Clinical Review - Epilepsy

Dr Yvonne Hart, consultant neurologist, Oxford Radcliffe Hospitals NHS Trust

Section 1: Epidemiology and aetiology
Epilepsy is the most common serious neurological condition, affecting around five per 1,000 of the population.

The risk of developing epilepsy is high in childhood, decreases in the middle years of life, then rises steadily, such that the greatest incidence is in the elderly (140 per 100,000 per annum), probably as a result of cerebrovascular disease.

Classification
Seizures are categorised according to the International Classification of Seizures (see box).1

Generalised seizures involve both cerebral hemispheres at the onset, and include generalised tonic-clonic seizures (formerly grand mal), absence seizures (petit mal) and myoclonus. The three types often co-exist.

Generalised seizures are most commonly idiopathic, although symptomatic generalised seizures, including damaging tonic and atonic seizures (drop attacks) may occur in patients with diffuse brain disease.

Partial seizures arise from a localised area of the brain. Simple partial seizures, in which there is no loss of awareness, commonly reflect the function of the area of brain from which they arise - hence occipital lobe seizures may take the form of elementary visual hallucinations, while temporal lobe seizures manifest as olfactory or gustatory hallucinations, fear, or memory disturbances such as deja vu.

Complex partial seizures involve some loss of awareness. They often arise from the temporal lobe and commonly involve a motionless pause, followed by chewing, lipsmacking, or other automatic behaviour.

Glioma in a 32 year old man

Either simple or complex partial seizures may develop into secondarily generalised tonic-clonic seizures.

Epilepsy is also classified by syndrome. This may merely involve determining whether the epilepsy is generalised or focal, and whether it is idiopathic (genetic), symptomatic (with an identifiable underlying cause) or cryptogenic (not thought to be genetic but no underlying cause found). However, more specific epilepsy syndromes are also recognised, with important implications for treatment and prognosis.

For example, juvenile myoclonic epilepsy is characterised by myoclonus, commonly occurring in the morning, with occasional generalised tonic-clonic seizures, and usually responds to sodium valproate, but has a very high rate of relapse if treatment is withdrawn.

Aetiology
The cause depends on the age of onset. Severe epilepsy early in life is often associated with developmental abnormalities or birth injury.

Idiopathic epilepsies are common in childhood and adolescence, and almost always become apparent before the age of 30.

In middle life, alcohol and low-grade tumours are more common causes, while in the elderly, cerebrovascular disease and other neurodegenerative conditions account for more than 50 per cent of epilepsy.

Classification of seizures1

I Partial (focal, local) seizures

A - Simple partial seizures (consciousness not impaired).

B - Complex partial seizures (with impairment of consciousness).

C - Partial seizures evolving to secondarily generalised seizures.

II Generalised seizures (convulsive or non-convulsive)

A - Absence seizures.

B - Myoclonic seizures.

C - Clonic seizures.

D - Tonic seizures.

E - Tonic-clonic seizures.

F - Atonic seizures.

III Unclassified epileptic seizures (inadequate or incomplete data)

Source: International Classification of Seizures

Section 2: Diagnosis
The NICE guidelines2 recommend that all patients suspected of having seizures should be referred to a specialist for diagnosis and initiation of treatment. Diagnosis relies on obtaining an accurate eye-witness description of the seizures.

Differential diagnoses

Syncope and psychogenic non-epileptic seizures (PNES) are most commonly mistaken for generalised tonic-clonic seizure.

SPECT and MRI: neuroimaging is important in establishing aetiology

Key points for distinguishing between seizures and syncope include the presence of an aura, which may occur at the onset of seizures but is usually present at the onset of syncope in the form of nausea, greying out of vision, muffled hearing, or light- headedness.

The presence of a precipitating factor such as pain or emotion is characteristic of syncope and loss of consciousness is rarely longer than 15 to 20 seconds. Any period of confusion is usually very brief after a faint. Limb jerking, eye-rolling, and urinary incontinence may occur in either syncope or seizures.

PNES commonly take the form of episodes of jerking, often asymmetric, violent (thrashing or flailing), with pelvic thrusting, a tendency for the activity to wax and wane (often over long periods of time) and sometimes retained consciousness.

The diagnosis may be suggested by rapid recovery even after prolonged seizures. PNES less commonly take the form of swoons (apparent sudden transient loss of consciousness without motor activity) or absences. The onset of PNES is sometimes explosive, with multiple attacks per day, and an underlying cause may not be apparent.

Hypoglycaemia and cardiac arrhythmia, particularly in the elderly, should be excluded.

All patients presenting with possible seizures should undergo ECG. The differential diagnosis of partial seizures includes migraine, TIA and panic attacks.

Investigations and imaging
In addition to establishing that the patient has had seizures, a complete diagnosis involves establishing the seizure type(s) and syndrome, and identifying the underlying cause.

Only about 50 per cent of patients with epilepsy will show epileptic activity on a routine interictal EEG, but if this is present, it may help in confirming the diagnosis and the seizure type.

Neuroimaging is important in identifying the underlying aetiology, and is appropriate in all patients except those in whom an idiopathic cause has clearly been established.

NICE recommends MRI as the imaging modality of choice.

Blood tests are usually unhelpful in diagnosis but are useful as a baseline (particularly LFTs).

Section 3: Management
The risk of recurrence after a single unprovoked generalised tonic-clonic seizure is around 50 per cent over the next two years. Treatment is usually deferred until a second seizure.

NICE recommends that the newer antiepileptic drugs (AEDs) should only be used where other medications, such as carbamazepine or valproate, have failed, or where issues such as pregnancy or interactions with other medications are relevant.

A recent study comparing standard and new AEDs indicated that for patients with partial seizures, lamotrigine is as effective as carbamazepine but better tolerated. Either is a suitable first choice.3 For patients with generalised seizures, the study indicated that valproate was the most effective medication, and was well tolerated.4

Adverse effects
In addition to seizure type, potential adverse effects, including teratogenicity, must also be considered. Chronic side-effects (such as the possibility of weight gain with valproate) may also be relevant.

AEDs should be started at a low dosage to avoid adverse effects and the dosage gradually increased until either seizure control is obtained or adverse effects occur. Where first-line drugs fail, a second first-line drug suitable for the seizure type is used. If this is unsuccessful the addition of a second-line drug (see box) may be necessary.

Medication in pregnancy
The UK Epilepsy and Pregnancy Register5 indicates that carbamazepine and lamotrigine, with incidences of major malformations of 2.2 per cent and 3.2 per cent respectively, are two of the safer drugs during pregnancy. The rate of major malformations in the offspring of women taking valproate in this study was 6.2 per cent.

There is concern that valproate taken during pregnancy may increase the risk of learning difficulties in the unborn child6 although further study is needed.

The teratogenicity of the newer drugs is unclear, although levetiracetam appears to be one of the safer AEDs,7 while concerns have been raised about topiramate.8

Folic acid 5mg daily is recommended prior to pregnancy and for the first trimester in women taking AEDs.

Contraception
AEDs inducing hepatic enzymes (carbamazepine, oxcarbazepine, phenytoin, phenobarbital and primidone) interact with various drugs including oral contraceptives. Topiramate also reduces the efficacy of the combined oral contraceptive pill (COCP), by a different mechanism.

It is recommended that women taking enzyme-inducing AEDs who wish to take the COCP use a preparation containing at least 50 microgram estrogen, and tri-cycle, ie take three pill packs end-to-end, then have a shortened, four-day pill-free interval.

Lamotrigine may theoretically also have a minor effect on the COCP, but in practice this rarely seems to be a problem. However, the COCP may lower lamotrigine levels, leading to possible loss of seizure control in women already established on lamotrigine treatment, and an increase in dosage may be required.

The progesterone-only pill and progesterone implants are not recommended in women taking enzyme-inducing AEDs, but medroxyprogesterone injections, the levonorgestrel intra-uterine system and barrier methods are all appropriate.

Counselling
Counselling is important. In addition to contraceptive issues, points to be addressed include the need to take AEDs regularly, the driving regulations, the need to avoid potentially dangerous situations, the risk of seizures after excess alcohol intake or sleep deprivation, eligibility for free prescriptions and for concessionary passes on public transport, and advice regarding employment and education.

First and second-line antiepileptic drugs (IN adults)

First-line for partial-onset seizures

Carbamazepine; lamotrigine; levetiracetam; oxcarbazepine; topiramate; valproate.

Second-line medication for partial-onset seizures
Clobazam; clonazepam; gabapentin; lacosamide; phenobarbital; phenytoin; pregabalin; primidone; tiagabine; vigabatrin (initiated and supervised by specialists); zonisamide.

First-line medication for generalised seizures
Valproate: All seizure types.

Lamotrigine: Generalised tonic-clonic seizures, seizures associated with Lennox-Gastaut syndrome.

Carbamazepine: Generalised tonic-clonic seizures only (may exacerbate absence seizures and myoclonic jerks).

Ethosuximide: Absence seizures only.

Topiramate: Generalised tonic-clonic seizures.

Second-line medication for generalised seizures
Clobazam: Adjunctive treatment for all seizure types.

Levetiracetam: Adjunctive treatment for generalised tonic-clonic seizures and myoclonus

Topiramate: Generalised tonic-clonic seizures and seizures associated with Lennox-Gastaut syndrome.

Clonazepam: All seizure types.

Phenobarbital: All seizure types except absence seizures.

Phenytoin: Generalised tonic-clonic seizures (may exacerbate absence seizures and myoclonic jerks).

Section 4: Prognosis
Seizures can readily be controlled by AEDs in approximately 70 per cent of patients. In the remainder, resistance to multiple AEDs is common.

Re-referral of such patients is appropriate for advice about further medical treatments and for consideration of epilepsy surgery, which may bring about complete freedom from seizures in about 70 per cent of appropriate patients.

Any patient with partial-onset epilepsy refractory to medical treatment should be considered for referral for pre-operative evaluation. For those patients in whom surgery is not appropriate, vagal nerve stimulation may be a helpful palliative treatment.

Recurrence
At least 50 per cent of patients with epilepsy will eventually lose the tendency to have seizures and be able to withdraw medication.9

Unfortunately, the risk of recurrent seizures following drug withdrawal is largely a matter of trial and error, although in idiopathic generalised epilepsy, an EEG showing ongoing epileptic activity indicates a high risk of seizure recurrence.

The risk of recurrence is also high in certain epilepsy syndromes, such as juvenile myoclonic epilepsy, whereas other syndromes have an excellent prognosis - an example being benign epilepsy of childhood with centrotemporal spikes, a common childhood syndrome where complete remission by the age of 16 is the rule.

Most neurologists would recommend continuing AEDs for a period of at least two years of seizure freedom.

The Driver and Vehicle Licensing Agency recommends that patients withdrawing medication should not drive during the tapering period and for six months afterwards. If they have a seizure during this period, the normal driving laws apply.

Annual review
The annual review of patients with epilepsy should include an evaluation of seizure frequency, adverse effects of antiepileptic medication, and the need for ongoing medication.

Pregnancy and contraception should be discussed in girls and women of child-bearing age as appropriate.

Monitoring
Routine monitoring of AED levels is not generally considered necessary in patients with good epilepsy control, but there has been recent concern about the risk of AEDs affecting bone health in the longer term.

NICE recommends that vitamin D levels, serum calcium and alkaline phosphatase should be checked every two to five years in patients taking enzyme-inducing drugs.

Resources

1. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981, 22: 489-501.

2. Stokes T, Shaw EJ, Juarez-Garcia A, Camosso-Stefinovic J, Baker R (2004). Clinical guidelines and evidence review for the epilepsies: diagnosis and management of the epilepsies in adults and children in primary and secondary care. London, Royal College of General Practitioners.

3. Marson AG, Al-Kharusi AM, Alwaidh M et al. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomized controlled trial. Lancet 2007; 369: 1,000-15.

4. Marson AG, Al-Kharusi AM, Alwaidh M et al. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalized and unclassifiable epilepsy: an unblinded randomized controlled trial. Lancet 2007; 369: 1,016-26.

5. Morrow J, Russell A, Guthrie E et al. Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and pregnancy register. J Neurol Neurosurg Psychiatry 2006; 77: 193-8.

6. Adab N, Kini U, Vinten J et al. The longer term outcome of children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry 2004; 75: 575-83.

7. Hunt S, Craig J, Russell A et al. Levetiracetam in pregnancy: preliminary experience from the UK Epilepsy and Pregnancy Register. Neurology 2006; 67: 1,876-9.

8. Hunt S, Russell A, Smithson WH et al. Topiramate in pregnancy: preliminary experience from the UK Epilepsy and Pregnancy Register. Neurology 2008; 71: 272-6.

9. Medical Research Council Antiepileptic Drug Withdrawal Study Group. Randomised study of antiepileptic drug withdrawal in patients in remission. Lancet 1991; 337: 1,175-80.

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