1) classifies epilepsy on the basis of clinical description and electrophysiologic findings.
- Partial seizures begin in one hemisphere of the brain and, unless they become secondarily generalized, result in an asymmetric seizure. Partial seizures manifest as alterations in motor functions, sensory or somatosensory symptoms, or automatisms. If there is no loss of consciousness, the seizures are called simple partial. If there is loss of consciousness, they are termed complex partial, and the patients may have automatisms, memory loss, or aberrations of behavior.
- Absence seizures generally occur in young children or adolescents and exhibit a sudden onset, interruption of ongoing activities, a blank stare, and possibly a brief upward rotation of the eyes. Absence seizures have a characteristic 2-4 cycle/second spike and slow-wave EEG pattern.
- In generalized seizures, motor symptoms are bilateral, and there is altered consciousness.
- Generalized tonic-clonic seizures may be preceded by premonitory symptoms (i.e., an aura). A tonic-clonic seizure that is preceded by an aura is likely a partial seizure that is secondarily generalized. Tonic-clonic seizures begin with a short tonic contraction of muscles followed by a period of rigidity. The patient may lose sphincter control, bite the tongue, or become cyanotic. The episode may be followed by unconsciousness, and frequently the patient goes into a deep sleep.
- Myoclonic jerks are brief shock-like muscular contractions of the face, trunk, and extremities. They may be isolated events or rapidly repetitive.
- In atonic seizures, there is a sudden loss of muscle tone that may be described as a head drop, dropping of a limb, or slumping to the ground.
The patient and family should be asked to characterize the seizure for frequency, duration, precipitating factors, time of occurrence, presence of an aura, ictal activity, and postictal state.
Physical, neurologic, and laboratory examination (SMA-20, complete blood cell count [CBC], urinalysis, and special blood chemistries) may identify an etiology. A lumbar puncture may be indicated if there is fever.
The goal of treatment is to control or reduce the frequency of seizures and ensure compliance, allowing the patient to live as normal a life as possible. Complete suppression of seizures must be balanced against tolerability of side effects, and the patient should be involved in defining the balance.
- The treatment of choice depends on the type of epilepsy and on drug-specific adverse effects and patient preferences. Figure 50-1 is a suggested algorithm for treatment of epilepsy.
- Begin with monotherapy; about 50% to 70% of patients can be maintained on one antiepileptic drug (AED), but all are not seizure free.
- Up to 60% of patients with epilepsy are noncompliant, and this is the most common reason for treatment failure.
- Drug therapy may not be indicated in patients who have had only one seizure or those whose seizures have minimal impact on their lives. Patients who have had two or more seizures should generally be started on AEDs.
- Factors favoring successful withdrawal of AEDs include a seizure-free period of 2 to 4 years, complete seizure control within 1 year of onset, an onset of seizures after age 2 and before age 35 years, and a normal EEG. Poor prognostic factors include a history of a high frequency of seizures, repeated episodes of status epilepticus, a combination of seizure types, and development of abnormal mental functioning. A 2-year seizure-free period is suggested for absence and rolandic epilepsy, while a 4-year seizure-free period is suggested for simple partial, complex partial, and absence associated with tonic-clonic seizures. According to the American Academy of Neurology guidelines, discontinuation of AEDs may be considered if the patient is seizure free for 2 to 5 years, if there is a single type of partial seizure or single type of primary generalized tonic-clonic seizure, if the neurologic examination and IQ are normal, and if the EEG normalized with treatment. AED withdrawal should always be done gradually.
MECHANISM OF ACTION
The mechanism of action of most AEDs includes effects on ion channels (sodium and calcium), inhibitory neurotransmission (GABA), or excitatory neurotransmission (glutamate and aspartate). AEDs that are effective against generalized tonic-clonic and partial seizures probably reduce sustained repetitive firing of action potentials by delaying recovery of sodium channels from activation. Drugs that reduce corticothalamic T-type calcium currents are effective against generalized absence seizures.
SPECIAL CONSIDERATIONS IN THE FEMALE PATIENT
- Enzyme-inducing AEDs, including topiramate and oxcarbazepine, may cause treatment failures in females taking oral contraceptives; a supplemental form of birth control is advised if breakthrough bleeding occurs.
- For catamenial epilepsy (seizures just before or during menses) or seizures that occur at the time of ovulation, conventional AEDs should be tried first, but hormonal therapy (progestational agents) may also be effective. Intermittent acetazolamide has also been used.
- About 25% to 30% of women have increased seizure frequency during pregnancy, and a similar percentage have decreased frequency.
- AED monotherapy is preferred in pregnancy. Clearance of phenytoin, carbamazepine, phenobarbital, ethosuximide, lamotrigine, and clorazepate increases during pregnancy, and protein binding may be altered. There is a higher incidence of adverse pregnancy outcomes in women with epilepsy, and the risk of congenital malformations is 4% to 6% (twice as high as in nonepileptic women). Barbiturates and phenytoin are associated with congenital heart malformations and facial clefts. Valproic acid and carbamazepine are associated with spina bifida and hypospadias. Other adverse outcomes are growth, psychomotor, and mental retardation. Some of these events can be prevented by adequate folate intake; prenatal vitamins with folic acid (approximately 0.4 to 5 mg/day) should be given to women of childbearing potential who are taking AEDs. Vitamin K, 10 mg/day orally, given to the mother during the last month before delivery can prevent neonatal hemorrhagic disorder.
- AED pharmacokinetic data are summarized in Table 50-3. For populations known to have altered plasma protein binding, free rather than total serum concentrations should be measured if the AED is highly protein bound. Conditions altering AED protein binding include chronic renal failure, liver disease, hypoalbuminemia, burns, pregnancy, malnutrition, displacing drugs, and age (neonates and the elderly). Unbound concentration monitoring is especially useful for phenytoin.
- Neonates may metabolize drugs more slowly, and infants and children may metabolize drugs more rapidly than adults. Lower doses of AEDs are required in the elderly. Some elderly patients have increased receptor sensitivity to central nervous system (CNS) drugs, making the accepted therapeutic range invalid.
THE ROLE OF SERUM CONCENTRATION MONITORING
Seizure control may occur before the â€œminimumâ€ of the accepted therapeutic serum range is reached, and some patients may need serum concentrations beyond the â€œmaximum.â€ The therapeutic range for AEDs may be different for different seizure types (e.g., higher for complex partial seizures than for tonic-clonic seizures).
The traditional treatment of tonic-clonic seizures is phenytoin or phenobarbital, but the use of carbamazepine and valproic acid is increasing, as efficacy is equal and side effects are more favorable.
Carbamazepine and valproic acid had equal retention rates for tonic-clonic seizures, but carbamazepine was superior for partial seizures, and valproic acid caused more adverse effects.
For a combination of absence and other generalized or partial seizures, valproic acid is preferred. If valproic acid is ineffective in treating a mixed seizure disorder that includes absence, ethosuximide should be used in combination with another AED.
The newer AEDs were first approved as adjunctive therapy for patients with refractory partial seizures. To date, lamotrigine and oxcarbazepine have received Food and Drug Administration (FDA) approval for use in monotherapy in patients with partial seizures. Felbamate has monotherapy approval but causes some significant side effects.
SPECIFIC ANTIEPILEPTIC DRUGS
Carbamazepine may act by inhibition of voltage-gated sodium channels.
Food may enhance bioavailability.
Controlled- and sustained-release preparations dosed every 12 hours are bioequivalent to immediate-release preparations dosed every 6 hours. These dosage forms, compared with immediate-release preparations, have lower peaks and higher troughs.
The liver metabolizes 98% to 99% of a dose of carbamazepine (mostly by CYP3A4), and the major metabolite is carbamazepine-10,11-epoxide, which is active.
Carbamazepine can induce its own metabolism (autoinduction); this effect begins within 3 to 5 days of dosing initiation and takes 21 to 28 days to become complete.
Carbamazepine is considered an AED of first choice for newly diagnosed partial seizures. It is also useful for primary generalized convulsive seizures that are not considered an emergency.
Neurosensory side effects (e.g., diplopia, blurred vision, nystagmus, ataxia, dizziness, and headache) are the most common, occurring in 35% to 50% of patients initially.
Carbamazepine may induce hyponatremia, a condition similar to the syndrome of inappropriate antidiuretic hormone secretion. The incidence may increase with age.
Thrombocytopenia and anemia are relatively rare events that respond to discontinuation of carbamazepine. Leukopenia is the most common hematologic side effect (up to 10%) but is usually transient. It may be persistent in 2% of patients. Carbamazepine may be continued unless the white cell count (WBC) drops to less than 2500/mm3 and the absolute neutrophil count drops to less than 1000/mm3.
Rashes may occur in 10% of patients. Other side effects include hepatitis, osteomalacia, cardiac conduction defects, and lupus-like reactions.
Carbamazepine may interact with other drugs by inducing their metabolism. Valproic acid increases concentrations of the 10,11-epoxide metabolite without affecting the concentration of carbamazepine. The interaction of erythromycin and clarithromycin (CYP3A4 inhibition) with carbamazepine is particularly significant.
Loading doses are used only in critically ill patients.
Although some patients, especially those on monotherapy, can be maintained on twice-a-day dosing, others may require more frequent administration, especially children. Larger doses can be given at bedtime. Dose increases can be made every 2 to 3 weeks.
The sustained- and controlled-release dosage forms allow for twice-a-day dosing. The sustained-release capsule can be opened and sprinkled on food.
Ethosuximide’s proposed mechanisms of action include inhibition of NADPH-linked aldehyde reductase, inhibition of sodium-potassium ATPase, a decrease in non-inactivating Na+currents, blocking of Ca2+-dependent K+channels, and inhibition of T-type Ca2+ channel currents.
It is a first-line treatment for absence seizures;
There is some evidence for nonlinear metabolism at higher doses. Metabolites are believed to be inactive.
A loading dose is not required. Titration over 1 to 2 weeks to maintenance doses of 20 mg/kg/day (divided into two doses) usually results in serum concentrations of 50 mcg/mL.
Felbamate appears to act as a glycine receptor antagonist.
It is approved for treating atonic seizures in patients with Lennox-Gastaut syndrome, and is effective for partial seizures as well.
Because of the reports of aplastic anemia (1 in 3000 patients) and hepatitis (1 in 10,000 patients), it is now recommended only for patients refractory to other AEDs. Risk factors for aplastic anemia may be a history of cytopenia, AED allergy or toxicity, viral infection, and/or immunologic problems.
It is recommended that the dose of phenytoin, carbamazepine, and valproic acid be decreased by about 30% when felbamate is added. Interactions with warfarin have also been reported.
If felbamate is used as monotherapy, the dose is initiated at 1200 mg/day (15 mg/kg in children) and then is increased by 600 mg every 2 weeks up to a maximum dose of 3600 mg/day (45 mg/kg in children).
Gabapentin may modulate specific voltage-sensitive Ca2+ channels and elevates human brain GABA levels. It is a second-line agent for patients with partial seizures who have failed initial treatment. It may also have a role in patients with less severe seizure disorders, such as new-onset partial epilepsy, especially in elderly patients.
Bioavailability decreases with increasing doses. It is eliminated exclusively renally, and dosage adjustment is necessary in patients with impaired renal function.
Common side effects are fatigue, sleepiness, dizziness, and ataxia.
Dosing is initiated at 300 mg at bedtime and increased to 300 mg twice daily on the second day and 300 mg three times daily on the third day. Further titrations are then made. The manufacturer recommends maintenance doses up to 1800 to 2400 mg/day, but higher doses (5000 to 10,000 mg/day) have been used safely. Most clinicians use doses of 2400 to 4800 mg/day.
Lamotrigine blocks neuronal sodium channels, produces dose-dependent inhibition of high-voltage activation Ca2+ currents, and blocks release of excitatory amino acid neurotransmitters.
It is useful as both adjunctive therapy and monotherapy in adults with partial epilepsy. It may also be useful in patients with primary generalized seizure types such as absence.
It does not induce or inhibit the metabolism of other AEDs.
The most frequent side effects are diplopia, drowsiness, ataxia, and headache. Rashes are usually mild to moderate, but Stevens-Johnson reaction has also occurred. The incidence of rash appears to be increased in patients who are also receiving valproic acid and who have rapid dosage titration.
Levetiracetam has a unique chemical structure and mechanism of action.
Renal elimination of unchanged drug accounts for 66% of drug clearance, and the dose should be adjusted for impaired renal function. The role of therapeutic drug monitoring is unknown. It has linear pharmacokinetics and is not metabolized by the cytochrome P450 (CYP) and UGT systems.
It is effective in the adjunctive treatment of partial seizures in adults who have failed initial therapy.
Adverse effects include sedation, fatigue, and coordination difficulties. A slight decline in red and white blood cells was noted in clinical trials.
It is believed to have a low potential for drug interactions.
The recommended initial dose is 500 mg orally twice daily, and this can be increased by 1000 mg/day every 2 weeks to a maximum recommended dose of 3000 mg/day (1500 mg b.i.d.).
Oxcarbazepine (a prodrug) is structurally related to carbamazepine, but it is converted to a monohydrate derivative (MHD), which is the active component.
It blocks voltage-sensitive sodium channels, modulates the voltage-activated calcium currents, and increases potassium conductance.
The MHD peaks within 4 to 6 hours after a dose. It undergoes glucuronide conjugation and is eliminated by the kidneys. Patients with significant renal impairment may require a dose adjustment. The half-life (9.3 Â± 1.8 hours) is shorter in patients taking enzyme-inducing drugs. The relationship between dose and serum concentration is linear.
It is indicated for use as monotherapy or adjunctive therapy for partial seizures in adults and as monotherapy and adjunctive therapy for partial seizures in patients as young as 4 years of age. It is also a potential first-line drug for patients with primary generalized convulsive seizures.
The most frequently reported side effects are dizziness, nausea, headache, diarrhea, vomiting, upper respiratory tract infections, constipation, dyspepsia, ataxia, and nervousness. It generally has fewer side effects than phenytoin, valproic acid, or carbamazepine. Hyponatremia has been reported in up to 25% of patients and is more likely in the elderly. About 25% to 30% of patients who have had a rash with carbamazepine will have a cross-reaction with oxcarbazepine.
Concurrent use of oxcarbazepine with ethinyl estradiol- and levonorgestrel-containing contraceptives may render these agents less effective. Oxcarbazepine may increase serum concentrations of phenytoin and decrease serum concentrations of lamotrigine (induction of UGT).
In adults, the starting dose of oxcarbazepine as monotherapy is 300 mg once or twice daily. This can be increased by 600 mg/day each week to a maximum dose of 2400 mg/day. For children aged 4 to 16 years, the starting dose is 8 to 10 mg/kg given twice daily, not to exceed 600 mg/day. This is titrated to the target dose over 2 weeks. See manufacturer’s recommendations for dosing by weight.
In patients converted from carbamazepine, the typical maintenance doses of oxcarbazepine are 1.5 times the carbamazepine dose.
Phenobarbital and Primidone
Phenobarbital decrease postsynaptic excitation, possibly through GABA mechanisms.
Phenobarbital is the drug of choice for neonatal seizures, but in other situations it is reserved for patients who have failed other AEDs.
Phenobarbital is a potent enzyme inducer.
The amount of phenobarbital excreted renally can be increased by giving diuretics and urinary alkalinizers.
The most common side effects are fatigue, drowsiness, and depression. Phenobarbital impairs cognitive performance. In children, hyperactivity can occur (see Table 50-4).
Ethanol increases phenobarbital metabolism, but valproic acid, cimetidine, phenytoin, felbamate, and chloramphenicol inhibit its metabolism.
Phenobarbital can usually be dosed once daily, and bedtime dosing may minimize daytime sedation.
Phenytoin alters ion fluxes, thus altering depolarization, repolarization, and membrane stability.
Phenytoin is a first-line AED for generalized seizures (except absence) and for partial seizures. Its place in therapy will be reevaluated as more experience is gained with the newer AEDs.
Absorption may be saturable. Absorption is affected by particle size, and the brand should not be changed without careful monitoring. Food may slow absorption. The intramuscular route is best avoided, as absorption is erratic. Fosphenytoin can safely be administered intravenously and intramuscularly. Equations are available to normalize the phenytoin concentration in patients with hypoalbuminemia or renal failure.
Phenytoin is metabolized in the liver mainly by CYP2C9, but CYP2C19 is also involved. Zero-order kinetics occurs within the usual dosage range, so any change in dose may produce disproportional changes in serum concentrations.
In nonacute situations, phenytoin may be initiated in adults at oral doses of 5 mg/kg/day and titrated upward. Subsequent dosage adjustments should be done cautiously because of nonlinearity in elimination. Most adult patients can be maintained on a single daily dose, but children often require more frequent administration. Only extended-release preparations should be used for single daily dosing.
One author suggested that if the phenytoin serum concentration is less than 7 mcg/mL, the daily dose should be increased by 100 mg; if the concentration is 7 to 12 mcg/mL, the daily dose can be increased by 50 mg; if the concentration is greater than 12 mcg/mL, the daily dose can be increased by 30 mg or less.
Common but usually transient side effects are lethargy, incoordination, blurred vision, higher cortical dysfunction, and drowsiness. At concentrations greater than 50 mcg/mL, phenytoin can exacerbate seizures. Chronic side effects include gingival hyperplasia, impaired cognition, hirsutism, vitamin D deficiency, osteomalacia, folic acid deficiency, carbohydrate intolerance, hypothyroidism, and peripheral neuropathy.
Phenytoin is prone to many drug interactions (see Tables 50-5 and 6). If protein-binding interactions are suspected, free rather than total phenytoin concentrations are a better therapeutic guide.
Phenytoin decreases folic acid absorption, but folic acid replacement enhances phenytoin clearance and can result in loss of efficacy. Phenytoin tablets and suspension contain phenytoin acid, while the capsules and parenteral solution are phenytoin sodium, which is 92% phenytoin. Clinicians should remember that there are two different strengths of phenytoin suspension and capsules.
Tiagabine is a specific inhibitor of GABA reuptake into glial cells and other neurons.
It is considered second-line therapy for patients with partial seizures who have failed initial therapy. The most frequently reported side effect is dizziness. Other side effects are asthenia, nervousness, tremor, and diarrhea. These side effects are usually transient.
It is oxidized by CYP3A4 enzymes, and enzyme inducers increase its clearance.
Tiagabine is displaced from protein by naproxen, salicylates, and valproate.
The minimal effective adult dose level is considered to be 30 mg/day. The initial dose is 4 mg/day, and this may be increased up to 56 mg/day in intervals of 4 to 8 mg/day added each week. The dosage typically employed is 32 to 56 mg daily.
Topiramate affects voltage-dependent sodium channels, GABA receptors, and antagonism of Î±-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionic acid (AMPA) subtype glutamate receptors.
It is a second-line AED for patients with partial seizures who have failed initial therapy.
Approximately 50% of the dose is excreted renally, and tubular reabsorption may be prominently involved.
The most common side effects are ataxia, impaired concentration, confusion, dizziness, fatigue, paresthesias, and somnolence. Nephrolithiasis occurs in 1.5% of patients. It has also been associated with acute narrow-angle glaucoma, oligohydrosis, and metabolic acidosis.
Enzyme inducers may decrease topiramate serum levels.
Starting doses are 12.5 to 50 mg/day, increasing by 12.5 to 50 mg/day every week or two. The minimally effective dose is approximately 200 mg/day. For patients on other AEDs, doses greater than 600 mg/day do not appear to lead to improved efficacy and may increase side effects. Monotherapy doses of 1000 mg/day have been well tolerated and effective.
Valproic Acid and Divalproex Sodium
Valproic acid may increase synthesis or inhibit degradation of GABA. It may also potentiate postsynaptic GABA responses, have a direct membrane-stabilizing effect, and affect potassium channels.
The free fraction may increase as the total concentration increases, and free concentrations may be a better monitoring parameter than total concentrations, especially at higher concentrations or in patients with hypoalbuminemia. Protein binding is decreased in patients with head trauma.
At least 10 metabolites have been identified, and some may be active. One may account for hepatotoxicity (4-en-valproic acid), and it is increased by concurrent dosing with enzyme-inducing drugs. At least 67 cases have been reported, and most deaths were in mentally retarded children less than 2 years old who were receiving multiple drug therapy.
The extended-release formulation (Depakote ER) is 15% less bioavailable than the enteric-coated preparation (Depakote).
It is first-line therapy for primary generalized seizures, such as absence, myoclonic, and atonic seizures, and is approved for adjunctive and monotherapy treatment of partial seizures. It can also be useful in mixed seizure disorders.
Side effects are usually mild and include gastrointestinal (GI) complaints, weight gain, drowsiness, ataxia, and tremor. GI complaints may be minimized with the enteric-coated formulation or by giving with food. Thrombocytopenia is common but is responsive to a decrease in dose. Other hematologic toxicities include leukopenia with transient neutropenia, transient erythroblastopenia, and bone marrow changes. Polycystic ovary syndrome and menstrual irregularities have also been reported with valproic acid therapy.
Although carnitine administration may partially ameliorate hyperammonemia, it is expensive, and there are only limited data to support routine supplemental use in patients taking valproic acid.
Valproic acid is an enzyme inhibitor that increases serum concentrations of concurrently administered phenobarbital and may increase concentrations of carbamazepine 10,11-epoxide without affecting concentrations of the parent drug. It also inhibits the metabolism of lamotrigine.
Twice daily dosing is reasonable, but children and patients taking enzyme inducers may require 3 or 4 times daily dosing.
The enteric-coated tablet divalproex sodium causes fewer GI side effects. It is metabolized in the gut to valproic acid.
Zonisamide is a broad-spectrum sulfonamide AED that blocks voltage-sensitive sodium channels by reducing voltage-dependent T-type Ca2+ channels; it also facilitates dopaminergic and serotonergic neurotransmission, weakly inhibits carbonic anhydrase, and blocks K+ evoked glutamate release.
It is approved as adjunctive therapy with partial seizures, but it is potentially effective in a variety of partial and primary generalized seizure types.
Zonisamide is 40% protein bound and has a half-life of 63 to 69 hours. It is metabolized by CYP3A4, and about 30% is excreted unchanged.
The most common side effects include somnolence, dizziness, anorexia, headache, nausea, and irritability. Symptomatic kidney stones may occur in 2.6% of patients. Hypersensitivity reactions may occur in 0.02% of patients, and history of allergy to sulfonamides is a contraindication. Monitoring of renal function may be advisable in some patients.
Enzyme inducers may reduce the half-life of zonisamide to 27 to 36 hours.
The initial dose in adults is 100 mg/day, and daily doses are increased by 100 mg every 2 weeks until a response is seen. The dosage range in adults 100 to 600 mg/day.