A stepwise approach should be taken to epilepsy therapy. If slow titration of a single agent to the maximum tolerated dose fails to provide seizure control, the dose should be tapered to allow the gradual substitution of an alternative agent. Although monotherapy is adequate for most patients, when polytherapy is necessary, care should be taken to reduce the risk of potential interactions. Many anticonvulsants induce hepatic microsomal enzymes, increasing the rate of metabolism of concomitant therapies. A cautious approach should also be taken to drug withdrawal as this may precipitate severe rebound seizures. The toxicity of anticonvulsant drugs necessitates regular renal and hepatic function monitoring. Pregnancy in epilepsy requires careful management as many agents adversely affect the foetus.
Drug choice depends on the type of seizure:
The barbiturate primidone is useful against partial and generalised tonic-clonic seizures, and is occasionally used in myoclonus and absences. Phenobarbital can be used in status epilepticus and all forms of seizures except absence seizures. Barbiturates cause sedation and can produce behavioural disturbances in children.
The benzodiazepines diazepam and lorazepam are used for acute seizure control, serial seizures and for status epilepticus. Clonazepam is used for absence seizures, Lennox-Gastaut syndrome, infantile spasms and myoclonus, while clobazam is used for partial and generalised seizures. Midazolam is given by buccal administration for prolonged acute seizures in children with epilepsy. The drawback of benzodiazepines is that tolerance may develop with continued use.
The GABA analogue/uptake inhibitor vigabatrin is used as adjunctive therapy for partial seizures and is the treatment of choice in infantile spasms. It may however worsen absence seizures and myoclonic jerks in some patients. Gabapentin and tiagabine are used as add-on therapy in partial seizures with or without secondary generalisation. Piracetam is used as add-on therapy for patients with myoclonus of cortical origin.
The hydantoin phenytoin is effective in partial and generalised tonic-clonic seizures. Small increases in dose can lead to large rises in plasma levels, and as it has a narrow therapeutic index, acute toxicity may result. Fosphenytoin is a water soluble pro-drug of phenytoin that has been developed to overcome the problems of parenteral phenytoin. Fosphenytoin itself has no anticonvulsant activity, but following parenteral administration it is rapidly and completely hydrolysed to the active phenytoin. The dose of fosphenytoin is expressed in phenytoin sodium equivalents (PE).
Sodium valproate is suitable for all seizure types and is the drug of choice in primary generalised epilepsies.
Other anticonvulsants include acetazolamide, which is useful for most types of seizures although tolerance often develops after three to six months. Brivaracetam is licensed as an adjunct for partial-onset serizures with or without secondary generalisation. Carbamazepine is first choice for partial and generalised tonic-clonic seizures, but in absence seizures and myoclonus it can exacerbate symptoms. Ethosuximide is used for absence seizures. Lamotrigine is indicated for partial and generalised tonic-clonic seizures. Levetiracetam is indicated as either monotherapy or as an adjunct in the treatment of partial seizures with or without secondary generalisation. In contrast to other agents it has a wide therapeutic ratio and a favourable pharmacokinetic profile that makes significant drug interactions unlikely.
Oxcarbazepine is an analogue of carbamazepine that can be used for partial seizures with or without secondarily generalised tonic-clonic seizures. Eslicarbazepine, lacosamide, perampanel, pregabalin, topiramate and zonisamide are used as adjunctive therapy in partial seizures with or without secondary generalisation. Topiramate can also be used for seizures associated with Lennox-Gastaut and primary generalised seizures. Rufinamide is effective in Lennox-Gastaut syndrome. Stiripentol is licensed as an adjunct for refractory generalised tonic-clonic seizures in severe myoclonic epilepsy in infancy (Dravet syndrome). Cannabidiol is licensed as an adjunct to clobazam for seizures associated with Lennox-Gastaut syndrome or Dravet syndrome).
PRESCRIBE BY BRAND
Loss of seizure control and/or worsening of side-effects may occur when medication is switched between different manufacturers' versions of the same anticonvulsant, owing to differences in bioavailability. The CHM has divided anticonvulsants into three categories to help healthcare professionals decide whether it is necessary to maintain patients on a particular manufacturer’s product. If this is considered necessary, the product should be prescribed using either the brand name or the generic drug name plus the name of the manufacturer. The three categories are:
Category 1: phenytoin, carbamazepine, phenobarbital, primidone
Patients should be maintained on a specific manufacturer’s product.
Category 2: valproate, lamotrigine, perampanel, rufinamide, clobazam, clonazepam, oxcarbazepine, eslicarbazepine, zonisamide, topiramate
The need for patients to be maintained on a specific manufacturer’s product should be based on clinical judgment and consultation with the patient and/or carer, taking into account factors such as seizure frequency and treatment history. Patient/carer-related factors such as negative perceptions about alternative products should also be taken into account.
Category 3: levetiracetam, lacosamide, tiagabine, gabapentin, pregabalin, ethosuximide, vigabatrin
It is not usually necessary to maintain patients on a specific manufacturer’s product unless there are specific reasons, such as patient anxiety and risk of confusion or dosing errors. Other patient/carer-related factors such as negative perceptions about alternative products should also be taken into account.
SUICIDAL THOUGHTS & BEHAVIOUR
Guidance from the MHRA and CHM states that antiepileptic treatment is associated with a small risk of suicidal thoughts and behaviour; available data suggest that the increased risk applies to all antiepileptics and is seen as early as one week after starting treatment. Patients should be alert to any mood changes, distressing thoughts or feelings about suicide or harming themselves at any point during treatment. They should be advised to seek medical advice if they develop such thoughts or behaviour and should be referred for appropriate treatment if necessary.
Use of carbamazepine, phenobarbital, phenytoin, or topiramate during pregnancy is associated with an increased risk of major congenital malformations. Phenobarbital and phenytoin may also be associated with neurodevelopmental adverse effects. Phenobarbital, topiramat, and zonisamide are associated with an increased risk of fetal growth restriction. Lamotrigine and levetiracetam are not thought to be associated with an increased risk of major congenital malformations or neurodevelopmental disorders, although data on neurodevelopmental outcomes are limited.
Guidance from the CHM states that women using anticonvulsants who are planning to become pregnant should be urgently referred for specialist advice and should be offered folic acid 5mg daily before any possibility of pregnancy. For lamotrigine, levetiracetam or other anticonvulsants that can be used during pregnancy, it is recommended to use monotherapy whenever possible, and use the lowest effective dose.