Anti-Epileptic Therapy
What is a Seizure
A "seizure" is the event caused by abnormal discharge in the brain, and epilepsy is the tendency to have seizures. Seizures are initiated by bursts of high frequency action potentials due to a longer depolarisation of the neuronal membrane than normal. This causes an influx of calcium ions which in turn opens voltage-dependent sodium channels. Sodium then enters the cell and causes a higher frequency action potential than normal. This is then followed by a hyperpolarising after-potential due to GABA receptors or potassium channels.
If there are enough abnormal synchronised action potentials from neighbouring neurones the burst activity can spread. This is because the surrounding neurones can have an increased intracellular potassium and accumulation of calcium in presynaptic terminals which enhances neurotransmitter release. This can then cause the spread of this abnormal discharge throughout the brain causing a partial or generalised seizure, dependent on the area of cortex involved.
In many patients no trigger is found to cause their seizures, but in some there is a developmental or acquired (for example stoke, tumour, head injury) pathological abnormality associated with hyperexcitability and capable of triggering a seizure. In a few patients mutations of the ion channels themselves have been found, and you can see from the explanation of how a seizure occurs how this can lead to abnormal discharges.
Medication Categories
Antiepileptic medications try to stop abnormal discharges from starting or spreading. They do this by a number of methods -
- Inhibiting sodium dependent action potentials - carbamazepine, phenytoin, lamotrigine
- Inhibiting voltage gated Calcium channels - phenytoin
- Potentiating GABA receptor function - benzodiazepines
- Increasing GABA availability - valproate, gabapentin
Selection of Therapy
It is rare for anyone other than a neurology specialist to commence anti-epileptic therapy. There are no hard and fast rules and drug selection will depend on individual risks and benefits.
According to the SIGN guidelines "In patients with focal onset seizures, lamotrigine is the drug of choice. Where lamotrigine is poorly tolerated, carbamazepine and levetiracetam may be reasonable alternatives.
In genetic generalised epilepsy or unclassified epilepsy, sodium valproate is the most effective antiepileptic drug. Where sodium valproate is poorly tolerated or contraindicated, lamotrigine and topiramate are suitable alternatives".
In 2013 the MHRA released advice on prescribing anti-epileptic medicines where they categorised them into one of three groups depending on whether they recommended that they be prescribed by their brand name;
- Category 1 – phenytoin, carbamazepine, phenobarbital, primidone
For these drugs, doctors are advised to ensure that their patient is maintained on a specific manufacturer's product
- Category 2 – valproate, lamotrigine, perampanel, retigabine, rufinamide, clobazam, clonazepam, oxcarbazepine, eslicarbazepine, zonisamide, topiramate
For these drugs, the need for continued supply of a particular manufacturer's product should be based on clinical judgement and consultation with patient and/or carer, taking into account factors such as seizure frequency and treatment history
- Category 3 - levetiracetam, lacosamide, tiagabine, gabapentin, pregabalin, ethosuximide, vigabatrin
For these drugs, it is usually unnecessary to ensure that patients are maintained on a specific manufacturer's product unless there are specific reasons such as patient anxiety and risk of confusion or dosing errors
Extra detail is to be found in the BNF if needed.
Women and Epilepsy
The implications of antiepileptic drugs can have a large impact on a woman's life.
Contraception
Antiepileptic drugs which induce hepatic enzymes can cause combined oral contraceptive failure due to increased oestrogen metabolism. As a consequence women on enzyme inducing antiepileptic drugs should take a combined oral contraceptive with a higher dose of oestrogen, but the risk of pregnancy is increased, even with this measure.
Progesterone only contraception also has a high failure rate for those on enzyme inducing antiepileptics. The depot injection can be given but needs to be given at a shorter interval than normal (10 weeks.) Progesterone implants are not suitable for those on antiepileptic drugs.
A higher dose of the emergency contraceptive Levonorgestrel needs to be given than usual for it to be adequate.
Pregnancy
When starting a woman of child bearing age on an antiepileptic drug the consequence of being on that medication while pregnant should be taken into consideration and those on antiepileptics should also have preconception counselling based on the most up-to-date evidence.
Most women with epilepsy have a normal pregnancy and delivery. However, seizure frequency increases in 25 - 33% of women, likely to be a combination of reduced adherence to medication due to concerns regarding teratogenicity and a change to the pharmacokinetics of the drug during pregnancy. Prolonged generalised seizures can result in hypoxia and acidosis in the mother, but it is not well established how this may affect the foetus.
There is a risk of teratogenicity with some antiepileptic drugs. Phenytoin and valproate probably have the highest risk of teratogenicity, but there is not enough information to give fully informed advice for those on newer antiepileptics. However, in those women on high doses or on multiple antiepileptics there is a much higher risk of teratogenicity (24% in women taking up to four). The most common malformations associated with antiepileptic drugs are neural tube defects (valproate 3%, carbamazepine 1%), orofacial defects, congenital heart abnormalities and hypospadias.
Due to the increased risk of neural tube defects all women with epilepsy should be given 5mg folic acid from preconception until their first trimester ends.
Osteoporosis
A combination of antiepileptic use and relative immobility or reduced exposure to light (particularly in those with epilepsy and physical disability) can lead to an increased risk of osteoporosis. Antiepileptics such as sodium valproate, carbamazepine and phenytoin have been implicated and the risk of osteoporosis with the newer antiepileptic drugs is unknown. Patients should be risk stratified and have advise or treatment to minimise the risk of osteoporosis.
Driving
If a patient has had a seizure, or you suspect they have on the basis of their history, you should advice them to stop driving and to inform the DVLA. They should be seen in a first seizure clinic by a neurologist for further assessment.
The DVLA has detailed instructions about how long a patient is unable to drive for, dependent on the circumstances of their seizure.
See
Medical Standards of Fitness to Drive.
Stopping Anticonvulsant Medication
In some cases, patients may be weaned off anti-epileptics after a few years treatment, as they may longer be necessary. However, this should only be advised by a specialist, and before commencing treatment with anti-epileptics, patients should be told to never stop taking their anti-epileptics suddenly, unless advised specifically by a specialist.
References
Sign Guidelines 70:
Diagnosis and Management of Epilepsy in Adults
Sign Guidelines 143: Diagnosis and Management of Epilepsy in Adults
Hauser S. Harrison's Neurology in Genral Practice. McGraw-Hill Companies Inc. 2006.
