Anticonvulsants used for Generalised Seizures

Other relevant articles include:

• Managing epilepsy in primary care
• Epilepsy in adults
• Epilepsy in children and young adults
• Epilepsy in elderly people

Generalized seizures are characterized by widespread involvement of bilateral cortical regions at the outset and are usually accompanied by impairment of consciousness:^1,2

• The familiar tonic-clonic seizure (grand mal) is often preceded by a cry. The patient suddenly falls to the ground and exhibits typical convulsive movements, sometimes with tongue or mouth biting and urinary incontinence. Other subtypes of generalized seizures include absence, myoclonic, clonic, tonic and atonic seizures.
• Absence seizures (petit mal) mainly affect children. Typical absence seizures usually last 5-10 seconds and commonly occur in clusters. They manifest as sudden onset of staring and impaired consciousness with or without eye blinking and lip smacking. The EEG typically shows a 3Hz spike and wave pattern. There is a strong genetic component for the seizures as well as for the EEG abnormality. While absences will remit during adolescence in around 40% of patients, related tonic-clonic seizures may continue into adulthood.
• Atypical absence seizures usually begin before 5 years of age in conjunction with other generalized seizure types and mental retardation. They last longer than typical absence seizures and are often associated with changes in muscle tone.
• Myoclonic seizures consist of sudden, brief muscle contractions, either singly or in clusters, that can affect any muscle group.
• Clonic seizures are characterized by rhythmic or semi-rhythmic muscle contractions, typically involving the upper extremities, neck and face.
• Tonic seizures cause sudden stiffening of extensor muscles, often associated with impaired consciousness and falling to the ground.
• Atonic seizures (drop attacks) produce sudden loss of muscle tone with instantaneous collapse, often resulting in facial or other injuries.

Systematic reviews have found insufficient evidence on which to base a choice among drugs in terms of seizure control.^1,2

• Tonic-clonic (grand mal) seizures:
  • The drugs of choice for tonic-clonic seizures are carbamazepine, lamotrigine, sodium valproate and topiramate.
  • For those patients who have tonic-clonic seizures as part of the syndrome of primary generalised epilepsy, sodium valproate is the drug of choice.
  • Phenobarbital and primidone are also effective but may be more sedating.
• Absence seizures:
  • Ethosuximide and sodium valproate are the drugs of choice in simple absence seizures.
  • Sodium valproate is also very effective in treating the tonic-clonic seizures which may co-exist with absence seizures in primary generalised epilepsy.
  • Lamotrigine may also be effective but this is an unlicensed indication.
• Myoclonic seizures (myoclonic jerks):
  • Occur in a variety of syndromes, and response to treatment varies considerably.
  • Sodium valproate is the drug of choice and clonazepam, ethosuximide or lamotrigine may also be used.
• Atypical absence, atonic and tonic seizures:
  • These seizure types are usually seen in childhood, in specific epileptic syndromes, or associated with cerebral damage or mental retardation.
  • They may respond poorly to the traditional drugs. Sodium valproate and lamotrigine are regarded as first line drug treatments. Clobazam, clonazepam, levetiracetam and topiramate are used as second line antiepileptic drugs¹.

Combination therapy

• Therapy with two or more antiepileptic drugs concurrently may be necessary. It should preferably only be used when monotherapy with several alternative drugs has proved ineffective.
• Combination therapy enhances toxicity and may lead to drug interactions between the antiepileptic drugs.

• The currently recommended first-line drugs in treating the majority of childhood epilepsies are sodium valproate and carbamazepine.
• Most paediatric epilepsies and epilepsy syndromes are associated with generalised seizures, and for these the current drug of choice is sodium valproate.
• For generalised seizures, lamotrigine and topiramate should be used if the older AEDs are unsuitable (e.g. contraindication, potential interaction, poorly tolerated or patient is female and likely to need treatment in childbearing years) or for those who have not benefitted from older AEDs.
• West syndrome (infantile spasms) is characterised by infantile spasms. In the UK, ACTH or prednisolone is the preferred treatment, whereas in many European countries vigabatrin or sodium valproate are the drugs of first choice and ACTH is rarely, if ever, prescribed.

• Interactions between antiepileptics are complex and may enhance toxicity without a corresponding increase in antiepileptic effect.
• Interactions are usually caused by hepatic enzyme induction or hepatic enzyme inhibition; displacement from protein binding sites is not usually a problem.
• These interactions are very variable and unpredictable. Plasma monitoring is therefore often advisable with combination therapy.

Indications for drug monitoring include:

• When drug therapy is initiated and after dosage adjustments (sampling at trough level at steady-state).
• Suspected therapeutic failure: identify inappropriate dosage, non-compliance, altered absorption, altered clearance (sampling at trough level at steady-state).
• Therapeutic confirmation (i.e. after optimum seizure control so that a drug level can serve as a reference point in the event that seizure control is lost or side effect occur) (sampling at trough level at steady-state).
• Signs of clinical intoxication (sampling at peak level or when symptoms are present).
• Suspected drug interaction (sampling at trough level).
• Monitoring of pharmacologically active metabolites.
• Special risk groups where drug pharmacokinetics is altered: neonates, elderly patients, pregnant women, patients with compromised elimination e.g. renal, hepatic disease (sampling at trough level).
• Suspected drug overdose.

• As many as 70-80% of patients on antiepileptic drug treatment will eventually become seizure free.
• Because of the possible long-term side effects of the drugs, it is common clinical practice to consider drug withdrawal after a patient has been in seizure free for three or more years.
• The probability of relapse after stopping treatment has varied between 11-41% in different studies. The risk is less for children than for adults. Most relapses occur within the first year of treatment reduction or withdrawal.
• The more severe and long lasting the patient's epilepsy before remission the greater the risk of relapse.
• Juvenile myoclonic epilepsy or the presence of a structural lesion underlying the epilepsy also enhance the risk of relapse.
• Whether EEG is helpful is controversial. Only those EEGs taken after a period of remission are likely to be of value. In children there seems little doubt that the presence of persisting EEG abnormalities has an adverse prognostic influence but whether this is true in adults remains uncertain.
• Social complications of failed drug withdrawal increase with adulthood and trials of drug withdrawal should ideally take place before school-leaving age. After this a number of factors may influence the decision, e.g. employment, driving, leisure activities, contraception and pregnancy.
• The final decision to come off drug treatment should be taken by the patients and their families following advice from the physician. If a decision to withdraw medication is made, discontinuation of treatment should be undertaken slowly, possibly over a period of months, to minimise the risks of relapse.