Epilepsy

A tendency to have recurrent seizures. Seizures are defined as transient neurological abnormalities that are caused by abnormal electrical activity in the brain. Human activities, thoughts, and emotions are normally the result of the regulated and orderly electrical excitation of nerve cells in the brain. During a seizure, a chaotic and unregulated electrical discharge causes various physical and mental symptoms.

Causes

In many people with epilepsy, the cause is unclear, although a genetic factor may be involved. In other cases, seizures may be the result of brain damage from a head injury; birth trauma; brain infection (such as meningitis or ; brain tumour; stroke (damage to part of the brain caused by an interruption to its blood supply); drug or alcohol intoxication; or a metabolic disorder.

Symptoms

Many people who suffer from epilepsy do not have any symptoms between seizures. Some people experience an aura (a peculiar warning sensation) shortly beforehand. In some cases, a stimulus such as a flashing light triggers a seizure. Epileptic seizures may occur more frequently during times of illness or stress.

Epilepsy in more detail (In later childhood and adults)

Epilepsy is defined as recurrent (two or more) epileptic seizures, unprovoked by any immediate identifiable cause, and is common, with a lifetime prevalence of 1.5 to 5%.

Pathophysiology

Epileptic seizures are thought to arise at cortical sites. Partial seizures begin focally; generalized seizures infer widespread, bilateral cortical involvement from the beginning. Underlying mechanisms have been best defined for absence seizures, where a thalamocortical circuit is responsible for generating synchronous burst-firing of neurones. In different types of epilepsy, roles for specific ion channels (e.g. voltage-dependent calcium channel, (T-channel)), receptors (e.g. GABAA receptors), and neurotransmitters (e.g. serotonergic) have been suggested.

Clinical features—partial seizures

These include (1) simple partial motor seizures—any part of the body can be affected, and sometimes the seizure ‘marches’ along the cortex, producing successional jerking of contiguous body parts; consciousness is lost with secondary generalization; (2) simple partial sensory seizures—produce paraesthesias or numbness; can march in an analogous fashion to motor seizures; (3) occipital lobe seizures—visual symptoms predominate; (4) frontal lobe seizures—commonly nocturnal; frequently associated with turning to a prone position and vocalization; (5) simple and complex partial (temporal lobe) seizures—associated with olfactory, gustatory and vertiginous sensations, and with psychic symptoms; distinguished by absence (simple) or presence (complex) of altered consciousness; various automatic activity or movement may occur (of which the patient is unaware) when consciousness is disturbed.

Clinical features—generalized seizures

These include (1) tonic-clonic seizures (grand mal epilepsy)—the tonic phase is associated with contraction of axial and then limb muscles; clonic movements appear and slowly increase in amplitude; finally all movements cease and the patient is flaccid. Injury is common; urinary and/or faecal incontinence may occur. Confusion and disorientation are usual when the patient wakes. (2) Absence seizures (petit mal)—activity suddenly ceases for 10 to 20 s, but without loss of posture. (3) Myoclonic seizures—brief, shock-like contractions of muscle, occurring either in a generalized or focal distribution. (4) Atonic seizures—result in sudden loss of muscle tone.

Status epilepticus—defined as a single seizure lasting more than 30 min or successional seizures without recovery of consciousness between.

Investigation

This may (1) provide valuable support for the diagnosis; (2) give an indication as to which part of the brain has initiated the seizure; and (3) allow a statement as to the underlying structural process (if any). After exclusion of common metabolic precipitants, most particularly hypoglycaemia, key investigations are often electroencephalography (EEG) and structural imaging (usually MRI).

Treatment

Does the patient require anticonvulsants?—80% of patients presenting with an epileptic fit will have another one if they are untreated. The decision as to whether or not to start anticonvulsant treatment is often determined by how soon the patient wishes to start driving.

Choice of anticonvulsant—(1) Generalized seizures (tonic–clonic, absence, or myoclonic)—sodium valproate is probably the drug of choice. (2) Partial seizures, with or without generalization—carbamazepine, phenytoin and valproate are probably the drugs of choice. (3) Status epilepticus—lorazepam is probably the drug of choice.

Newer anticonvulsants and problems with anticonvulsants—eight new antiepileptic drugs have been introduced over the last 20 years: each has an individual role and profile of unwanted effects. Drug therapy induces enzymes, may require biochemical monitoring, and poses specific problems in relation to pregnancy, breast feeding, drug withdrawal and driving.

Epilepsy in great detail (In later childhood and adults)

Definitions

Using guidelines developed by the International League Against Epilepsy (ILEA), epilepsy is defined as recurrent (two or more) epileptic seizures, unprovoked by any immediately identifiable cause. Excluded are febrile seizures and neonatal seizures (the latter are defined as those occurring in the first 4 weeks of life). Multiple seizures occurring within a 24-h period are considered to represent a single event. The epileptic seizure itself is defined as the clinical manifestation of an abnormal and excessive discharge of a set of brain neurons. The manifestation is a sudden transient phenomenon which may include alteration of consciousness, or motor, sensory, autonomic, or psychic events that are perceived by either the individual or an observer. Problems arise, when using the term ‘epilepsy’, with those individuals who may have had only two or three attacks in a lifetime. To take account of this, the terms ‘active epilepsy’ and ‘inactive epilepsy’ are used, the former referring to patients with at least one seizure in the previous 5 years, the latter to patients who have been seizure free over the same period. The definitions are further qualified, for inactive cases, according to whether the individual is taking drug therapy.

The idiopathic epilepsies are defined as those epileptic disorders (partial or generalized) that have characteristic clinical and electroencephalogram (EEG) features coupled with a genetic predisposition. Cryptogenic epilepsy defines cases of partial or generalized epilepsy in which no aetiological factor has been identified. Symptomatic seizures are those occurring in association with a known risk factor. Epileptic syndromes have been defined by the ILEA on the basis of clinical characteristics, age of onset, and EEG findings.

Epidemiology

Incidence

Most reported incidence rates lie between 40 and 70/100 000. Figures for developing countries usually exceed 100/100 000. Age-specific rates show a bimodal distribution, with the highest peak in the first decade, falling thereafter until a second peak in later life. In industrialized countries, there has been a decrease in incidence in children and an increase in older people over the last three decades.

Prevalence

Prevalence figures are more widely available. For adults, rates usually lie between 4 and 10/1000 with higher rates in resource-poor countries. Cumulative incidence (or lifetime prevalence) rates, excluding febrile seizures, are higher, producing a figure between 1.5 and 5% with up to twice that figure in resource-poor countries.

Sex

Males have slightly higher prevalence rates than females.

Socioeconomic status

Higher prevalence rates have been reported in the lower socioeconomic groups, in both developed and developing countries.

Pathophysiology

Inherent in any discussion of epilepsy mechanisms is the need to define a homogeneous population of patients in whom epilepsy occurs. Generalized tonic–clonic seizures, for example, can occur with many different epileptic syndromes. Epileptic seizures are thought to arise at cortical sites: partial seizures begin focally in the cortex and generalized seizures infer widespread, bilateral, cortical involvement from the start. An interictal discharge occurs when a group of pyramidal neurons is synchronously activated. During the discharge, the cells develop a large and prolonged depolarization, which is terminated by a hyperpolarizing potential. It is conceived that the generation of synchronized neuronal activity results from an imbalance between inhibitory (γ-aminobutyric acid (GABA)-mediated) and excitatory (glutamate-mediated) neurotransmission, the latter prevailing.

The underlying mechanisms behind epileptic discharges have been best defined for absence seizures where a thalamocortical circuit is responsible for generating synchronous burst firing of neurons. The circuit involves neocortical pyramidal neurons, thalamic relay neurons, and neurons of the nucleus reticularis thalami. The last are exclusively GABA in type. A voltage-dependent calcium channel (T channel) appears critical in allowing burst firing of neurons. After activation, the T channels acquire repolarization via GABAB-receptors present on thalamic relay neurons. GABAA-receptors also play an important regulatory role in synchronized thalamocortical burst firing.

Less information is available on the pathophysiological mechanisms of generalized convulsive seizures. Roles for GABAA-receptors and altered serotoninergic neurotransmission have been suggested.

Classification

The ILEA classification scheme, as revised in 1989, is now widely used for epidemiological, management, and research purposes. The scheme divides seizures into focal, generalized, and unclassifiable forms (Table 1).

Table 1 Classification of epilepsy
I. Partial (focal, local) seizures
A. Simple partial seizures (consciousness not impaired)
1. With motor symptoms
2. With somatosensory or special sensory symptoms
3. With autonomic symptoms
4. With psychic symptoms
B. Complex partial seizures (with impairment of consciousness)
1. Beginning as simple partial seizures and progressing to impairment of consciousness
(a) With no other features
(b) With features as in simple partial seizures
(c) with automatisms
2. With impairment of consciousness at onset
(a) With no other features
(b) With features as in simple partial seizures
(c) With automatisms
C. Partial seizures evolving to secondarily generalized seizures
1. Simple partial seizures evolving to generalized seizures
2. Complex partial seizures evolving to generalized seizures
3. Simple partial seizures evolving to complex partial seizures to generalized seizures
II. Generalized seizures (convulsive or non-convulsive)
A. 1. Absence seizures
2. Atypical absence seizures
B. Myoclonic seizures
C. Clonic seizures
D. Tonic seizures
E. Tonic–clonic seizures
F. Atonic seizures (astatic seizures)
III. Unclassified epileptic seizures

Although it is widely used, the classification has disadvantages. The ability to determine whether consciousness is preserved, in order to make the distinction between simple and complex partial seizures, is often limited. Some individuals, although appearing alert, can be shown to have impaired awareness when carefully tested.

An elaboration of the classification consists of a list of epileptic syndromes into which, theoretically, all generalized and partial epileptic seizures can be fitted. The idiopathic generalized seizures are classified according to age of onset and seizure type. The partial seizures, attributed to dysfunction of restricted cortical areas, are predominantly classified according to their clinical features, supplemented by EEG findings. Much criticism has been made of this syndromic classification. In routine clinical practice many cases (probably the majority) are left in nonspecific categories. Moreover, the classification fails to incorporate data derived from CT or MRI.

Clinical features

Partial seizures

Simple partial motor seizures

Any part of the body can be affected by a focal motor seizure, according to the site of origin of the discharge. Sometimes the seizure remains localized to the same area (e.g. the hand) and sometimes it ‘marches’ along the motor cortex, producing successional jerking of contiguous body parts (Jacksonian seizures). During the focal stage, consciousness is preserved. With secondary generalization (i.e. diffuse bilateral spread) consciousness is lost. The parts of the body most commonly affected by this type of seizure correlate with their area of representation in the motor cortex. Other focal motor disturbances reflecting epileptic discharges include rotation of the head and eyes contralaterally (from the dorsolateral prefrontal cortex), tonic foot movements ipsilaterally (the paracentral lobule), and head turning with arm extension on the same side (supplementary motor cortex). After such seizures there may be paralysis of the affected part lasting for minutes or hours (Todd’s paresis).

Simple partial sensory seizures

Seizures emanating from the sensory cortex produce paraesthesias or numbness. The seizure can march in an analogous fashion to a motor seizure and, similarly, can then become generalized. Where the tongue or face is involved, the symptoms are sometimes felt bilaterally. More complex sensory phenomena may be experienced and, with discharges in the second sensory area, the limb sensations can be ipsilateral, contralateral, or bilateral.

Occipital lobe seizures

Visual symptoms predominate, usually as simple rather than complex phenomena. The latter phenomena, producing alteration of size, shape, or depth of objects, are associated with seizures arising at the occipitoparietotemporal interface. In addition there may be ocular deviation, jerking, or forced closure of the eyelids. Visual hallucinations may occur.

Frontal lobe seizures

Frontal lobe seizures are commonly nocturnal and frequently associated with turning to a prone position. Vocalization is common and tends to consist of a continuous monotone with moaning or grunting. An aura before the attack is unusual. Other recognized features include pelvic thrusting, rocking of the body, and head movements. Rapid postictal recovery is common.

Simple partial (temporal lobe) seizures

The distinction between simple and complex partial seizures is difficult, based as it is on evidence of altered consciousness with the latter. Olfactory, gustatory, and vertiginous sensations occur. The taste and smell sensations are sometimes pleasurable but often disagreeable. A metallic taste is common. Abdominal sensations also occur, which are typically ill-defined, and may ascend to the chest and throat. Psychic symptoms are more often associated with complex partial seizures. There may be intense pleasure or fear ushering in the attack. The patient can experience a sense of loss of personal or environmental reality (depersonalization and derealization, respectively). There may be a sense of intense familiarity (déjà vu) or unfamiliarity (jamais vu). Epileptic anger is unprovoked and rapidly subsides. Illusions are encountered, in the form of disordered visual perceptions, and visual or auditory hallucinations, sometimes of considerable complexity.

Where consciousness is disturbed, various automatic activities or movements that the patient is unaware of (automatisms) may occur. These may take the form of eating (chewing or swallowing), speaking, gesture, or more elaborate skilled activities. Some of these automatic movements are also seen with absence seizures. When elaborate, the patient may partly undress, or move about from one room to another. The symptomatology of mesial and lateral temporal lobe discharges has been distinguished, the latter having somatosensory, visual, or auditory manifestations in addition to the other features mentioned above.

Other, rarer focal seizure types are confined to childhood. In benign childhood epilepsy with centrotemporal spikes, consciousness is preserved. The sensory phenomena are usually confined to the mouth where motor activity may also occur. Speech arrest occurs if the dominant hemisphere is affected.

Any of the focal epilepsies can lead to secondary generalization. Consciousness is lost, and a tonic–clonic seizure is the usual outcome. Prolonged focal seizures (epilepsia partialis continua) lead to a repetitive or continuous focal motor activity that may last for weeks or months and is most often the consequence of a focal cortical insult.

Generalized seizures

Tonic–clonic seizures (grand mal epilepsy)

Some patients report a premonition for hours or even days before the attack. The symptoms are usually a vague sense of loss of well-being and do not imply a focal origin for the attack. An aura lasting a few seconds before the onset, on the other hand, implies a focal origin for the attack, demanding classification as a focal seizure with secondary generalization. The tonic phase is associated with contraction of axial and then limb muscles. If upright, the patient falls heavily. Injury is common. Contraction of the jaw can lead to tongue injury. Forcible contraction of the diaphragm results in a sudden gasp or epileptic cry. Cyanosis results from a loss of respiratory activity. Subsequently clonic movements appear and slowly increase in amplitude. Gradually, periods of relaxation intervene between the clonic contractions until finally all movements cease. The patient is then flaccid. Urinary or faecal incontinence or both may occur at this stage. Subsequently the patient is liable to sleep, often heavily. If the patient wakes, initial confusion and disorientation are usual. Headache and muscle pains are common. Incomplete forms occur in which the clonic or tonic phase predominates.

In addition to injuries incurred in falling, and those resulting from biting of the cheeks or tongue (typically the lateral margin is affected), the seizures may be of such violence that vertebral compression fractures occur. Sudden death occurring soon after a tonic–clonic seizure is a recognized, although rare, complication. Its incidence lies between 1/500 and 1/1000 deaths per person-year.

Absence seizures (petit mal)

Patients are totally unaware of their absence seizures. Activity suddenly ceases but without loss of posture. Adventitious movements occur, e.g. slight contractions of the eyes or some lip movement. The head may drop slightly. More typically, the patient simply stares blankly and is unresponsive. Attacks last around 10 to 20. In some cases more overt limb movement occurs.

Atypical absences are defined as attacks that begin less abruptly, last longer, and frequently lead to loss of postural tone. They usually coincide with other seizure types. Absence seizures begin in childhood and usually cease in adult life, although some 50% of patients will later develop tonic–clonic seizures.

Myoclonic seizures

Myoclonus consists of brief, shock-like contractions of muscle, occurring in either a generalized or a focal distribution. Many forms of myoclonus are nonepileptic. Those associated with epilepsy are accompanied by an ictal EEG discharge. In primary generalized epileptic myoclonus, the myoclonus is accompanied by diffuse cortical epileptic discharges.

Atonic seizures

Atonic seizures result in sudden loss of muscle tone. If the hypotonus is generalized, falls occur, often with substantial injury. The attacks begin in infancy or childhood. The episodes are brief and recovery rapid unless injury has occurred.

Status epilepticus

Status epilepticus is defined as a single seizure lasting more than 30 min or successional seizures without recovery of consciousness between. The seizures are usually tonic–clonic. Both complex partial seizures and absence seizures can occur in the form of status epilepticus. In such cases, alteration of the conscious level is likely to be the major clinical feature with little motor activity, particularly with absence seizures.

Epilepsy syndromes

The need to define epileptic syndromes arises from the fact that individual seizure types may be a manifestation of a number of differing conditions, all with individual characteristics and prognosis. The epileptic syndrome is based on a combination of seizure type, presumed localization (according to clinical features and EEG characteristics in the case of the partial seizures), and age of onset. In routine, as opposed to heavily specialized, practice only a third of patients with newly diagnosed epilepsy can be fitted into such a classification system.

Causes of Epilepsy

In most surveys, only about a quarter to a third of epilepsy cases has been attributable to a specific cause. With modern imaging methods, this proportion is likely to rise significantly.

Genetically determined

In some genetically determined disorders, epilepsy is only one feature of the condition. Many such disorders have features other than epilepsy and typically produce significant neurological disability. Examples include the forms of progressive myoclonic epilepsy associated with Lafora body disease and Unverricht–Lundborg disease. More relevant, in clinical terms, are those genetically determined conditions in which epilepsy is the sole or major manifestation.

Idiopathic generalized epilepsies

The idiopathic generalized epilepsies account for about 20 to 30% of the epilepsies and have a significant genetic influence. Childhood and juvenile absence epilepsy, juvenile myoclonic epilepsy, and generalized tonic–clonic seizures in isolation have been associated with several susceptibility loci.

Most of the idiopathic epilepsies for which the molecular basis is known are channelopathies, where mutations disrupt normal electrical transmissions between neurons. Childhood absence epilepsy is linked to a mutation in the GABAA-receptor, γ2 subunit. Autosomal dominant juvenile myoclonic epilepsy has been shown to be a channelopathy associated with a GABAA-receptor, α1-subunit mutation. A gene encoding the CLC-2 voltage-gated chloride channel (CLCN2 gene), located on chromosome 3q26, has been found in families with idiopathic generalized epilepsy. Through association studies, it has been suggested that the α1A subunit of the voltage-gated calcium channel gene (CACNAIA) may affect susceptibility to idiopathic generalized epilepsy. Recently, non-ion channel genes have emerged as causes of specific epilepsy syndromes.

Where ion channel or nonion channel defects have been identified, they generally account for only a minority of familial or sporadic cases of the relevant epilepsy syndrome. It has been suggested that the genetic predisposition for idiopathic epilepsy represents a continuum, in which only a small fraction follow monogenic inheritance, while the majority display oligogenic or polygenic traits.

Idiopathic focal epilepsies

Several forms of familial focal epilepsy have now been identified. Benign familial neonatal seizures are caused by mutations in the potassium channel genes, KCNQ2 and KCNQ3. Benign familial infantile convulsions, which present between 4 and 8 months of life, are associated with three loci mapped to chromosomes 19, 16, and 2. Benign familial neonatal infantile seizures, an intermediate clinical variant of the previous two, are associated with mutations of the sodium channel, α2 subunit.

Autosomal dominant, nocturnal, frontal lobe epilepsy is a childhood-onset epilepsy characterized by the clustering of nocturnal frontal lobe seizures. The syndrome has been associated with mutations in genes coding for the α4 subunit and β2 subunit of the neuronal nicotinic acetylcholine receptor (CHRNA4 and CHRNB2).

Autosomal dominant, lateral temporal lobe epilepsy is characterized by focal seizures with auditory, visual, psychic, or dysphasic symptoms. In some families the condition is linked to mutations in the leucin-rich glioma-inactivated 1 (LGI1) gene—epitempin.

Febrile seizures are the most common seizure type in children, with an incidence of 2 to 5%. The inheritance is complex and the clinical pattern heterogeneous. Loci have been reported on chromosomes 6q22, 8q13–q21, 19p, 2q23–q24, and 5q14–q15. Typically, febrile seizures occur between the ages of 6 months and 3 years. Simple febrile seizures are generalized and last less than 15 min. Complex febrile seizures have focal features, are longer lasting, or recur within a 24-h period. About two-thirds of children with febrile seizures do not have a recurrence. A proportion of children with febrile seizures develop epilepsy at a later age.

Malformations of cortical development

Malformations of cortical development (MCD) are structural brain defects that are acquired during cortical development. They are a common cause of drug-refractory epilepsy in adults. The defect may be global (agyria), hemispheric (hemimegalencephaly), or focal—focal cortical dysplasia (FCD), and periventricular and subcortical nodular heterotopia (PNH and SNH).

The associated epilepsy tends to arise during childhood and adolescence. The seizure may be generalized or focal, and the type of seizure does not necessarily follow the distribution of the malformation.

EEG frequently reveals continuous epileptiform discharges in patients with FCD. MRI can detect particular signal changes in FCD, although often specialized sequencing is required.

Trauma

Approximately 70% of those individuals who eventually develop post-traumatic epilepsy will have their first seizure within 2 years of the original injury. Risk factors that predict post-traumatic epilepsy include early seizures (those occurring in the first week), a depressed skull fracture, or evidence of intracranial haemorrhage. There is no justification for the use of prophylactic anticonvulsants in the hope of preventing the development of post-traumatic seizures.

Tumour

Although adult-onset epilepsy is often equated with the presence of tumour, the cause of symptomatic epilepsy in later life is more likely to be cerebrovascular or Alzheimer’s disease. The likelihood of a tumour producing seizures increases as the tumour is sited more anteriorly in the hemisphere, so that over 50% of patients with frontal lobe tumours have epilepsy. Adult-onset status, in someone without a history of epilepsy, is particularly suggestive of frontal lobe tumour. Epilepsy is more common with slow-growing tumours and may be generalized or focal in nature.

Cerebrovascular disease

The prevalence of epilepsy after stroke has been reported to lie between 6 and 15%, and appears as likely with cerebral infarction as with cerebral haemorrhage.

Infection

In large-scale surveys, infection has been considered the cause of epilepsy in 3 to 5% of cases. Differences in rate between countries are often attributed to the variable prevalence of certain aetiologies, e.g. cysticercosis. Other tropical infections that have been considered potential contributors to epilepsy prevalence include malaria, schistosomiasis, and trypanosomiasis. Epilepsy is a recognized feature of bacterial, tuberculous, and fungal meningitis, and of viral encephalitis. Epilepsy is often the first symptom of a tuberculoma.

Dementia

Patients with Alzheimer’s disease of mild-to-moderate severity have a cumulative incidence of unprovoked seizures of around 8% over a 7-year period.

Multiple sclerosis

The prevalence of epilepsy in multiple sclerosis (MS) is probably of the order of 2%. Both generalized and focal seizures have been attributed to MS. Rarely, status epilepticus and epilepsia partialis continua have been recorded.

Alcohol

Alcohol lowers seizure threshold. Seizures may occur during binge drinking or during a period of withdrawal after alcohol excess.

Metabolic disorders

Seizures may occur in association with hypocalcaemia, hypercalcaemia, hypomagnesaemia, hypoglycaemia, hyponatraemia, and hypernatraemia. Severe renal and hepatic failure can both precipitate seizures.

Certain drugs are considered to lower the seizure threshold and are relatively contraindicated in patients with epilepsy. The drugs in question include the tricyclic antidepressants, the phenothiazines, and isoniazid. Rapid withdrawal of barbiturates or benzodiazepines can trigger seizures in those without a history of epilepsy.

Precipitants of epilepsy

Recognized precipitants of epilepsy include inadequate sleep, alcohol abuse, and ingestion of certain drugs. In catamenial epilepsy the attacks are confined to the menstrual period. Seizures confined to sleep are well recognized and indeed sleep EEG recordings are characteristically more likely to register abnormal discharges than recordings made in the alert individual. In reflex epilepsy, attacks are virtually inevitably triggered by a particular stimulus. Precipitants include photic stimulation, startle, noise, and movement. Rarer forms of reflex epilepsy have been linked to musical passages, eating, and performance of certain mental tasks.

Differential diagnosis

Syncope

Most individuals who faint experience a characteristic set of symptoms before loss of consciousness. These include mental slowing, fading of vision, altered hearing, malaise, and sweating. The process is the result, in varying combination, of bradycardia and profound arterial vasodilatation in skeletal muscle. Unless the individual lies down, loss of consciousness occurs and the patient falls to the ground. Characteristically the fall is gentle, and self-injury relatively uncommon. In falls associated with tonic–clonic or atonic seizures, the fall is precipitate and injury much more likely. Rarely, in complicated faints, there may be brief clonic jerks of the limbs. More commonly, multifocal myoclonus is observed, lasting a few seconds and following the loss of posture. The eyes tend to remain open. Lateral head turns, repetitive movements (such as lip licking), and hallucinations are all recognized features. After the episode there may be brief confusion and feelings of weakness, but these rapidly resolve. If, on the other hand, the upright posture is maintained (typically the individual is a soldier on parade) then stiffness of the limbs or repetitive generalized shaking occurs which is virtually indistinguishable from the movements occurring with epilepsy. Usually, however, a true tonic–clonic sequence does not occur in these circumstances.

Micturition syncope

Micturition syncope occurs predominantly in males, but of any age group. The attacks are almost always nocturnal, typically after an evening of alcohol consumption. Onset is usually during or shortly after micturition. The warning symptoms are often brief. The attacks seldom occur frequently; if they do, then the individual, if male, is advised to micturate in the sitting position.

Cough syncope

Patients with cough syncope effectively perform Valsalva’s manoeuvre during a bout of prolonged coughing. Treatment is directed at the underlying chest condition.

Cardiac syncope

Various cardiac abnormalities, all having in common the endresult of failing output and reduced cerebral perfusion, are associated with syncopal attacks. Mechanisms include complete heart block, paroxysmal ventricular tachycardia or fibrillation, and supraventricular tachycardia or bradyarrhythmia. In addition to disorders of rhythm, abnormalities of ventricular contractility or obstruction of outflow can have a similar outcome, usually when increased output is required during a period of exertion. Rarely, pedunculated masses within the heart, e.g. an atrial myxoma, cause outflow obstruction when the patient assumes certain postures. Features suggesting that a cardiac lesion may be responsible for a syncopal attack include a history of cardiac disease, palpitations, or chest pain in association with the attack, and the finding of cardiac abnormalities on clinical examination.

Separate from these mechanisms are cases of syncope associated with postural hypotension. Autonomic failure resulting in postural hypotension is a feature of multisystem atrophy, certain neuropathies with autonomic fibre involvement, such as diabetes and drug therapy, e.g. with phenothiazines and tricyclic antidepressants. The correct diagnosis is usually readily established from the history.

Carotid sinus syncope

Patients with this condition usually present with either vertigo or syncopal attacks. The syncopal attacks are sometimes followed by flushing and may be triggered by pressure over the neck, e.g. during neck rotation. In most patients, the syncope is related to atrioventricular block or asystole. Occasionally, a pure vasodilator reaction occurs, with peripheral pooling of blood.

Transient ischaemic attacks

These attacks should seldom be confused with epilepsy. In some patients with carotid occlusion (or severe stenosis), attacks of limb shaking occur in which involuntary limb movements described as shaking, trembling, or twitching occur, usually for seconds. The movements, which are coarse and irregular, predominate distally. Sometimes the attacks coincide with limb weakness or speech difficulty. The attacks are not influenced by anticonvulsants but can be relieved by endarterectomy where there is an underlying carotid stenosis.

Migraine

Loss of consciousness is a recognized feature of basilar migraine. The condition presents in children or adolescents. The headache is occipital. Visual disturbances are common, along with altered sensations (typically bilateral), ataxia, and dysarthria. Typically the patient, if unconscious, can be roused. Rarely, tonic–clonic seizures are seen with the attacks.

Hyperventilation

Most patients with the hyperventilation syndrome do not develop carpopedal spasm or tetany. Rather, they have a constellation of symptoms that are liable to be confused with other conditions such as epilepsy. Those symptoms include dizziness or vertigo, weakness, paraesthesias, chest pain, and altered consciousness. Probably some 5 to 15% of patients lose consciousness during hyperventilation, but never with a tonic–clonic progression that would cause real diagnostic difficulty.

Narcolepsy and cataplexy

Narcolepsy is defined as excessive daytime sleepiness, often occurring under unusual circumstances. The onset of sleep is usually preceded by a feeling of tension, tiredness, or a noise in the head. In some patients, onset occurs without warning. At times, patients have periods of semiautomatic behaviour for which they may subsequently be amnesic.

Cataplexy is typically triggered by sudden arousal. Attacks are brief, and may lead to such loss of muscle control that the patient falls. During the attack, the patient is flaccid, the eyes may roll or diverge, and the facial muscles flicker. Despite this, the patient usually remains fully alert.

Drop attacks

Drop attacks are almost confined to women in the last third of life. Typically, while walking, the patient drops to her knees without warning. The patient is aware of the fall, and is usually able to get up quickly, provided that there is no injury. The attacks occur in otherwise fit individuals, are not due to vertebrobasilar ischaemia, and eventually remit completely. They are untreatable.

The parasomnias

Parasomnias are largely confined to children. They consist of either abnormal motor activity or excessive autonomic activity. Motor activity includes sleep starts, sleep myoclonus, bruxism, and head banging. Sleep myoclonus produces repetitive leg contraction, typically dorsiflexion of the feet. It increases with age and is usually idiopathic. Head banging, which may coincide with body rocking, is usually only seen in children or infants. The movements, which typically occur in clusters, are often accompanied by various forms of vocalization. In most cases, the child is normal. Sleep terrors usually happen within the first hour or two of sleep, occur in children, and result in a sudden cry followed by anxiety, tachycardia, sweating, and hyperkinesis. The child is not completely aware of the episodes, which sometimes necessitate short-term treatment with benzodiazepines.

Psychogenic nonepileptic seizures

Psychogenic nonepileptic seizures sometimes occur in isolation, but sometimes in those with true epilepsy. They account for 20% of the patients referred to specialist epilepsy units, usually with a diagnosis of intractable epilepsy. The prevalence is around 33/100 000 or 4% of that of epilepsy. The vast majority of people who have it are women. They are more likely to have a family history of psychiatric disorders, a past personal history of psychiatric disorder, a history of suicide attempt(s), evidence of sexual maladjustment, and current depressive symptoms. Indeed there is a substantial overlap, in terms of clinical characteristics, between psychogenic nonepileptic seizures and multiple personality disorder. In addition to the features noted above, up to 90% of patients give a history of sustained trauma, including childhood abuse, which may have been physical or sexual.

Certain features from the history should alert the physician. The attacks usually take place with witnesses present. They develop gradually rather than suddenly, and the movements displayed are often unpredictable and bizarre. Attempts to constrain the patient are resisted. Vocalization is common; incontinence is uncommon and tongue biting particularly so, but self-injury is a recognized feature. Typically the seizures are difficult to control. Serum prolactin levels taken 20 min after the event are normal, in contrast to tonic–clonic seizures where they are commonly, although not inevitably, elevated. Videotelemetry has proved of considerable value in differentiating epileptic from nonepileptic seizures. Seizures can be provoked by injections of saline, saline patches, hypnosis, hyperventilation, or photic stimulation. Management is extremely difficult, but earlier diagnosis is associated with a better outcome. Drug withdrawal is resisted by the patient, who often resents suggestions of psychiatric referral and exploration of psychological morbidity.

Investigations

Investigation of a patient with suspected epilepsy (or a single seizure) is performed for three main reasons: the investigation may provide valuable support for the diagnosis, it may give an indication as to which part of the brain has initiated the seizure, and, finally, imaging may allow a statement as to the underlying structural process, where such exists.

Routine haematological and biochemical tests should be undertaken in all patients with suspected epilepsy although they seldom point to a metabolic disturbance that has not already been recognized.

Electroencephalography

Certain facts about the EEG must be understood before interpretation is attempted. Epileptiform discharges are encountered in between 0.5 and 4% of individuals who have never had a seizure and who do not do so during a period of follow-up. Furthermore, a routine EEG in adults with established epilepsy shows epileptiform abnormalities in only some 40 to 50% of cases. With repeat recording, with or without sleep records, the figure rises to 70 or 80%. In other words, some patients with unequivocal epilepsy will have persistently normal or, at least, nonepileptic EEGs. Serial EEG recording is sometimes helpful in an attempt to define the origin of the seizure and to delineate the seizure type better. If photosensitivity is suspected (10% of individuals with seizures occurring between 1 and 7 years are photosensitive), serial recordings are appropriate, as they are in any individual with atypical status or in whom cognitive impairment might be due to subclinical epileptic activity. Where surgical intervention is being planned for the epilepsy, routine and sleep recordings are followed by videotelemetry in order to record individual attacks. For some patients, depth electrodes will be needed to establish the seizure source. Magnetoencephalography (MEG) localizes focal epileptic discharges by measuring the changes in the extracranial magnetic fields that these discharges generate. The system costs some 25 times as much as a conventional EEG system. Although in most patients spikes can be detected on both MEG and EEG, in certain patients spikes are seen with only one or other technique. It may be that MEG has a particular role in identifying focal cortical dysplasia. Depth electrodes are positioned stereotactically at sites determined by clinical and surface EEG criteria. Depth recordings are more accurate and sensitive in detecting focal discharges than either nasopharyngeal or sphenoidal electrodes, but are increasingly less used.

The EEG has also been used to attempt prediction of seizure recurrence in individuals after a single seizure of unknown cause. Epileptic discharges, in one series, predicted a seizure recurrence over 2 years of 83%, compared with a 12% rate in individuals with a normal recording. The EEG has also been used to predict seizure recurrence during or after drug withdrawal in someone whose epilepsy has gone into remission on medication. The predictive value of EEG abnormalities in such cases has varied widely from series to series.

CT

Neuroimaging is carried out in order to define whether a structural abnormality underlies the patient’s epilepsy and, if so, whether some additional treatment, other than anticonvulsants, might be required. CT scanning was originally the most frequently used imaging process, before the more widespread availability of MRI. Some authors advocate MRI in all patients with epilepsy, other than for those epilepsies that are clearly idiopathic (e.g. absence seizures, juvenile myoclonic epilepsy, and benign rolandic epilepsy). In practice, this is probably unreasonable, e.g. a patient with the onset of epilepsy in the 70s or 80s, who has a normal CT (at least, with no evidence of focal pathology), hardly merits MRI if the epilepsy is well controlled.

MRI

MRI is undoubtedly both more sensitive and more specific than CT in detecting small brain lesions and abnormalities of the cerebral cortex thought to be relevant in the genesis of epilepsy (Fig. 24.5.1.3). Protocols setting out to achieve high sensitivity and specificity require T 1-weighted, thin-slice volumetric sequences, T 2 FLAIR (fluid-attenuated inversion recovery), and high-resolution T 2 spin echo. All coronal sequences need to be oriented orthogonal to the long axis of the hippocampus. The most common abnormalities detected are hippocampal sclerosis, malformations of cortical development, vascular malformations, tumours, and acquired cortical damage. MRI is particularly indicated for partial seizures, onset of generalized or unclassified seizures in adult life, patients with fixed focal clinical or neuropsychological deficit, and for those patients with poor seizure control. Quantitative measures of the hippocampi improve the diagnostic sensitivity of MRI for hippocampal sclerosis. MRI is much more sensitive than CT for detecting malformations of cortical development. MR spectroscopy (MRS), examining nuclei 31P and 1H, has been used for assessment of patients with complex partial seizures for possible surgery. Transient MRI abnormalities are a recognized occurrence in patients with epilepsy. Functional MRI is commonly used to localize the motor cortex before resection of adjacent neocortex and to lateralize language function. It is being developed to predict the consequences of temporal lobe resection on memory.

Single-photon emission computed tomography

As a result of its poor time resolution, ictal perfusion SPECT usually displays both the ictal onset zone and the seizure propagation pathways. Although it has been assumed that the region with the most intense hyperperfusion is the ictal onset zone, this is not necessarily the case. The earlier the injection is given after seizure onset, the more likely it is that the most intense focus represents the ictal onset zone. Analysis of ictal SPECT is usually done in comparison with an interictal SPECT image, using a variety of techniques.

Positron emission tomography

Interictal fluorodeoxyglucose positron emission tomography (FDG-PET) has proved a valuable tool in the presurgical evaluation of patients with refractory partial epilepsy.

FDG-PET appears to be superior to standard MRI in the detection of neuronal migration disorders. Sequential scans indicate a correlation between the extent of cortical glucose hypometabolism on PET and the quality of epilepsy control. Besides measurement of cerebral blood flow and regional cerebral glucose metabolism, PET can be used to assess the distribution of specific receptors—such as the benzodiazepine–GABAA-receptor complex, using [11C]fluamzenil (FMZVD). It appears that abnormalities in FMZVD are also linked to the pattern of recent seizure activity.

15O-labelled water PET is at least as reliable as the intracarotid amytal (Wada) test for language lateralization, but this role is being rapidly supplanted by functional MRI.

It has been suggested that high uptake of α-[11C]methyl-L-tryptophan (AMT) on PET occurs in a subset of epileptogenic tubers in patients with tuberous sclerosis, consistent with the location of the seizure focus.

Treatment: drug therapy

Choice of drug therapy

A number of principles can be stated in relation to drug therapy.

Does the patient require anticonvulsants?

The issue of whether isolated seizures should be treated remains unresolved. Seizure recurrence rate after a single seizure reaches 80% in untreated individuals, the vast majority recurring within 2 years of onset. Many patients prefer to defer treatment after a single seizure, a decision substantially influenced by how soon they wish to start driving. For a patient who has very infrequent seizures, say 5 or more years apart, it may seem logical to withhold medication.

Choice of anticonvulsant

An algorithm can provide some guidelines regarding drug treatment. For generalized seizures (tonic–clonic, absence, or myoclonic) sodium valproate is the drug of choice. Further choices are determined by seizure type. There are no controlled trial data indicating the most appropriate add-on drug or combination of drugs. Myoclonus can be exacerbated by carbamazepine, gabapentin, and lamotrigine and absences by carbamazepine and gabapentin. For partial seizures, with or without generalization, carbamazepine, phenytoin, and valproate are probably the drugs of choice.


In addition, choice of drug will be influenced by the patient’s age, sex (regarding the use of oral contraceptives and likelihood of pregnancy), and reliability of adherence to a particular drug regimen. The patient should always be started on a single drug.

Dosage

Although standard dose regimens tend to be quoted, many anticonvulsants are sometimes effective in relatively low doses. Accordingly the drug is introduced in low dosage, which is then gradually increased according to need and tolerance. Sometimes only dosages that lead to toxic serum levels appear effective. Some patients tolerate such toxic levels without difficulty.

Failure of first drug

When this occurs, a second drug should be gradually introduced without withdrawing the first. If the patient responds, the drug used originally can be slowly withdrawn.

Drug combinations

If drugs given individually have failed then drug combinations should be considered, remembering that they may interact with each other.

Generic prescribing

The bioavailability of the anticonvulsant drugs should be unaffected by whether they are prescribed generically, or as a specific branded product. Patients sometimes do not believe this assumption and prefer branded products. If they are given generic prescriptions, they should be warned that the appearance of their medication may change from prescription to prescription.

The problem of noncompliance

Noncompliance is a significant problem with anticonvulsants and is a potent cause of poor control. A full explanation of each drug’s side-effect profile and its potential interactions is essential and appears conducive to improved compliance. Drugs that are given once or twice a day are preferred to ones needing more frequent prescriptions. Slow-release preparations allow drug regimens to be simplified.

Mechanisms of action 

The prime role of GABA-mediated inhibition in the epileptic process implies that drugs that enhance GABAA-receptor-mediated inhibition will have anticonvulsant activity. The GABAA-receptor complex comprises at least three subunits—α, β, and δ—which appear to combine as a five-membered structure forming an anion-permeable channel. Both barbiturates and benzodiazepines act by potentiating GABAA-mediated inhibition. The barbiturates bind to the β subunit to potentiate action of endogenous agonist GABA and prolong the opening time of the chloride ion channel. Benzodiazepines bind to the α subunit to potentiate the action of GABA and increase the frequency of opening of the chloride ion channel. GABA is metabolized by GABA transaminase. Vigabatrin irreversibly binds to GABA transaminase to inhibit degradation of GABA and thereby elevates brain GABA levels. GABA-mediated inhibition can also be enhanced by blocking GABA uptake into glia and neurons after its release into the synaptic cleft during synaptic transmission.

The second major neurotransmitter system involved in the genesis of epileptic activity is excitatory utilizing glutamate and, perhaps, aspartate as neurotransmitters. They act on several different receptors including α-amino-3-hydroxy-5-methylisoxazole-proprionic acid (AMPA) and N-methyl-D-aspartate (NMDA). The NMDA receptor is activated by glutamate or aspartate together with glycine. Blockade of the NMDA receptor results in antiepileptic effects.Tiagabine blocks uptake of synaptically released GABA into both presynaptic neurons and glial cells, allowing GABA to remain at its site of action for longer periods. Gabapentin acts presynaptically to promote GABA synthesis or release.

Voltage-dependent calcium ion currents are thought to be of importance in the genesis of epileptic events. Ethosuximide acts by inhibition of one class of voltage-dependent calcium ion currents (T currents). Valproate may have a similar role. Pregabalin binds to the α2δ subunit of the voltage-dependent calcium channel.

Regulation of sodium channels also appears of relevance in the modification of the epileptic process. Phenytoin, carbamazepine, and possibly valproate reduce the rate of recovery from inactivation of depolarized voltage-dependent sodium channels, thereby blocking sustained repetitive firing of action potentials in depolarized neurons. Lamotrigine inhibits glutamate and aspartate release, suggesting that it may act at voltage-dependent sodium channels to decrease the presynaptic release of glutamate. Lamotrigine may have additional effects on calcium channels. Oxcarbazepine may act by reducing glutamate release via a blocking action on presynaptic calcium channels. Topiramate influences sodium channel activity, suggesting that its anticonvulsant properties are similar to those of phenytoin. Felbamate probably acts primarily through its effects on the NMDA receptor.

Selected drugs

Carbamazepine

Carbamazepine is a first-line drug for both partial seizures and generalized tonic–clonic seizures. In its standard form, it needs to be given three times a day, but a slow-release preparation allows twice-daily prescribing. Dosage ranges from 300 mg/day to 1600 mg/day. Sedation is common and the drug should be introduced slowly. A drug rash occurs in perhaps 3% of patients and demands immediate drug withdrawal. Signs of intoxication include drowsiness, blurred vision, and dizziness. Leucopenia occurs and can lead to a frank aplastic anaemia. Hyponatraemia and oedema are recognized features, associated with a mild degree of inappropriate antidiuretic hormone production. The drug influences atrioventricular conduction and should not be given to patients with atrioventricular conduction abnormalities unless they are already paced. The relationship between dosage and plasma concentrations is linear. Carbamazepine is a liver enzyme inducer and is teratogenic (see below).

Sodium valproate

Sodium valproate is considered, at least by some doctors, to be the drug of choice for all epilepsy types. It is not enzyme inducing, and therefore does not influence the metabolism of the oral contraceptive. Liver toxicity is a recognized, although rare, hazard. Elevated serum liver enzyme activities are more common, but usually return to normal without the need for drug withdrawal. Thrombocytopenia occurs rarely. Gastrointestinal effects are fairly common. Nausea and weight loss are seen, but appetite stimulation with weight gain is more common. Tremor occurs as a dose-related effect and hair loss, of a mild degree, is not uncommon; after a few months, hair regrowth occurs, often more curly than before. Sedation is less troublesome than with other anticonvulsants. Disturbances of menstruation are recognized. It has been suggested that the drug can trigger polycystic ovarian disease, although this may not necessarily translate to a clinically relevant condition. The dose ranges from 600 mg/day to 2500 mg/day and it is given two or three times a day. A slow-release preparation can be given once daily. Plasma levels are not a useful guide to efficacy.

Other drugs

Phenytoin

Experience with phenytoin is vast and, despite its side-effect profile and complex pharmacokinetics, large quantities of the drug continue to be prescribed. A 100-mg tablet, in the United Kingdom, costs approximately one-thirtieth of the price of a comparable dose of lamotrigine. The drug is effective in both generalized tonic–clonic seizures and the partial seizures. It has a long half-life, and can be given once daily, conveniently at bedtime. Sedation is common. Toxic effects, generally dose related, include drowsiness, ataxia, confusion, blurred vision, and dizziness. Most patients who are intoxicated with the drug have nystagmus. Permanent cerebellar ataxia and peripheral neuropathy are recorded. Other side effects or toxic effects include rashes, gum hypertrophy, thickening of the facial features, chorea, and sleep disturbance. The drug is a potent enzyme inducer and is teratogenic. The relationship between dosage and plasma concentrations is nonlinear. Once the dose exceeds 300 mg/day, increments should be pegged to 50 mg or even 25 mg at a time.

Lamotrigine

Lamotrigine is licensed for both generalized and partial seizures. Occasionally it exacerbates myoclonus. Doses seldom exceed 400 mg/day. A drug rash occurs in about 3% of patients. It interacts with enzyme-inducing anticonvulsants, which lower its plasma level. Valproate enhances lamotrigine levels. The drug can be given once daily. Originally said to be nonteratogenic, recent studies suggest that this is not the case.

Phenobarbital

Phenobarbital is a very effective anticonvulsant but often badly tolerated. Children may become hyperactive on the drug and adults (particularly older people) heavily sedated. Doses of up to 180 mg/day are used. It has a long half-life and can be given once daily. Rapid withdrawal of phenobarbital in patients who do not have epilepsy can trigger seizures. Over-rapid withdrawal in someone with epilepsy can trigger status epilepticus. Methyl phenobarbital is largely converted to phenobarbital by the liver and phenobarbital is the main metabolite of primidone, although primidone’s other metabolite, phenylethylmalonamide, probably possesses anticonvulsant activity.

Vigabatrin

Vigabatrin is probably a more potent anticonvulsant than many of the other recently introduced drugs. Increasingly, it has been recognized to cause retinal damage. Up to a third of patients develop concentric constriction of the visual fields, more marked nasally than temporally. The defect is often asymptomatic and probably irreversible. It is now recommended that vigabatrin should be used only as add-on therapy where other combinations have been unsuccessful. Dosage should not exceed 3 g/day. Regular visual field analysis is mandatory.

Gabapentin

Gabapentin is used as add-on therapy for partial seizures with or without secondary generalization. Up to 4.8 g is given in three divided doses. The drug is generally well tolerated and does not interact with other anticonvulsants. Its anticonvulsant effect appears to be relatively weak.

Ethosuximide

Ethosuximide is seldom used in adults as its role is confined to the treatment of absence seizures. Gastrointestinal disturbances are common along with drowsiness, dizziness, and ataxia. Agranulocytosis or aplastic anaemia has rarely been encountered. The dose range is usually 1 to 1.5 g daily.

Clonazepam

Clonazepam is effective for tonic–clonic seizures but is particularly valuable in the treatment of myoclonic epilepsy. Sedation is a major problem, and the drug must be introduced cautiously. The maximum tolerated dose is about 8 mg/day.

Clobazam

Tolerance to clobazam tends to develop fairly readily. It is sedative. Adult dosage ranges from 30 mg daily to 60 mg daily. Used intermittently it can be very effective for the treatment of catamenial epilepsy.

Acetazolamide

Use of this drug is largely confined to childhood epilepsies.

Topiramate

This drug is licensed both for primary generalized tonic–clonic seizures and as adjunct therapy for partial seizures. It is sedative and must be introduced slowly. The total daily dose (given as a twice-daily regimen) seldom exceeds 400 mg. Nausea, anorexia, and weight loss are encountered. Behavioural disturbances are reported, including emotional lability, mood change, and aggression. There is an increased incidence of renal stones in those taking the drug.

Tiagabine

Tiagabine is a GABA uptake inhibitor, resulting in increased synaptic GABA levels. The initial dose in adults is 4 to 5 mg twice daily. Most studies have used 32 to 56 mg/day, in three divided doses. The drug is licensed as add-on therapy in refractory epilepsy. Side effects include dizziness, tiredness, tremor, and altered mood.

Oxcarbazepine

This drug is closely related to carbamazepine but is a less potent hepatic enzyme inducer. It is licensed as monotherapy or adjunctive therapy in partial seizures with or without secondary generalization. Its side-effect profile is similar to that of carbamazepine. Patients who are hypersensitive to carbamazepine should not receive oxcarbazepine. The dosage range lies between 600 and 2400 mg daily, in adults.

Levetiracetam

The mode of action of levetiracetam is not understood. It is not metabolized in the liver nor does it inhibit or induce hepatic enzymes. There are no known interactions with other anticonvulsants. Two-thirds of an oral dose are excreted unchanged in the urine. A quarter is metabolized to an inactive metabolite, also excreted in the urine.

Levetiracetam was originally licensed as adjunctive therapy in the treatment of partial seizures with or without secondary generalization and was licensed for use in idiopathic generalized epilepsy in 2006. The daily dose in adults ranges from 1000 mg to 3000 mg. The dose needs to be adjusted in the presence of renal impairment. It is not advised for use in pregnancy.

Side effects include asthenia, somnolence, headache, gastrointestinal disturbances, mood changes, and skin rash. Behavioural and neuropsychiatric side effects have been noted.

Pregabalin

Similar to gabapentin, pregabalin binds to the α2δ subunit of the voltage-dependent calcium channel in the CNS. It is used as adjunctive therapy in partial seizures with or without secondary generalization. Adverse effects include dizziness, drowsiness, blurred vision, and ataxia. There are no interactions with other anticonvulsants.

Zonisamide

Zonisamide is unrelated to other antiseizure agents. Its effect appears to come through action at sodium and calcium channels. It is licensed as adjunctive therapy in patients with partial seizures with or without secondary generalization. Somnolence is a common side effect. The drug is a sulphonamide and various toxic effects have been described including the Stevens–Johnson syndrome. It is teratogenic.

Felbamate

Felbamate is licensed for use in partial seizures. The drug has serious side effects, including liver failure and aplastic anaemia, and is used only as last-line therapy.

Particular issues

Enzyme induction

Drugs that induce liver enzymes (phenytoin, phenobarbital, carbamazepine, topiramate, and possibly lamotrigine) will alter the pharmacokinetics of other agents or drugs that undergo hepatic metabolism. Women taking an oral contraceptive pill need to take a preparation containing at least 50 µg ethinylestradiol. If breakthrough bleeding still occurs, the dose of oestrogen can be increased to a maximum of 100 µg daily. Alternatively, an injectable long-term contraceptive can be used. The interactions between anticonvulsants are complex, another reason for avoiding drug combinations where possible.

All the enzyme-inducing anticonvulsants have the potential for accelerating vitamin D metabolism. Those individuals at risk for developing vitamin D deficiency (e.g. due to poor nutrition) are at risk of developing osteomalacia or rickets when taking certain anticonvulsants.

Drug monitoring

Anticonvulsant levels are measured far too frequently. There are specific circumstances where their measurement is of value:

  • to ascertain compliance
  • to monitor dosage adjustment with phenytoin
  • to ascertain the unpredictable effect of combining anticonvulsant preparations.

Phenytoin undergoes saturatable hepatic metabolism. Regular monitoring of the serum level is advisable, particularly after dose adjustment. Occasionally, measurement of the levels of carbamazepine, phenobarbital, and ethosuximide aids management, particularly where epilepsy control has been poor. Carbamazepine epoxide, a metabolite of carbamazepine, can sometimes be the cause of carbamazepine toxicity even when carbamazepine levels are in the therapeutic range. There is no value in the routine monitoring of levels of valproate, vigabatrin, lamotrigine, gabapentin, topiramate, clonazepam, or clobazam.

When measuring levels, the same time after the last dose should be used, wherever possible. Examples of therapeutic serum levels are given in Table 24.5.1.2. The therapeutic ranges of the anticonvulsants should be interpreted with caution. Some patients respond to a drug despite subtherapeutic levels. Others need toxic levels to achieve seizure control and can often tolerate such levels without overt difficulty.

Pregnancy

There is an increased risk of congenital malformations in women who have taken anticonvulsants during pregnancy (approximately 4 to 8% overall risk). Most evidence has accumulated for phenytoin, phenobarbital, valproate, and carbamazepine. There are very few data on the newer anticonvulsants. The critical period for development of the major malformations is from 3 weeks’ gestation to 8 weeks’ gestation.

Phenytoin and phenobarbital

Both these drugs are associated with cardiovascular malformations (2% risk) and cleft lip/palate syndromes (1.8% risk).

Valproate

Valproate is associated with an increased incidence of neural tube defects along with other midline abnormalities such as hypospadias, partial agenesis of the corpus callosum, and ventricular septal defects. The risk approaches 10% and is probably dose related. There is some evidence that exposure in utero leads to subsequent neurodevelopmental delay.

Table 2 Anticonvulsants, dosage range, and serum levels (where appropriate)

 

Anticonvulsant Typical adult dose levels range (mg/24 h) Therapeutic serum (μmol/l)
Sodium valproate 800–2500  
Phenytoin 150–350 40–80
Carbamazepine 600–1600 17–42
Phenobarbital 60–180 65–170
Lamotrigine 200–400  
Gabapentin 900–3600  
Vigabatrin 1000–3000  
Topiramate 200–400  
Tiagabine 30–45  
Ethosuximide 1000–1500 285–700
Clonazepam 2–8  
Clobazam 30–60  
Oxcarbazepine 600–2400  
Levetiracetam 1000–3000  

 

Carbamazepine

Carbamazepine is associated with spina bifida (1% risk) and hypospadias.

A folic acid supplement of 5 mg daily should be given to women with epilepsy who are taking valproate or carbamazepine and who are contemplating pregnancy. Doses of valproate should be less than 1000 mg/day if possible and slow-release forms of the drug prescribed. For women on other anticonvulsants, a dose of 0.4 mg/day of folic acid suffices.

Seizure frequency increases in pregnancy in about a third of patients with epilepsy. Tonic–clonic seizures are associated with an increased risk of miscarriage. Vitamin K at 20 mg/day should be given in the last month of pregnancy in women on enzyme-inducing drugs to reduce the risk of haemorrhagic disease of the newborn baby.

The epilepsy risk in the offspring of an affected patient is around 2 to 4% but higher where the epilepsy of the parent has a strong genetic basis.

Breastfeeding

All the commonly used anticonvulsants are present in low concentrations in breast milk. If the mother is on a barbiturate or a benzodiazepine, significant sedation of the baby is possible. If breastfeeding then ceases abruptly, a withdrawal reaction can occur in the infant with tremor and agitation.

Drug withdrawal

Generally medication is continued until at least a 2- to 3-year period free of seizures has been established. Approximately two-thirds of patients remain fit free after drug withdrawal. Factors known to predispose to recurrence include neurological abnormalities on examination, an underlying structural basis for the epilepsy, the need for multiple drug therapy, and a history of difficulty in establishing initial control. The EEG is of limited value in predicting outcome although rather better in children than in adults. Any drug withdrawal should be gradual, say over 3 to 6 months. Absence seizures usually remit spontaneously in late adolescence, but juvenile myoclonic epilepsy tends to recur after drug withdrawal.

Driving

In the United Kingdom, driving must cease for 6 months after any type of seizure, providing that the patient has been assessed by an appropriate specialist and no relevant abnormalities found on investigation. If a nocturnal pattern of seizures has been established for 3 years, driving can then continue even if nocturnal seizures are still occurring. The Driver and Vehicle Licensing Agency (DVLA) prefers patients not to drive during a period of drug withdrawal, and for 6 months after the withdrawal has been completed. For drivers of large goods vehicles, a 5-year period of freedom must be established, and the criteria defined above again met. Furthermore, a continuing liability to epilepsy has to be excluded.

Status epilepticus

Status epilepticus has already been defined. The most common type is tonic–clonic status. The most common precipitants are sudden anticonvulsant withdrawal, poor compliance in a patient with known epilepsy, and alcohol abuse. The mortality figures for status epilepticus have varied substantially from series to series. In one recently published, prospective, population-based study, the overall incidence was estimated at 41 to 61/100 000 person-years with a mortality rate of 22%. Incidence rises in older people, as does mortality. From other series, overall mortality rates lie between 8 and 37%. At least half the cases occur in the absence of previous epilepsy. Although noncompliance and subtherapeutic drug levels are often quoted as causes of status, several studies have established that most individuals with epilepsy who present in status have therapeutic drug levels at or around the time of presentation. Status in the absence of previous epilepsy is followed by unprovoked seizures in about half the cases.

The diagnosis is by no means straightforward. In one study, half the patients transferred to a specialist centre for management of their status were either in pseudostatus or in drug-induced coma. The diagnosis of pseudostatus should be considered if the attacks are atypical or if the status does not respond to initial therapy. Subtle forms of status can be difficult to recognize, often presenting as coma.

Analysis of immediate management of patients in status suggests that many are given inadequate loading and maintenance doses of anticonvulsants. The patient should be moved away from possible hazard, such as broken glass, an airway established, and oxygen administered. Lorazepam is probably the drug of choice. It is given in a dose of 0.l mg/kg intravenously at the rate of 2 mg/min. Alternatives included diazepam (Diazemuls) given intravenously in a dose of 10 to 20 mg at a rate of 5 mg/min or clonazepam given in a dose of l mg by slow intravenous injection.

Using the intravenous route, 50% glucose should be administered to a total volume of 50 ml after blood has been taken to establish the glucose concentration. Thiamine (Pabrinex I/V High Potency) in a dose of 250 mg should be given by slow intravenous injection over 10 min if there is suspicion of alcohol withdrawal, but remember that the infusion can produce an anaphylactic response. In addition to plasma glucose measurement, blood should be taken for urea, electrolytes (including calcium and magnesium), acid–base balance, liver function tests, and full blood count. A serum sample should be stored in case anticonvulsant or alcohol levels are required subsequently. Blood cultures should be performed if the patient is febrile.

If immediate therapy is successful and the patient is receiving phenytoin or valproate, those drugs can be given intravenously before reverting to oral therapy. If the patient is not on anticonvulsants, a phenytoin infusion at 20 mg/kg in 0.9% sodium chloride should be given at a maximum rate of 50 mg/min. An alternative is fosphenytoin, a water-soluble drug, which is metabolized to phenytoin with a half-life of 8 to 15 min. It is given intravenously in the same dose at 150 mg/min in order to achieve a comparable effect. The drug is more expensive than phenytoin but causes less phlebitis and less hypotension, and is better tolerated.

Midazolam has been developed for intranasal use and may prove of value where immediate intravenous access is difficult, e.g. in young children.

If phenytoin infusion is unsuccessful, valproate infusions can be used, with 25 mg/kg as a loading dose delivered at 3 to 6 mg/kg per min. If seizures continue phenobarbital can be considered, given at 20 mg/kg intravenously at 50 to 75 mg/min. Intramuscular or rectal paraldehyde is now seldom used, most experts suggesting a move instead to thiopental, propofol, or midazolam.

Propofol or midazolam is rapidly metabolized and has fewer hypotensive effects than the barbiturates. The suggested dose of propofol is 3 to 5 mg/kg followed by a continuous infusion of 5 to 10 mg/kg per h. Midazolam is given in an intravenous bolus of 0.2 mg/kg followed by 0.1 to 0.4 mg/kg per h.

It has been suggested that a more aggressive approach aimed at EEG burst suppression, rather than simply seizure suppression, reduces the risk of seizure recurrence after initial control.

For all the therapies used in patients with refractory status, intensive care placement is essential with the patient intubated and haemodynamic monitoring in place.

Sudden death

Patients with epilepsy have an increased risk of death compared with age- and sex-matched controls. Sudden unexpected death in epilepsy predominates in younger age groups and in those with more severe epilepsy. The median incidence in patients with refractory epilepsy has been estimated at 3.6/1000. It is likely that most of the deaths are the result of unwitnessed seizures producing respiratory complications, cardiac arrhythmias, or both.

Surgery

Despite optimal treatment, some 30% of patients with new-onset seizures continue to have attacks. A prerequisite in patient selection for surgery is accurate localization of the epileptic discharge and understanding of circumstances where a resection might prove detrimental in terms of functional deficit.

Assessment for epilepsy surgery demands localization techniques incorporating seizure characteristics, electrophysiological recording, and imaging. Equally important is the recognition by the physician that certain epilepsy syndromes are likely to be resistant to medical therapy and that early rather than delayed referral for surgical opinion is beneficial. Mesial temporal lobe epilepsy, secondary to hippocampal sclerosis, is the most common cause of medically refractory partial seizures. In most such patients, a unilateral structural abnormality can be confidently established, resection of which leads to a 70% chance of remission. Disabling neurological complications after surgery, such as hemianopia, hemiparesis, or dysphasia, occur in about 2% of patients. Depression and psychosis are recognized complications of temporal lobectomy.

MRI characteristics of mesial temporal sclerosis include atrophy or increased signal on T 2-weighted images. The presence of atrophy is the best predictor for a good surgical outcome. Besides visual inspection, measurement of hippocampal volume and techniques for measuring the T 2 signal change are used to improve sensitivity.

SPECT and PET measure the changes in cerebral blood flow and cerebral glucose metabolism, respectively, that accompany the epileptic process. Both have relatively high sensitivity and moderate specificity for the diagnosis of temporal lobe seizures, but lower sensitivity for epilepsy arising at other sites. Interictal PET and ictal SPECT produce very similar results in predicting outcome after temporal lobectomy.

Proton MRS can contribute to recognition of the lateralization of the epileptic focus and to the identification of those patients with bilateral changes who are less likely to respond to surgery.

Continuous surface EEG monitoring is usually undertaken as part of the work-up for patients being considered for surgical intervention. The technique, however, has limitations. It often fails to detect seizure activity arising in areas distant from surface electrodes, such as the orbitofrontal cortex, and may falsely lateralize foci, particularly in the presence of large lesions. For improving EEG localization, some form of intracranial recording is necessary. Depth electrodes are used to sample deeper structures such as the hippocampus. Electrocorticography is performed at the time of surgery. Subdural electrodes, sometimes with depth electrodes, measure directly from the surface of the exposed brain.

Other less commonly performed surgical procedures include neocortical resections, lesionectomies, hemispherectomies, multilobar resections, and corpus callostomy. Hemispherectomy is performed when a diffuse epileptogenic region has been localized within one hemisphere, the other hemisphere being normal. As an alternative hemispherotomy has been devised, attempting a complete deafferentation of hemispheric neural connections with maximal preservation of cerebral tissue. Division of the corpus callosum is performed in patients with severe secondary generalized epilepsy who have disabling drop attacks. Cortical dysplasia is increasingly recognized as a cause of intractable epilepsy. MRI criteria have been developed to allow recognition of areas of focal cortical dysplasia and assist in planning the extent of cortical resection. Multiple subpial transection disconnects horizontally coursing cortical fibres over 5 mm apart while preserving vertically oriented projection fibres. Although the procedure is designed to reduce postoperative neurological deficit, it is probably less effective in seizure control compared with cortical resection.

Vagal nerve stimulation

Vagal nerve stimulation is achieved through the implantation of a small stimulator on the left vagus. The exact mechanism of action remains uncertain. The nucleus of the tractus solitarius, the main terminus for vagal afferents, has projections to the locus ceruleus, raphe nuclei, reticular formation, and other brainstem nuclei, which have been shown to influence cerebral seizure susceptibility. In patients with chronic refractory partial seizures, there is a reduction in the number of seizures, rather than their elimination. There is a suggestion that effectiveness increases with the passage of time. The long-term role of this procedure is not yet determined, nor its role in the management of generalized seizures.

Psychiatric aspects of epilepsy

A substantial proportion of patients with poorly controlled epilepsy are likely to have psychiatric symptoms. Those symptoms may partly reflect the underlying structural process in the brain, the effects of repeated seizures, the effects of any social stigma attached to the diagnosis, and as a reaction to the patient’s anticonvulsants. Psychiatric symptoms occurring around the time of the seizures tend to be affective or cognitive if before or with the seizure, but psychotic afterwards. Additional psychiatric morbidity is encountered as an interictal phenomenon. It correlates with multiple drug use, the serum concentrations of those drugs, and certain of the anticonvulsants including the newer agents, such as lamotrigine, vigabatrin, and topiramate. In addition, an adverse psychiatric outcome may follow epilepsy surgery and vagal nerve stimulation.

Patients with poorly controlled epilepsy may require referral to a clinical psychologist, partly with a view to helping in the psychological adjustment to the condition, and partly to identify specific areas of cognitive impairment that might require attention.

The role of specialist nurses and the general practition

Patients almost inevitably indicate some dissatisfaction with the level of information and support that they receive for their epilepsy. Studies suggest that improvement in these areas can occur using a specialist nurse, working either in general practice or in association with a hospital clinic. Where joint care is to be achieved between general practice and hospital, it is vital that good quality communication and record keeping are achieved. Giving the patient files that document vital information, including their drug regimen, is valuable. Patients prefer the continuity of care achievable through seeing the same doctor at each consultation and are more likely to adhere to medical advice under those circumstances.

Prognosis

Prognosis for patients with epilepsy followed in the community is considerably better than for a hospital-based population. Factors that influence outcome adversely include a combination of complex partial and tonic–clonic seizures, clustering of seizures, abnormal physical signs, and the presence of learning difficulties. The influence of antiepileptic drugs on the natural history remains unknown and it has been suggested that a proportion of patients with epilepsy enter permanent remission regardless of treatment.

Overall care

For many patients, shared care among hospital, a specialist nurse, and general practice is ideal. Such an arrangement necessitates a reasonable level of epilepsy experience from the GP, allowing many issues to be resolved without recourse to hospital consultation. The complexities of epilepsy care in terms of new drug developments, issues relating to pregnancy, the question of nonepileptic seizures, and the potential for surgery for many patients with poorly controlled epilepsy make the case for epilepsy clinics staffed by doctors with a particular interest in epilepsy.