The Pharmaceutical Journal Vol 262 No 7034 p297-300
February 27, 1999 Continuing education

Epilepsy

(1) The Disease

By Theodora Michael, BPharm, MRPharmS

Other articles in the series
Epilepsy treatment - the established drugs (PJ, March 27, 1999, pp432-5)
Epilepsy - new treatments (PJ, April 3, 1999, pp470-3)

The word epilepsy comes from the greek word "epilamabanie" meaning to seize or attack. The greek physician Hippocrates wrote about epilepsy as far back as 400BC, describing it as a "Sacred Disease". Nowadays, although more is known about epilepsy, it is still not fully understood and it remains a condition without a cure.
The epileptic seizure is a complex symptom which can take a variety of forms and may be caused by a large number of pathological processes.
In a seizure there is a transient excessive electrical discharge in the cerebral neurones, leading to a variety of manifestations usually associated with a disturbance of consciousness. Epilepsy is the term used when such seizures recur.

EPIDEMIOLOGY
Epilepsy is the commonest serious neurological condition in the United Kingdom, affecting at least 350,000 people.¹ Around 30,000 people develop epilepsy every year and the condition will affect about 1 person in 20 at some time during their lives.²

Incidence There are around 20 to 70 new cases of epilepsy per 100,000 people per year.² Many studies have found a slightly higher incidence among men than women. The incidence is higher in the first two decades of life but falls over the next few decades only to rise again in late life.³ The cumulative incidence expressed as the chance of having epilepsy in a lifetime is 2-5 per cent.⁴

Prevalence The prevalence of epilepsy has been found to vary but about 5 per cent of people will suffer at least one non-febrile convulsion in their life and convulsions will recur in about half of these cases.³ Prevalence rates are highest among children. At any given time the number of people with active epilepsy is 4 to 10 per 1,000.⁵
In the United Kingdom, 65 people suffer each day from their first seizure and about 250,000 people take antiepileptic drugs.⁶

Prognosis About 70 to 80 per cent of all people who develop epilepsy will eventually become seizure free with treatment. Withdrawal of therapy can be considered in those who have been seizure free for a period of three to five years, and about half of these will successfully withdraw their drug therapy.^2,5
The other 20 to 30 per cent continue to have seizures despite drug treatment and develop chronic active epilepsy; of these, fewer than 5 per cent will be unable to live independently. The prognosis of patients with chronic active epilepsy is generally poorer and patients will often have additional psychological or neurological problems.^2,5

Mortality The overall mortality rates for people with epilepsy are about two to four times those of the general population, especially in younger sufferers and those with severe epilepsy.^2,5 The most common causes of death include accidents, status epilepticus, tumours and suicide. Sudden, unexpected death is an unexplained cause of death in people with epilepsy and is more common in young males.

Table 1: COMMON CAUSES OF EPILEPSY
Onset	Causes
Neonatal	Hypoxia/asphyxia at birth Intracranial trauma at birth Intracranial haemorrhage Metabolic and electrolyte disturbances Infection Congenital malformations of the brain Genetic disorders
Childhood/adolescents	Febrile convulsions Idiopathic epilepsy Trauma/cerebral palsy Specific epileptic syndromes, eg, Lennox-Gastaut syndrome Brain tumours and hydrocephalus Infection Metabolic disturbances Toxicity, eg, drugs, lead Systemic diseases, eg, leukaemia, renal disease Cerebral degenerative diseases Hereditary, eg, tuberous sclerosis Trauma, eg, battered baby syndrome Congenital malformations of the brain Genetic disorders
Adult	Idiopathic epilepsy Trauma Head injury, eg, haemorrhage Brain tumours Cerebrovascular disease, eg, infarction,   haemorrhage, ischaemia Infection Cerebral degenerative diseases Birth trauma/congenital disease Toxicity, eg, alcohol, drugs Drug withdrawal Metabolic disturbances

PATHOPHYSIOLOGY
Each person has their own threshold for seizure activity. The spread of electrical activity between cortical neurones is normally restricted and the neurones discharge repetitively at a low baseline frequency. If the neurones are damaged or are exposed to metabolic or biochemical insults, a change in neuronal activity may develop.
In epilepsy, the regular discharges are replaced by bursts of high frequency discharges, usually followed by periods of inactivity. A seizure may be triggered when a group of neurones discharge together abnormally. This abnormal discharge may spread to adjacent areas or may remain local. The area from which the abnormality arises is known as the epileptic focus. In other cases, the abnormality may involve widespread areas of the brain simultaneously with no focus.

AETIOLOGY
Epileptic seizures may be caused by any abnormal process that affects the physiology of neuronal function. They have a variety of causes. In some cases the cause is multifactorial but in the majority of cases, almost 70 per cent, no cause is found.^2,5 This is termed idiopathic or cryptogenic epilepsy (see p300). The likely causes of epilepsy depend upon the age of the patient and the type of seizures and are summarised in Table 1.^3,5,6
Hereditary factors can be important since epilepsy can be genetically inherited; however, in most cases genetics plays a limited role. About 30 per cent of patients with true, idiopathic epilepsy have a history of seizures in first degree relatives.^5,6 The mode of inheritance is uncertain. A low seizure threshold appears to run in some families.^2,5
Neonatal seizures occur in over 1 per cent of neonates and 90 per cent of these are due to birth complication, hypoglycaemia, hypocalcaemia, hypomagnesaemia or meningitis.⁵
Febrile convulsions occur in 3 per cent of all children between the ages of 6 months and 5 years, with the highest incidence between 10 months and 2 years of age. In 30 per cent of these children there is a family history of febrile convulsions.⁵ The majority will have a single seizure only and the prognosis of such cases is excellent. Where febrile convulsions are recurrent, prolonged or there is a neurological pathology, the prognosis is less clear and such symptoms may mark the onset of epilepsy. Febrile convulsions themselves may result in anoxic brain damage and thus present a cause of epilepsy.^5,7
Trauma is one of the more common causes of epilepsy. In open head injuries the risk of developing epilepsy is 40 per cent and in severe closed head injuries the risk is 5 per cent.⁵
About half of those who develop post-traumatic epilepsy have seizures within the first year of the injury and three-quarters have seizures within two years.⁵
Brain tumours account for about 10 to 15 per cent of adult onset epilepsy but are a rare cause in childhood. Slow-growing tumours, eg, meningiomas, may cause epilepsy up to 20 years before the tumour is identified.⁵
In people developing epilepsy over the age of 50 years, up to 50 per cent of cases are caused by cerebrovascular disease. Thrombotic, haemorrhagic and embolic stroke are all associated with epileptic seizures and up to 25 per cent of patients may develop epilepsy after a stroke.⁵
Viral encephalitis is most commonly caused by the Herpes simplex (type 1) virus in the UK. Epilepsy will develop in most severe cases. Other types of encephalitis cause less damage and hold less risk of epilepsy.
Epilepsy is three times more common in patients with multiple sclerosis than in the general population. Other degenerative brain disorders, such as Alzheimer's disease, can also be associated with seizures.⁵
Many drugs, medicinal or recreational, can precipitate seizures, either as a result of toxicity or withdrawal. Drugs that may cause seizures are listed in Table 2.⁸ Withdrawal seizures can, of course, occur when antiepileptic therapy is withdrawn but are also associated with alcohol, benzodiazepine, opiate and amphetamine withdrawal. Chronic alcohol abuse is a common cause of seizures and these may occur while drinking or during periods of abstention. Alcohol-induced hypoglycaemia can also provoke seizures.

Table 2: DRUGS THAT MAY CAUSE SEIZURES 8
Drug class	Specific drugs
Antimicrobials	Amphotericin, cephalosporins, chloroquine, cycloserine, fluconazole, isoniazid, mefloquine, penicillins, proguanil, quinolones, zidovudine
Cardiovascular	Lignocaine (intravenous), procaine
Antidepressants/antipsychotic and other CNS drugs	Amantadine, antimuscarinics, antiepileptics (exacerbation), baclofen, clozapine, cocaine, lithium, methylphenidate, phenothiazines, tricyclic antidepressants
Endocrine	Desmopressin, insulin, oral contraceptives, oxytocin, prednisolone
Stimulants	Aminophylline, caffeine, doxapram, theophylline
Anaesthetics	Enflurane, halothane, ketamine, methohexitone propofol
Radiographic contrast media	Meglumine derivatives (Conray, Dimer-X) metrizamide
Miscellaneous	Allopurinol, camphor, measles vaccine, strychnine

CLASSIFICATION
There are international classifications for both seizure types and epileptic syndromes.⁷

CLASSIFICATION OF SEIZURES
There are many types of seizure and in 1981 the International League Against Epilepsy (ILAE) developed a classification of seizure types (Table 3).⁹ In population terms, generalised and partial seizures are distributed evenly. Seizures that do not fit in either of these two groups are termed unclassifiable.

Generalised seizures Seizure activity starts in both hemispheres of the brain simultaneously and consciousness is impaired from the outset. The most common is the generalised tonic-clonic seizure which accounts for over 75 per cent of generalised seizures.¹

Tonic-clonic seizures - At the onset of a tonic-clonic seizure the patient will become stiff and fall (tonic phase). They may cry out or bite their tongue. As they lie rigid they may become cyanosed. The tonic phase can last up to a minute. As the clonic phase begins the patient will convulse. This usually involves all four limbs; breathing may be difficult and saliva may froth from the mouth. This phase may continue for a couple of minutes after which the muscles will gradually relax - incontinence is common at this stage.
The patient may remain unconscious for a variable time, up to several hours. Post-ictal (post- seizure) confusion and drowsiness are common and patients often fall into deep sleep to recover.

Absence seizures - Absence seizures are mainly seen in children and adolescents. Typical absence seizures involve a sudden loss of awareness during which all motor activity stops. The patient will be motionless and unresponsive, with a blank stare; the seizure is sometimes accompanied by minor automatisms (repetitive movements), such as fluttering of the eyelids or mouth, or may involve sudden loss of tone causing the head to flop or relaxation of a grip. The seizure lasts from a few seconds up to a minute and will end suddenly. The patient will be unaware that an attack has occurred and will continue what he or she was doing before the attack. If other features occur, such as erks, spasms or automatisms, the attacks are called atypical absence seizures. These usually last longer than typical absence seizures.

Myoclonic seizures - These seizures are characterised by jerks of a muscle group or several muscle groups which may be single or repetitive. The patient may fall but recovery is almost immediate. Myoclonus can also occur in neurological conditions other than epilepsy, such as spinal cord lesions.

Atonic seizures - Atonic seizures are also known as drop attacks. There is sudden loss of muscle tone, resulting in the patient falling. Sometimes tone is only lost in selected muscle groups, such as in the neck. Recovery is rapid and may happen before the patient falls. These seizures are rare and may be confused with non-epileptic drop attacks seen in other conditions.

Tonic seizures - Tonic seizures are also rare. They cause the patient to fall because of a sudden increase in muscle tone.

Clonic seizures - Clonic seizures are characterised by repetitive jerks which lessen as the seizure progresses.

Partial (focal) seizures In partial seizures, seizure activity starts in a localised area of the cerebral cortex (usually the temporal or frontal lobes) and the clinical manifestations reflect the area affected. A tumour can also act as a focal point. Activity may remain localised or may spread to other areas of the brain.
In simple partial seizures there is no loss of consciousness, whereas in complex partial seizures consciousness is impaired or even lost. Seizures involving the motor centre (frontal lobe) manifest as jerks or spasms and those of the sensory centre as tingling or numbness. These symptoms are usually unilateral and may progress, eg, from a hand to an arm to a leg. The olfactory centre is commonly involved in complex partial seizures, involving changes in the sense of smell. Other common symptoms in complex partial seizures range from dizziness, altered perceptions and memory disturbances to hallucinations. The most common manifestation of a complex partial seizure is an automatism, such as lip smacking, facial movements or fidgeting, that last a few minutes.
In secondarily generalised seizures, there is a warning, or "aura", in the seconds before the seizure which is indicative of a focal onset. The aura is, in effect, a partial seizure, in which the activity then spreads to develop a generalised seizure.

Unclassifiable seizures About one third of seizures fall into this category and may be a mixture of several types of seizure.

Status epilepticus Most seizures will cease after a few minutes. However, in some cases a seizure may continue or seizures may follow each other without recovery of consciousness. This is termed status epilepticus. The condition can occur with any seizure type and can be life threatening where cardiorespiratory function is compromised, as in tonic-clonic seizures.

Table 3: CLINICAL CLASSIFICATION OF EPILEPTIC SEIZURES 9
Classification	Type of seizure
Generalised seizures	Tonic-clonic seizures (grand mal ) Absence seizures (typical "petit mal" or atypical) Myoclonic Tonic Clonic Atonic
Partial (focal) seizures	Simple partial seizures Complex partial seizures Secondarily generalised seizures
Unclassifiable seizures

CLASSIFICATION OF EPILECTIC SYNDROMES
The Commission on Classification and Terminology of the International League Against Epilepsy separates epilepsies of known aetiology from those that are idiopathic and those that are cryptogenic.¹¹

Symptomatic epilepsies These arise from a known or suspected disorder of the central nervous system and can occur at any time of life.

Idiopathic epilepsies These have no underlying cause apart from a hereditary predisposition and tend to occur early in life.

Cryptogenic epilepsies These are presumed to be symptomatic of a hidden cause of unknown aetiology.

DIAGNOSIS
Diagnosis can be difficult as other conditions in which consciousness is temporarily impaired, such as syncope and transient ischaemic attacks, may be confused with epilepsy. It is essentially a clinical diagnosis and depends on a clear and detailed witnessed account of the attacks. Most people with epilepsy will tend to have one type of seizure but some may have two or more different types.
Along with routine tests, more specific tests are used in the investigations for epilepsy.

Electroencephalography (EEG) This is a recording of the electrical activity of the brain. Up to 24 leads are placed on the scalp and can detect and amplify the signals from the surface of the brain. EEG does have its limitations and 20 to 40 per cent of newly diagnosed patients with epilepsy will have a normal EEG. On the other hand, about 15 per cent of people who do not have epilepsy have an abnormal EEG. This test therefore is mainly useful in the classification and assessment of patients. Portable equipment is also available to take recordings over a 24-hour period. In video EEG telemetry, a video camera is linked up with the EEG to correlate EEG changes with the clinical changes of the patient.

Computed tomography (CT) and magnetic resonance imaging (MRI) These tests can identify any structural abnormalities of the brain and can be useful in finding the focal point of seizures, especially when surgical treatment is being considered.

SOCIAL ASPECTS OF EPILEPSY
The great majority of people with epilepsy can be managed by a general practitioner or as an outpatient. Up to 70 per cent of patients are controlled successfully with a single antiepileptic drug, allowing minimal impact on the pattern of their daily lives.
People with epilepsy should be encouraged to lead as normal life as possible and this, in turn, will help to remove the social stigma attached to the diagnosis of epilepsy.
Most children with epilepsy attend mainstream school but a small minority may have special educational needs as a result of the nature and frequency of their seizures. In most patients, epilepsy has no detrimental effect on intellect. Both adults and children are encouraged to lead lives as unrestricted as possible, although with sensible precautions in certain activities, such as not swimming alone and not locking bathroom doors. Very few jobs are unsuitable for people with epilepsy and they should be considered no differently from others for the majority of jobs. With regard to driving, the issue of HGV and PSV licences is prohibited in those who develop seizures after the age of 5 years. Those who have had more than one seizure are unable to hold a driving licence in the UK unless they have been free from any seizures while awake for a period of two years prior to the issue of a licence. In cases of seizures during sleep, the seizures must have occurred only while asleep over the previous three or more years prior to the issue of a licence.
Research shows that drinking more than one or two units of alcohol per day may increase the risk of seizures in those who are prone to them. People with epilepsy should therefore be advised to be cautious of alcohol and to avoid excessive intake. Even in people who do not have epilepsy, excessive drinking can cause seizures.

CONCLUSION
Epilepsy is a common neurological condition and as yet no cure has been found. The majority of patients who develop seizures do not develop chronic epilepsy. Of those that do, many can be managed successfully on a single antiepileptic agent. Rarely will patients with chronic epilepsy require long term institutionalisation. Most lead a normal life.

ACKNOWLEDGMENTS I would like to thank Professor Simon Shorvon (professor in clinical neurology, Institute of Neurology, and consultant neurologist, National Hospital for Neurology and Neurosurgery) for his helpful comments.

Ms Michael is clinical pharmacist at the National Hospital for Neurology and Neurosurgery, Queen Square, London