Introduction.
An epileptic seizure has been defined as a paroxysmal discharge of cerebral neurones accompanied by clinical phenomena apparent to the patient or to an observer. The phenomena can be motor, sensory, or autonomic and there may also be impairment or complete loss of consciousness. Motor disturbances may include convulsions—which are involuntary, violent, and spasmodic—or prolonged contraction of skeletal muscles. Epilepsy is defined as a condition characterised by a recurrence of such seizures.
The following is a broad account of the classification of seizures based on the views of the International League Against Epilepsy (ILAE). Epileptic syndromes are not covered within this review.
Partial seizures or focal seizures (localisation-related seizures) are epileptic seizures in which the initial neuronal discharges are localised in one area of the brain. If there is no loss of consciousness, the seizure has been known as a simple partial seizure. If there is impaired consciousness the seizure is referred to as a complex partial seizure. Partial seizures may become secondarily generalised seizuresif the neuronal discharge spreads to involve the entire brain.
Generalised seizures are characterised by neuronal discharges involving both cerebral hemispheres simultaneously from the outset.
Absences (petit mal) are generalised seizures characterised by a sudden loss of consciousness lasting for a few seconds. There is usually accompanying motor activity which may vary in degree from eyelid blinking to more extensive clonic body movements. Atypical absence seizures are those with a slower onset and longer duration.
Myoclonic seizures are epileptic seizures in which the motor manifestation consists of brief, involuntary, jerky movements of sudden onset caused by muscular contractions or inhibitions.
Clonic seizures are characterised by loss of consciousness, autonomic symptoms, and rhythmic clonic contractions of all muscles.
Tonic seizures are also associated with loss of consciousness and autonomic symptoms accompanied by tonic contractions of the limbs.
Tonic-clonic seizures (grand mal) are characterised by disordered contraction of muscles. During the tonic phase, all the muscles go into spasm followed up to a minute later by rhythmic clonic contractions. Finally, the patient enters a deep stupor followed by a period of confusion as consciousness is regained.
Atonic seizures are characterised by loss of postural tone; the head sags or the patient falls.
Drug treatment of epilepsy
The established anti-epileptics’ major advantages are their proven efficacy in comparative trials and an often quantifiable understanding of their long term serious adverse. The newer anti-epileptics do not offer better symptom control but may be better tolerated. Their role in treatment has yet to be fully established although head-to-head trials are now underway.
The following list is a brief description of anti-epileptic medicines in use:
Note: this is not an exhaustive list. For more information refer to national and local guidelines
Carbamazepine
Carbamazepine is one of the most widely used antiepileptics. Carbamazepine is considered the drug of first choice with the least toxicity for treating partial seizures with or without secondary generalization. In comparison with phenobarbital, phenytoin, and primidone, carbamazepine appears to have the least effect on cognitive function and behavioural disturbances.
The dose is determined by the patient's response rather than the serum level. Immediate and slow release oral preparations are available, as are suppositories. Adverse effects occur in up to one-third of patients but in only 5 per cent of cases will treatment need to be stopped. The most common adverse effects are dizziness, blurred vision, diplopia, headache and nausea. Carbamazepine causes a rash in 5 to 10 per cent of patients. Rarely bone marrow depression, toxic hepatitis and Stevens-Johnson occur. At high doses, hyponatraemia and neutropenia are common but they are usually mild and asymptomatic.
Oxcarbazepine
Oxcarbazepine is considered in epileptic patients unable to tolerate carbamazepine, including those with hypersensitivity. It is licensed for monotherapy and adjunctive treatment of partial seizures with or without secondarily generalised tonic-clonic seizures.
Oxcarbazepine appears to be as effective as carbamazepine in the treatment of epilepsy; severe adverse effects have occurred to a lesser degree with oxcarbazepine in some studies.
Its side effect profile and tolerability is similar to carbamazepine.
Phenytoin
Phenytoin remains one of the most effective drugs for the treatment of partial and generalised tonic-clonic seizures. However, due to its unpredictable pharmacokineticsand its undesirable adverse effects in chronic use, it is not used as a first line drug. Intravenous phenytoin is useful in the treatment of status epilepticus. Because of its long half-life, a loading dose needs to be given; time to steady state is between two and four weeks.
The monitoring of phenytoin is complicated by non-linear kinetics, a narrow therapeutic range and by being highly protein bound.
Adverse effects are common in about 50 per cent of patients, with 10 per cent requiring drug withdrawal. Dose-related adverse effects include ataxia, nystagmus, lethargy, slurred speech and haematological disturbances. Hirsuitism, gingival hyperplasia and aggravation of acne are also seen in chronic use, making phenytoin less favourable than other anti-epileptics.
Sodium valproate
Sodium valproate is reported to be effective in all types of epilepsy. Valproic acid appears to have less of an effect on cognitive function and behavioural disturbances in comparison with phenobarbital, phenytoin, and primidone.
The daily variation in serum concentration of sodium valproate is wide and routine monitoring is not usually useful.
Common dose-related adverse effects are tremor, appetite stimulation leading to weight gain, thinning or (reversible) loss of hair and menstrual irregularities. Gastric irritation and nausea are common at the start of treatment, especially with the non-enteric coated preparations.
Less commonly hepatotoxicity, pancreatitis and thrombocytopenia occur. Valproate has also been shown to have teratogenic effects.
Barbiturates
Phenobarbital is now reserved for patients who cannot tolerate other anti-epileptics because of its potential neurological toxicity.
Its adverse effects include sedation and impairment in cognition, mood and behavioural changes (especially depression). In children, it may cause hyperactivity, insomnia and aggression. Other effects include skin rashes, megaloblastic anaemia and osteomalacia. The development of tolerance to the ant-epileptic effect may limit the usefulness of serum concentration monitoring. Chronic use can cause dependence.
Given intravenously, phenobarbital is an alternative to phenytoin in the treatment of status epilepticus.
Thiopental is also an effective agent in status epilepticus.
Primidone is metabolised by the liver to form phenobarbital. Its efficacy and adverse effects are similar to phenobarbital, although primidone actually has a higher incidence of adverse effects and is less well tolerated.
Benzodiazepines
Benzodiazepines are potent antiepileptic drugs but are usually prescribed as adjuncts or add-on therapy. Diazepam is the first line treatment of status epilepticus, given either intravenously or rectally. Lorazepam injection is an alternative. Both have little practical use in chronic treatment.
Clonazepam is mainly used as an adjunct for myoclonic seizures and but can be used in other seizure types.
Sedation is the most common adverse effect of clonazepam. Ataxia, lack of co-ordination, and behavioural and personality changes are also common. Few patients have a good response to the drug and tolerance, associated with worsening of all seizure types, is common.
Clobazam is less sedating than diazepam or clonazepam and is used as an adjunct in patients with poorly controlled epilepsy.
Development of tolerance limits the therapeutic use of clobazam. Treatment in short courses as an adjunct in the treatment of seizure clusters has been beneficial, especially in the treatment of catamenial epilepsy (exacerbation of seizures around menstruation).
Vigabatrin The drug is licensed as add-on therapy for partial seizures with or without secondary generalisation, and as monotherapy for infantile spasms.
The drug has been shown to be at least comparable in efficacy to carbamazepine in newly diagnosed patients with partial seizures but to be less effective than carbamazepine in patients with primary generalised seizures, most of whom did not respond.
The most common adverse effects are sedation and fatigue and weight gain. The main serious adverse effects are depression, psychosis and visual field defects. Serious psychiatric symptoms occur in 7 per cent of patients. Visual field defects recently reported with vigabatrin are of concern, and regular testing is required in patients who take the drug.
Lamotrigine
It is licensed as add-on therapy and monotherapy (adults only) in the treatment of partial seizures and primary and secondarily generalised tonic clonic seizures. It can also be effective in generalised absences and myoclonic jerks. The drug has been shown to be as effective as carbamazepine in the treatment of newly diagnosed patients with partial seizures and primary tonic clonic seizures. Blood level monitoring is rarely used, however slow titration of dosage is essential because of the possibility of rare but severe allergic reactions.
The most common adverse effects are blurred vision, diplopia, rash and headaches; less common are nausea, vomiting, dizziness and ataxia. Sedation and psychiatric reactions, such as agitation, confusion and depression, are rare. Tremor may be seen in high doses. The main advantage of lamotrigine is that it causes little cognitive impairment and is well tolerated. The pharmacokinetic profile of lamotrigine, including its long elimination half-life, relatively low protein binding, lack of effects on drug-metabolizing enzymes, and lack of active or toxic metabolites are advantageous. A positive cost effectiveness model has been reported for lamotrigine.
Gabapentin
Gabapentin is licensed as add-on therapy in partial seizures with or without secondary generalisation. It has been shown to be particularly effective in secondarily generalised partial seizures and complex partial seizures, being more effective in the former than the latter.
The most common adverse effects are somnolence, fatigue, dizziness, nausea, headache and ataxia. Weight gain, diplopia and tremor have also been reported. No significant alterations in haematologic, hepatic, or renal function tests have been observed.
Unlike other antiepileptic drugs, gabapentin does not show withdrawal seizures, even if the drug is rapidly tapered down. Adverse effects and interactions of gabapentin have been minimal.
The good tolerability of gabapentin makes it a useful drug in patients in whom other add-on drugs may cause problems with additive adverse effects or interactions.
Topiramate
Topiramate is licensed for use as add-on therapy in partial and secondarily generalised seizures and has been shown to be effective in idiopathic epilepsies. It has a similar antiepileptic activity to carbamazepine and phenytoin and appears to have synergistic properties when combined with these drugs.
Potential advantages of topiramate are its apparent lack of effect on serum levels of conventional antiepileptic agents (although phenytoin and carbamazepine can decrease topiramate serum concentrations), relatively long elimination half-life, and overall better tolerability compared to conventional agents; haematotoxicity or hepatotoxicity has not been reported in available trials.
The most common adverse effects, occurring in over a third of patients, are dizziness, fatigue, paraesthesia, ataxia and somnolence. Cognitive impairment (abnormal thinking and impaired concentration) is also common with higher doses. The clinical significance of this effect with respect to continuation of therapy and long-term sequelae requires further evaluation.
Levetiracetam
Levetiracetam is indicated for monotherapy or adjunct therapy in the treatment of partial onset seizures with or without secondary generalisation and for myoclonic seizures. It may be particularly useful in patients who are unresponsive to other antiepileptic agents.
Potential advantages of levetiracetam include a high therapeutic index, a desirable pharmacokinetic profile (i.e. rapid and complete oral absorption, low protein binding, lack of active or toxic metabolites), minor adverse effects, and a lack of effect on serum levels of other antiepileptic agents (although levetiracetam can increase phenytoin serum levels). Additional long-term controlled clinical and comparative studies with other antiepileptic agents are needed to further elucidate the therapeutic role and benefit/risk profile of levetiracetam.
Common side effects include somnolence, dizziness, headache, balance disorders and emotional and psychiatric changes.
Pregabalin
Pregabalin is indicated as adjunctive therapy in adults with partial seizures with or without secondary generalisation. Comparative data remain limited, and its place in therapy in these indications will be more adequately defined upon completion of comparative trials. In particular, comparisons of pregabalin with agents such as gabapentin, tiagabine, lamotrigine, topiramate, oxcarbazepine, and levetiracetam as adjunctive therapy in refractory partial seizures are needed.
Pregabalin does not appear to interact with other anti-epileptics and is well tolerated. No major haematological disturbances have so far been reported. The most common adverse effects reported during therapy are dizziness and somnolence. Other common adverse effects include blurred vision, diplopia, increased appetite and weight gain, dry mouth, constipation, vomiting, flatulence, euphoria, confusion, reduced libido, erectile dysfunction, irritability, vertigo, ataxia, tremor, dysarthria, paraesthesia, fatigue, and oedema.
Ethosuximide
Ethosuximide is only useful in the treatment of absence seizures and, sometimes, in myoclonic seizures. An alternative first-line therapy is valproic acid.
Ethosuximide is of little value in treating generalized tonic-clonic seizures (grand mal), simple partial seizures, or complex partial seizures.
The most common adverse effects are gastric irritation, anorexia, abdominal pain, nausea and vomiting. Others include lethargy, dizziness, depression and headache, and inability to concentrate. Rarely, blood dyscrasias have been reported.
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