BMJ Learning

Epilepsy - in association with NICE

National Institute for Health and Clinical Excellence (NICE)
د. حسين محمد جمعة
اختصاصي الامراض الباطنة
البورد العربي
كلية طب الموصل
2010

Key points

Epilepsy is one of the leading neurological disorders worldwide with prevalence of 1-2%.
The correct diagnosis of epilepsy depends on an accurate description of the events occurring before, during, and after the attack. And as the patient usually cannot remember what happened during a seizure, an eyewitness account from a relative or friend is essential.

It is important to attempt to classify the type of epilepsy as this has an influence on treatment and prognosis.
The conditions that most commonly mimic epilepsy are syncope and non-epileptic attacks (formerly known as psychogenic seizures).


Classification of epileptic seizures

Partial seizures

• Simple partial seizures (no loss of consciousness)
• Complex partial seizures:
• With impairment of consciousness at onset
• Simple partial onset followed by impairment of consciousness
• Partial seizures evolving to generalised tonic-clonic convulsions

Primary generalised seizures

(Convulsive or non-convulsive with bilateral discharges involving sub-cortical structures)
Absence
Myoclonic
Clonic
Tonic
Tonic-clonic
Atonic
Unclassified seizures
(These usually occur when an adequate description is not available)

Tonic-clonic seizures

Abrupt onset. Start with loss of awareness and stiffening of the body and limbs, followed by rhythmic jerking of the limbs. The seizure typically has a symmetrical distribution. There is often tongue biting and urinary incontinence. Jerking usually lasts for up to two minutes. There is often cyanosis and irregular breathing followed by a post-ictal phase of confusion and muscle pains lasting from hours to days after the attack.


Absence seizures
These are staring spells that are usually short (10 seconds) and rapid in onset with no warning. Recovery is very quick. They begin in childhood or early adolescence. They may be provoked by hyperventilation, and have a characteristic EEG pattern
(spikes and waves at 3 Hz).

Myoclonic seizures

These involve abrupt muscle jerks in part of the body or all of the body. For example, a hand may suddenly fling out, a shoulder may shrug, a foot may kick, or the entire body may jerk. These seizures can occur as a single event or in series. Consciousness and memory are not impaired. They typically occur in teenagers and are also more common in females. Patients often get generalised tonic-clonic seizures as well.

Atonic seizures (drop attacks)

These cause a loss of consciousness. Muscles suddenly relax, making patients fall down suddenly or drop their head forward.

Partial seizures

Patients may experience auras (unusual sensations that warn of an impending seizure). Manifestations of aura are an indication of the site or focus from which the abnormal brain discharge emerges. Partial seizures may become complex which means that the patient loses their consciousness once the electrical discharge reaches the midline and may spread to involve the other hemisphere with emergence of generalised tonic-clonic seizures.

Simple partial seizures

Motor, sensory, autonomic, or psychiatric symptoms, depending on the location of the electrical discharge. Patients may experience stiffening of muscles in the arms, legs, and face, and twitching limbs on one side of the body,may also experience strange smells, distorted vision, a rising feeling in the stomach, changes in emotion, and feelings of fear or deja vu. Symptoms relate to area of the brain from which the seizure arises. Patients do not get impairment of consciousness.

Complex partial seizures (CPS)

Patients often have an aura (a simple partial seizure) followed by loss of consciousness or altered consciousness (such as a dream-like experience).
Automatisms (automatic, repetitive acts such as blinks, twitches, chewing, lip smacking, or walking in a circle) may also occur without the patient's recollection. A period of confusion often follows the seizure.

Absence and complex partial seizures

Some key differences that distinguish between them: absence takes seconds while complex partial seizures last longer (minutes), post-ictal confusion never occurs in absence while it often occurs with complex partial seizures. Absence is often precipitated by hyperventilation while hyperventilation rarely provokes complex partial seizures. EEG shows 3 Hz in absence while temporal slowing or epileptic activity (sharp activity or spikes) in complex partial seizures.


What is it?
The term epilepsy is different from the term seizures
A seizure is not a disease but an immediate manifestation of an obvious cause that transiently alters the electrochemical characteristics of excitable neuronal cells.
A seizure is defined as a brief, excessive surge of electrical activity in the brain that causes a change in how the person feels, senses things, or behaves.

A person with diabetes in whom the blood sugar becomes extremely low or high can have a seizure. A person who drinks too much alcohol can have seizures, especially during the first several days after drinking is stopped. High fevers, especially in infants and young children, can cause seizures.

However, epilepsy is not a single disorder but refers to the condition of recurrent and unprovoked seizures (two or more seizures). The cause of epilepsy is usually unclear (idiopathic or cryptogenic) or may follow severe brain insult such as stroke, trauma, infection, or brain tumour (symptomatic epilepsy).

Seizures occurring in epilepsy are divided into two major subtypes:

Generalised seizures involve the brain diffusely at the onset. The two most common types of generalised seizures are tonic-clonic (formerly called grand mal) seizures and absence (formerly called petit mal) seizures.

Partial seizures initially involve one area of the brain, though they may spread to become generalised. Partial seizures may cause a wide range of symptoms and signs depending on the area of the brain involved. A simple partial seizure involves no alteration of consciousness. A complex partial seizure involves a change in consciousness.

The age distribution is bimodal with a peak in childhood and also in old age. The risk of epilepsy in children who have a first degree relative with epilepsy is approximately 9%.
Seizures are much more common than epilepsy. Around 9% of the general population will experience at least one seizure in their lifetime. However, only one third of these people will have epilepsy (recurrent seizures not linked to a specific medical illness).

About 3% of people will be given a diagnosis of epilepsy at some time in their lives. For most patients epilepsy is a lifelong disorder and they will have to take medications for the rest of their lives. For these reasons it is vital to manage patients with epilepsy correctly. It is equally important that patients with epilepsy receive the information that they need.

Learning bite

If you suspect a patient has had a seizure you should give them essential information on how to recognise a seizure, give first aid, and the importance of reporting further attacks. You should also advise your patient not to drive.


Learning bite
If patients with seizures or suspected epilepsy have particular needs for information, you should consider referring them to an epilepsy specialist nurse. They can give information, training, and support to the patient and to their families, carers and, in the case of children, others involved in the child's education, welfare, and wellbeing.

An EEG should not be performed in patients if you suspect probable syncope because of the possibility of a false positive result.
You should request an EEG only when the clinical history suggests a diagnosis of epilepsy.

An EEG may be used to help determine the type of epilepsy. This enables patients to be given the correct prognosis. An EEG can also sometimes help to predict the risk of recurrence.

Clobazam

You can prescribe clobazam as a second line agent in patients with generalised tonic-clonic epilepsy.
Vigabatrin
Vigabatrin may worsen seizures in patients with generalised tonic-clonic epilepsy.
Sodium valproate
Is one of the first line treatments for patients with primary generalised epilepsy.

Learning bite

You should treat patients with a single antiepileptic drug whenever possible.
You should consider drug therapy after a first unprovoked seizure if:
• The patient has a neurological deficit
• The EEG shows unequivocal epileptic activity
• The patient or their family or carers consider the risk of having a further seizure unacceptable
• Brain imaging shows a structural abnormality.
• There is status epilepticus at onset
Patients should generally start drug therapy after a second epileptic seizure.


Valproate and lamotrigine are among the best drugs for generalised seizures. If initial treatment is unsuccessful or cannot be tolerated, you can try monotherapy using another drug. But the patient should be cautious during the changeover.

You should consider combination therapy only when attempts at monotherapy have failed. You should be careful when giving lamotrigine to a patient who is already taking valproate. This can cause serious skin reactions (such as Stevens-Johnson syndrome) especially when patients increase the dose more rapidly than is recommended.

Tiagabine

Tiagabine may worsen seizures in patients with primary generalised epilepsy.

Gabapentin

Gabapentin is effective only in patients with partial seizures.

Learning bite

You should advise women with generalised tonic-clonic seizures that the fetus may be at relatively higher risk of harm during a seizure, although the absolute risk remains low.
Reassure women that there is no evidence that simple partial, complex partial, absence, and myoclonic seizures affect the pregnancy or developing fetus adversely unless they sustain an injury.
Aim to achieve freedom from seizures during pregnancy.

All women on anticonvulsants should start taking folic acid supplements of 5 mg per day well before the pregnancy. You should tell all women of childbearing potential that anticonvulsant drugs can increase the risk of fetal malformation, although the absolute risk is low. The risk is particularly increased in women taking valproate and phenytoin.

Breast feeding for most women taking anticonvulsant drugs is generally safe and should be encouraged.

The risk of a tonic-clonic seizure during labour and the 24 hours after birth is low (1-4%).


Key points
You should treat patients with a single anti-epileptic drug if possible
The addition of second line drugs sometimes reduces seizure frequency in people with partial epilepsy who have not responded to usual treatment
Each additional second line drug increases the chance of side effects.

Educational interventions, relaxation plus behavioural modification therapy, and family counselling can all improve a patient's psychosocial functioning. But they do not reduce seizure frequency
Cognitive behavioural therapy can improve depression in people with epilepsy and depression. But it doesn't improve seizure control and may not improve psychosocial functioning.

A person who has prolonged convulsive seizures (lasting five minutes or more)

or serial seizures (three or more seizures in an hour) in the community should receive urgent care and treatment. Rectal diazepam is safe and effective as first line treatment of prolonged seizures. Buccal midazolam is an alternative and is easier to give, but it is not licensed for treating status epilepticus. You should secure the patient's airway and assess their respiratory and cardiac function.

Intravenous diazepam is potentially dangerous. It is best reserved for specialist centres with intensive care facilities.
Intravenous clonazepam
Intravenous clonazepam is similarly dangerous.

Learning bite

If events continue despite an optimal dose of a first line drug, you should consider:
Poor concordance
Whether the diagnosis correct.
The newer drugs (gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and vigabatrin) are recommended for managing epilepsy in people who have not benefited from treatment with the older antiepileptic drugs or are unsuitable.


When are patients more likely to remain free from seizures?
• If they have a single type of partial seizure (simple partial, complex partial, or secondary generalised tonic-clonic seizure) or a single type of primary generalised tonic-clonic seizure.
• If they have a normal neurological examination.
• If they have been free from seizures for more than two years while taking antiepileptic drugs.
• I f their EEG was always normal or became normal with treatment.

Absence seizures are staring spells that are usually short (10 seconds) and rapid in onset with no warning. Recovery is quick. They begin in childhood or early adolescence.
Simple partial seizures may cause motor, sensory, autonomic, or psychiatric symptoms, depending on the location of the electrical discharge. They do not include loss of awareness.

complex partial seizures patients often have an aura followed by loss of consciousness or altered consciousness (such as a dream-like experience). Automatisms may occur. These are automatic, repetitive acts (such as blinks, twitches, chewing, lip smacking, and walking in a circle), of which the patient has no recollection. A period of confusion often follows the seizure.

How should I treat it?

You should aim to achieve complete control of seizures without giving patients unacceptable side effects.
Treat patients with a single anti-epileptic drug if possible. There is no good evidence that one drug is better than another in controlling seizures.
The addition of second line drugs reduces seizure frequency in people with partial epilepsy who have not responded to usual treatment. Each additional second line drug increases the frequency of side effects.

Drug choice should be guided by the type of epilepsy.

Educational interventions, relaxation plus behavioural modification therapy, and family counselling can all improve a patient's psychosocial functioning. But they do not reduce seizure frequency. Cognitive behavioural therapy can improve depression in people with epilepsy and depression. But it may not improve seizure control or psychosocial functioning.

The best traditional anti-epileptic drugs for partial seizures include:

Carbamazepine
Lamotrigine.
The best standard anti-epileptic drugs for generalised seizures include3:
Valproate
Lamotrigine
Levitiracetam.


There is no need to routinely test anticonvulsant levels in the blood.

You should consider checking anticonvulsant levels in the following circumstances:

• Suspected poor concordance
• Suspected toxicity
• Managing pharmacokinetic interactions
• Specific clinical conditions, for example status epilepticus and organ failure
• Adjusting the dose of phenytoin.

Juvenile myoclonic epilepsy typically occurs in teenagers. Myoclonic seizures involve abrupt muscle jerks in part or all of the body. These seizures can occur as a single event or in series. Consciousness and memory are not impaired.


Some 40% of patients on vigabatrin develop visual field abnormalities (these can be irreversible). Patients on vigabatrin should have their visual fields checked every six months. You should not prescribe vigabatrin de novo for epilepsy outside specialist units.

Tremor, weight gain, and alopecia are typical side effects of valproate.

The best drugs for generalised seizures include:
Valproate
Lamotrigine.
Vigabatrin is not licensed as monotherapy.

Carbamazepine is best for partial seizures. Gabapentin is not licensed as monotherapy.

Surgery
It is a standard treatment for drug resistant patients with complex partial seizures that are resistant to usual drugs.
A randomised controlled trial found surgery was better than anti-epileptic drugs for seizure control. At one year, 58% of surgically treated patients but only 8% of medically treated patients were free from seizures, also had better quality of life.

Vagus nerve stimulation

Vagus nerve stimulation has recently been introduced as a treatment for epilepsy.
Surgeons wrap a stimulating electrode around the vagus nerve in the neck and then implant a programmable pulse generator and battery pack in the anterior chest wall. The intensity and frequency of stimulation can be adjusted.

The stimulator is typically programmed to deliver a pulse intermittently throughout the day and night, and the patient can activate the device for additional stimulations by using a hand held magnet.

The stimulator is always placed on the left, due to the higher risk of cardiac arrhythmias with stimulation of the right vagus nerve. The mechanism of action is unknown. Vagal stimulation may activate inhibitory circuits in relevant brain regions to suppress seizure activity.

Benefits

Vagus nerve stimulation appears to reduce the frequency of seizures in patients with partial epilepsy.
Side effects
Side effects include hoarseness while the pulse generator is working, cough, pain, paraesthesias, and dyspnoea. Vagus nerve stimulation does not cause side effects seen with anti-epileptic drugs such as ataxia and dizziness.

Evidence

In a recent systematic review, vagus nerve stimulation for partial seizures appeared to be an effective and well tolerated treatment.
The effectiveness of vagus nerve stimulation for other types of seizures is unknown.


Drug treatment
Carbamazepine, phenytoin, lamotrigine, and sodium valproate are commonly used anti-epileptic medications.
There are few placebo controlled trials of these drugs but there is a wide consensus that they are effective in generalised and partial seizures.
The benefits and adverse effects of each drug are different as is their spectrum of therapeutic efficacy in different types of epilepsy.

The addition of a second line drug for drug resistant partial epilepsy (gabapentin, pregabalin, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin, zonisamide, and lacosamide) reduces the frequency of seizures compared to placebo but there is insufficient evidence to choose between these drugs.

Anti-epileptic monotherapy

You should aim to control seizures with a single drug.
Benefits
Anti-epileptic monotherapy controls seizures in most people with partial or generalised epilepsy.

Side effects

Sedation, dizziness, ataxia, and headache. Some can cause suicidal ideation, you should reduce the dose.
Idiosyncratic reactions can be serious and life threatening. They can occur with both the traditional anti-epileptic drugs and the new agents. These reactions include agranulocytosis, Stevens-Johnson syndrome, aplastic anaemia, liver failure, allergic dermatitis, serum sickness, and pancreatitis.

All anti-epileptic drugs can cause a paradoxical increase in the frequency and severity of seizures.
All are probably teratogenic. The background risk of major congenital abnormalities (eg spina bifida, cleft lip and palate, and neural tube defects) is about 1.5%, though it is probably higher in patients with epilepsy taking no anti-epileptic medication.

Children exposed to anti-epileptic drugs have a higher risk (carbamazepine about 2.5%, lamotrigine about 5%, and sodium valproate about 7%).
In addition valproate treatment in pregnancy may carry a risk of inducing learning disability in the offspring.


You should describe the risk of teratogenicity and the risks to the mother and baby caused by seizures during the pregnancy, emphasising that the main risk is at the time of conception - before the woman realises she is pregnant. The ultimate decision on treatment must be the patient's.

The side effects that were more common with sodium valproate were weight gain, tremor, and alopecia

The side effects that were more common with carbamazepine were rashes, dizziness, headaches, ataxia, sleepiness, fatigue, and diplopia

Nine percent of people on sodium valproate stopped their treatment due to side effects compared with 18% on carbamazepine.

About three-quarters of people with epilepsy can control their seizures with one epilepsy drug.
One randomised controlled trial found that about 80% of people who took carbamazepine or valproate remained free of seizures for one year and 60% remained free of seizures for two years

Persistent seizures were more likely in patients with symptomatic epilepsy (such as epilepsy caused by a stroke) than in those with idiopathic epilepsy
Persistent seizures were more likely in patients who had experienced lots of seizures (more than 20) before starting treatment than in those who had had fewer
Remission was similar in patients who were treated with a single established drug (67%) and in patients who were treated with a single new drug (69%)

Among 470 previously untreated patients, 47% became free of seizures during treatment with the first anti-epileptic drug they tried, and 14% became free of seizures during treatment with a second or third drug
Among patients who were not controlled with the first drug, failure of treatment due to lack of efficacy predicted subsequent treatment failure more than having to withdraw the first drug due to intolerable side effects.

Specific agents

There are four traditional anti-epileptic drugs: carbamazepine, phenobarbitone, phenytoin, and sodium valproate.
Since the 1990s, eleven new anti-epileptic become available:
Gabapentin
Tiagabine
Topiramate
Vigabatrin
Levetiracetam
Lamotrigine


Oxcarbazepine
Pregabalin
Zonisamide
Lacosamide
Rufinamide.

You can use the traditional anti-epileptic drugs in both partial seizures and primary or secondary generalised seizures and some of the new anti-epileptic drugs (such as lamotrigine) for monotherapy after failure of one or more traditional agents, as well as second line drugs for partial epilepsy resistant to conventional agents

Doses

Sodium valproate at 300 mg twice daily and increase the dose by 200 mg/day at three day intervals to a maximum of 2.5 g daily in divided doses.
You should start carbamazepine at a dose of 100-200 mg of the controlled release preparation one or two times daily and increase in increments of 100-200 mg daily no faster than every second week until either the seizures come under control or the patient experiences symptoms of intoxication. If seizures are infrequent, titration to 300 mg twice daily is a reasonable starting point.

Comparing phenytoin with sodium valproate

Clinical Evidence found one systematic review of five randomised controlled trials that compared sodium valproate to phenytoin (250 people with partial epilepsy).
It found that the two drugs were equally effective and that patients tolerated both drugs equally well.

Anti-epileptic monotherapy for newly diagnosed generalised epilepsy

Benefits
You should aim to treat most of your patients with generalised epilepsy with a single drug. Sodium valproate, the drug of first choice in men, cannot be recommended in women of childbearing age because of its teratogenic risk. Levetiracetam and lamotrigine are reasonable choices for people with generalised epilepsy.

Addition of second line drugs for drug resistant partial epilepsy

Benefits
The addition of second line drugs significantly reduces the frequency of seizures in people with partial epilepsy who have not responded to treatment with a single drug.
Side effects
Each additional drug increases the frequency of side effects (mainly central nervous system side effects).


Gabapentin: dizziness, fatigue, sleepiness, weight gain
Lamotrigine: ataxia, diplopia, dizziness, insomnia
Levetiracetam: dizziness, irritability
Oxcarbazepine: ataxia, dizziness, fatigue, nausea, diplopia
Tiagabine: dizziness
Topiramate: dizziness, fatigue, sleepiness, weight loss
Vigabatrin: 40% of patients developed concentric visual field abnormalities (these can be irreversible).
Lamotrigine also may cause a rash.

Remember, all anti-epileptic drugs are teratogenic. You should balance the risk of teratogenicity against the risks to the mother and baby caused by seizures during the pregnancy.

Daily dose

% response
% response for placebo

Gabapentin

1800 mg
28.5
9.9
Tiagabine
56 mg
29.8
6.2
Topiramate
400 mg to 1000 mg
45.7
11.6
Vigabatrin
3000 mg or 6000 mg
45.9
13.8
Levetiracetam
3000 mg
20 to 30
Not available


Daily dose
Odds ratio for 50% or greater reduction in seizure frequency compared with placebo

Lamotrigine

200-500 mg
2.49

Oxcarbazepine

600 mg to 2400 mg
2.96

The response to specific agents is summarised as follows: ("Response" means 50% or greater reduction in frequency of seizures)

Non-drug treatment

Educational interventions
Relaxation plus behavioural modification therapy
There is no good evidence that patients with epilepsy benefit from:
Biofeedback
Yoga
Relaxation therapy.


He should start on 25 mg every other day for 14 days and then 25 mg daily for a further 14 days. The usual maintenance dose is 100-200 mg daily in one or two divided doses. He should start at a very low dose as valproate increases the plasma concentration of lamotrigine.
The usual starting dose of lamotrigine if not on another anticonvulsant is 25 mg.
A 25 year old man with epilepsy continues to have seizures despite being on sodium valproate. His neurologist advises that lamotrigine be added to the valproate. What dose should he start on?

All women with epilepsy should take folic acid supplements of no less than 0.4 mg per day during their reproductive years.

Once a second seizure occurs, 75% of untreated people will have a third event.

After one seizure, the risk of recurrence is only about 35% at five years. However, this can be much higher if risk factors are present, in which case treatment can be considered even after one seizure.

Once a second seizure occurs, 75% of untreated people will have a third event.

You should refer a patient who is pregnant or who plans to become pregnant to a neurologist, ideally before she becomes pregnant.
All anti-epileptic drugs are teratogenic. But the mother and baby are also at risk if the mother has uncontrolled seizures during the pregnancy. So the patient, GP, and neurologist must weigh these risks against each other.

All women with epilepsy should take folic acid supplements of no less than 0.4 mg per day throughout their reproductive years, tell the patient about the risks of seizures and of drug treatment.If the decision is made to stop the drugs, you should do this at least six months before conception.If seizures are well controlled with a single drug, this should ordinarily be continued.You should optimise treatment before the pregnancy and counsel women about the importance of concordance with medication

You should not change medication during pregnancy to reduce teratogenic risk because this can precipitate seizures and because overlapping drugs during such a change exposes the fetus to the effects of an additional drug.

Breast feeding is not contraindicated in women taking anti-epileptic medication. However, if the drugs are sedating, you should monitor the baby for sedation


Enzyme inducing anti-epileptic drugs can cause vitamin K deficiency in children born to women with epilepsy. Vitamin K (10 mg per day) can be prescribed in the last month of pregnancy for women taking such anti-epileptic drugs.
Alternatively, the baby should get 1 mg of vitamin K parenterally as soon as possible after labour.

Learning bite

Sodium valproate seems to have a higher teratogenic risk than other drugs so if a patient presented pre-conception on valproate you would need to refer her to a neurologist with a view to the drug being changed.

What is sudden unexplained death in epilepsy and what can I do to prevent it?

Compared with the general population, people with epilepsy have a 24 times higher risk of sudden unexplained death.

Sudden unexplained death in epilepsy refers to sudden death that:

May or may not be associated with a seizure (but not with status epilepticus)
Is not associated with trauma
Has no cause to explain the death.
There is evidence that the risk of sudden unexplained death is proportional to the severity of the epilepsy. So in people with epilepsy, complete freedom from seizures is the aim.

What is the prognosis?

For most the prognosis is good.
About 70% go into remission, defined as being free of seizures for five years on or off treatment.
This leaves 20-30% who develop chronic epilepsy, which is often treated with many anti-epileptic drugs.
A small minority of these patients may require surgical treatment for their epilepsy.


After a single unprovoked seizure, the most important question for patients and doctors is the risk of recurrence. Patients do not have epilepsy until they have had a second seizure. A diagnosis of epilepsy has implications for drug treatment, lifestyle, and employment. So you must be sure before you make the diagnosis.

After one unprovoked seizure, only 35% of people will have a second seizure in the next five years, although this percentage varies a lot depending on whether risk factors are present or not.
Reported rates of recurrence of seizures are 23-71%, depending on the presence of risk factors.

Risk factors include:

• Neurological deficit
• Abnormal electroencephalogram
• Structural abnormalities on brain imaging.