Epilepsy is a Greek word for seizures. It is a common chronic neurological problem. It affects about 0.5% of the population. In most of the patients, the etiology is unknown. It is characterized with brief episode of seizures which appear with or without loss of consciousness. An epileptic seizure is precipitated by high frequency electrical discharge of certain neurons in the brain. The abnormal electrical activity during a seizure can be recorded by an electro-encephalograph (EEG).
The exact pathophysiology of epileptic seizure is not known. However, it is believed to be either due to lack of GABA (an inhibitory neurotransmitter) or increase in glutamate (an excitatory neurotransmitter) in brain. The epileptic seizures are classified on the basis of locus, nature and spread of the abnormal discharge.
1. Grandmal type (tonic, clonic seizures).
2. Petitmal type (clonic-clonic; also known as absence seizures).
3. Psychomotor or temporal lobe epilepsy (partial seizures and repetitive bizarre behaviour).
4. Infantile myoclonus type.
5. Status epilepticus (rapid repetitive grandmal seizures).
Classification
1. Hydantoin derivatives: Diphenyl hydantom (phenytoin), ethotoin, mephenytoin.
2. Barbiturates: Phenobarbitone, mephobarbitone.
3. Deoxybarbiturate: Primidone.
4. Iminostilbenes: Carbamazepine.
5. Benzodiazepines: Diazepam, clonazepam, clobazepam.
6. Succinimides: Ethosuximide, methosuximide.
7. GABA transaminase inhibitors: Sodium valproate, vigabatrin.
8. GABA reuptake inhibitors: Tiagabine.
9. GABA agonists: Gabapentin.
10. Others: Lamotrizine, felbamate, topiramate, zonisamide, acetazolamide (carbonic anhydrase inhibitor), oxazolidinediones (trimethadione) and phenacemide are no longer used due to toxicity.
Phenytoin (diphenyl hydantoin): It is effective in all types of epilepsy except petitmal. It does not produce sedation. It has stabilizing effect on excitable cell membranes. It reduces Na conductance and reduces Ca influx. So it will attenuate action potential
generation in excitable cells and increase seizure threshold. Phenytoin reduces the spread of the seizure process from an active focus into adjacent normal brain tissue through an increase in the activity of the inhibitory neurotransmitters like GABA and possibly glycine. It is well absorbed from gut. 80—90% is bound to plasma proteins. It is metabolized in the liver by oxidation and conjugation. Rate of inactivation follows saturation kinetics.
Gum hyperplasia is the most common side effect in children. The other side effects include gastric distress, ataxiä, nystagmus, vertigo, muscle incoordination, dizziness, skin rashes and drug allergy.
It is given in a dose of 150—300 mg per day. It has narrow range of safety. So plasma levels should be checked up periodically. In children, its dose is 5—8 mg/kg daily.
Phenobarbitone: It is effective in all types of epilepsy except petitmal epilepsy. Like phenytoin, it reduces spread of the seizure process and seizure discharge. It is well absorbed from gut and about 50% is bound to plasma proteins. 75% of the drug is metabolized in liver by oxidation and conjugation while rest of it is excreted unchanged in urine. The dose is 90—375 mg daily in divided doses by oral route. It may be given as a single dose at bedtime. In children below 12 years of age, up to 90 mg is the daily dose. Important side effects are sedation, ataxia, nystagmus, folic acid deficiency anaemia.
Primidone: It is also effective in all types of epilepsy except petitmal epilepsy. It acts by reducing seizure discharge and spread of seizure process. It is well absorbed from gut and is metabolized into phenobarbitone and phenyl-ethyl malonamide by liver. Activity is mainly due to these active metabolites. About one-third prirnidone is excreted unchanged by kidney. Its side effects are similar to phenobarbitone. However, rarely it may cause anaemia, leukopenia, and lymph node enlargement.
Dose: 250—500 mg twice a day; children 10— 20 mg/kg/day.
Carbamazepine (tegretol; mezetol): It is structurally similar to phenothiazines or tricyclic antidepressant drug. However, it causes less sedation than phenothiazine and has questionable mood elevating property. It acts by reducing spread of seizure discharge. It is effective in all types of epilepsy. It is drug of choice for psychomotor epilepsy. It is also useful in trigeminal neuralgia and manic depressive psychosis. It is well absorbed from gut and is metabolized in liver. Its initial half- life is reduced over first few weeks from 30 to 15 hours due to enzyme induction. Side effects include visual and gastrointestinal disturbances, dizziness, allergic reactions and blood dyscrasias.
Dose: 200—400 mg three times a day.
Benzodiazepines: They act as anticonvulsant agents by enhancing GABA activity and inhibiting seizure discharge.
Clonazepam: Its oral absorption is slow and erratic. It is completely metabolized in liver and conjugated metabolites are excreted in urine. It is primarily used in petitmal epilepsy. It is also useful as an adjunct in myoclonic and akinetic epilepsy and may afford some benefit in infantile spasm. Important adverse effects are sedation and tolerance. Due to later side effect, its value in epilepsy is limited.
Dose: Adults 0.5—4 mg three times daily; children 0.2 mg/kg/day.
Diazepam: It is a potent anticonvulsant drug. But it is not used for long-term therapy of epilepsy because of prominent sedative effect and rapid development of tolerance to the anti-epileptic effect. However, it is drug of choice for emergency control of convulsions, e.g. status epilepticus, tetanus, eclampsia, covulsant drug poisoning, etc. For this purpose, it is given by slow i.v. injection in doses of 0.2—0.5 mg/kg. Dose may be repeated as required (maximum 100 mg/day). It may cause thrombophiebitis of injected vein, marked fall in blood pressure and respiration. For febrile convulsions in children, it is preferably administered by rectal instillation.
Clobazepam: Its actions and advantages are similar to diazepam. It is used as an adjunct in treatment of epilepsy. It is useful:
• In short courses in patients in whom seizure occurs in clusters
• To prevent exacerbations around menstruation in catamanial epilepsy
• To ensure seizure control during examination and marriage
Ethosuximide: It is a succinimide. Its mechanism of action is not clear. Clinically, it is effective only in petitmal epilepsy. It is rather slowly and completely absorbed from gut. It is largely metabolized in liver by hydroxylation and glucuronide conjugation. It is excreted in urine as conjugates. it may cause anorexia, hallucinations, anxiety, hypersensitivity reactions like Stevens-Johnson syndrome, lupus erythematosus, pancytopenia, aplastic anaemia.
Dose: 20—30 mg/kg/day.
Valproic acid (sodium valproate): It is a propylacetic acid derivative. It increases GABA activity by inhibiting GABA transaminase. It is a broad-spectrum anticonvulsant and is used in all types of epilepsy. It is well absorbed from gut. It is 90% bound with plasma proteins. It is metabolized in liver and excreted in urine as giucuronide conjugates. Its adverse effects are hair loss, rarely hepatitis and acute pancreatitis. Coagulation defects due to reduced prothrombin fibrinogen and platelet levels may be seen.
Dose: Adults—initial: 200 mg three times daily; maximum 800 mg/day in three divided doses; children; 15—30 mg/kg/day.
Vigabatrin: It is an analog of GABA. It inhibits the enzyme GABA transaminase and thus enhances GABA activity. It is well absorbed from gut and is excreted unchanged in urine. It is effective in all types of epilepsy. It has also been used in seizures not controlled by conventional antiepileptic agents. Important side effects are ataxia, drowsiness, dizziness, and behavioural changes.
Tiagabine: This is a nipecotic acid analogue. Tiagabine decreases neuronal and astrocytic reuptake of inhibitory transmitter GABA. Thus it leads to an increase in synaptic GABA which is responsible for its antiepileptic action. It is mainly used as an “add-on” drug for the treatment of partial seizures in doses of 4—12 mg 3 times a day. Common side effects are headache, dizziness and somnolence.
Gabapentin: It acts by increasing the release of GABA by unknown mechanism. It is used in combination with other drugs in partial seizures resistant to other drug therapy in the dose of 900—1800 mg per day in 3 divided doses. Common adverse effects are:
Somnolence, dizziness, ataxia and fatigue.
Lamotrizine: It is phenyltriazine derivative. Its anti-seizure effect is due to its ability to suppress sustained rapid firing of neurons and to produce a voltage and use dependent inactivation of sodium channels. It also reduces voltage-activated low threshold Ca44 current.
On oral administration, the drug is completely absorbed. It is metabolized primarily by glucuronidation to the 2-N- glucuronide, which is excreted in the urine.
Uses: It is used:
• As an add-on therapy
• As monotherapy for partial seizures
• In absence and monoclonic seizures in children
Its side effects are dizziness, headache, diplopia, nausea, somnolence and skin rash.
Dose: 100—300mg per day: Vaiproate causes 2 fold increases in the drug’s half-life. In patients receiving valproate, the initial dosage of lamotrizine must be reduced to 25 mg every other day.
Felbamate: It is recommended only as a third line drug for refractory cases of partial seizure because it causes aplastic anaemia and severe hepatitis at unexpectedly high rates. Probably it acts by blocking NMDA receptor via the glycine binding site. It is readily absorbed on oral administration. It is metabolized by hydroxylation and conjugation; a significant percentage of drug is excreted unchanged in the urine. Usual dosages are 1—4 gm/day. It is also effective against the seizures that occur in LennoxGastaut syndrome.
Topiramate: It is a substituted monosaccharide. Its antiseizure effect is due to:
• Blocking of voltage-dependent sodium channels
• Potentiation of inhibitory effect of GABA and
• Depression of the excitatory action of kainite on AMPA receptors.
On oral administration, it is rapidly absorbed. It is minimally plasma protein bound and is moderately metabolized. The drug is primarily excreted unchanged in the urine.
Topiramate is effective against partial and general tonic-clonic seizures. It is also effective against Lennox-Gastaut syndrome, West’s syndrome and even absence seizures.
Dose: 200—600 mg/day. Dose related side effects occur most frequently in the first 4 weeks and include somnolence, fatigue, dizziness, cognitive slowing, paraesthesia, nervousness and confusion.
Zonisamide: It is a sulfonamide derivative. It acts primarily by prolonging inactive state of voltage-dependent Na channels with a concomitant prolongation of refractiveness. It also reduces low threshold Ca current. The drug is effective against partial and general tonic-clonic seizures and may also be useful against infantile spasms and certain myoclonias. It has good bioavailability, linear kinetics, low protein binding, renal excretion and a half-life of 1—3 days. Doses range from 100 to 600 mg/day in adults and from 4—12 mg/day in children. Adverse effects are drowsiness and cognitive impairment.
Levetiracetam: Levetiracetam is a piracetam analog. Its mechanism of action against seizures is unknown. It is used for the treatment of partial seizures in doses of 500 mg orally twice a day. It has excellent bioavailability, linear kinetics, low protein binding, renal excretion and a half-life of 6—8 hours. Adverse effects include somnolence, asthenia and dizziness.
Treatment of status epilepticus: Status epilepticus is an emergency condition. Its treatment consists of i.v. diazepam infusion (2 mg/min; maximum dose given in adults is 20 mg) plus phenytoin i.v. infusion (50 mg /min; maximum dose in adults is 100 mg). Diazepam has rapid onset and short duration of action while phenytoin has slow onset but sustained duration of action. If seizures are not controlled, increase the i.v. dose of phenytoin to 100 mg/mm (maximum dose 1000 mg). As these drugs induce hypotension and respiratory depression, keep adequate measures ready for cardiorespiratory support. ECG monitoring is desirable.
Alternative drugs are clonazepam and lorazepam. During pregnancy, chlormethiazole is preferred in seizures because of virtual absence of teratogenicity.
