Anticonvulsants used for Generalised Seizures

Other relevant articles include:

Status Epilepticus Management
Managing Epilepsy in Primary Care
Epilepsy in Adults
Epilepsy in Children and Young People
Epilepsy in Elderly People

Generalised seizures are characterised 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 generalised 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 electroencephalograph (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 generalised 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 characterised 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.

• Tonic-clonic (grand mal) seizures:
  • The drugs of choice for tonic-clonic seizures are carbamazepine, lamotrigine, and sodium valproate.⁴
  • Second-line drugs include clobazam, levetiracetam, oxcarbazepine and topiramate.⁴
  • For those patients who have tonic-clonic seizures and absence seizures, sodium valproate is the drug of choice.
  • For those patients who have tonic-clonic seizures and myoclonic seizures, sodium valproate and levetiracetam are effective.
  • 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.⁴
  • Sodium valproate is also very effective in treating the tonic-clonic seizures which may co-exist with absence seizures in primary generalised epilepsy.⁴
  • Lamotrigine and clonazepam may also be effective.
• Myoclonic seizures (myoclonic jerks):
  • Response to treatment varies considerably.
  • Sodium valproate is the drug of choice; clonazepam, levetiracetam and topiramate can also be effective.
• Atypical absence, atonic and tonic seizures:
  • These seizure types are usually seen in childhood, either in specific epileptic syndromes or associated with cerebral damage or mental retardation.
  • Response to treatment is often poor but sodium valproate, lamotrigine, clobazam, clonazepam, levetiracetam and topiramate may be effective.¹

Combination therapy

• Therapy with two or more AEDs 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 AEDs.

• Tonic-clonic (grand mal) seizures: drugs of choice are carbamazepine, lamotrigine, levetiracetam, topiramate or sodium valproate. Second-line drugs include clobazam or oxcarbazepine.
• Absence (petit mal) seizures: drugs of choice are ethosuximide or sodium valproate. Second-line drugs include lamotrigine. Sodium valproate is very effective in treating co-existing generalised tonic-clonic and absence seizures in primary generalised epilepsy.
• Myoclonic seizures: the drug of choice is sodium valproate. Second-line drugs include clobazam, clonazepam, ethosuximide, lamotrigine, levetiracetam or topiramate.
• Atypical absence, atonic and tonic seizures: sodium valproate, lamotrigine or ethosuximide can be used for atypical absence and atonic seizures; sodium valproate can be used for tonic seizures. Second-line drugs include clobazam, clonazepam, levetiracetam or topiramate.
• Epilepsy syndromes:
  • Infantile spasms: vigabatrin is the drug of choice if associated with tuberous sclerosis; otherwise high-dose corticosteroids or tetracosactide. Second-line drugs include clobazam, clonazepam, sodium valproate or topiramate.
  • Lennox-Gastaut syndrome: lamotrigine, sodium valproate or topiramate are first-line; clobazam, clonazepam, ethosuximide or levetiracetam can also be effective.
  • Landau-Kleffner syndrome: prednisolone, lamotrigine or sodium valproate are often used; alternatives include clobazam, levetiracetam or topiramate.
• Neonatal seizures: It is essential to make a very thorough assessment to identify and treat any underlying cause. Clonazepam, diazepam, lorazepam, midazolam or rectal paraldehyde if seizures are brief with low risk of recurrence; phenobarbital if there is a risk of seizure recurrence.

• Interactions between AEDs 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-effects 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 anti-epileptic 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 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.