Epilepsy

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Epilepsy

The epilepsies are a group of disorders characterized by abnormal electrical activity in the brain. This leads to recurrent unprovoked seizures (Greek: epilēpsia, to seize) in which there are paroxysmal disturbances of movement, sensation or behaviour. The clinical features of a seizure (or ‘ictus’) reflect the location of the abnormal discharges and their extent of spread through the cerebral cortex.

Epilepsy is the most common serious neurological disorder worldwide, affecting up to 1% of the general population. A single seizure does not usually warrant a diagnosis of epilepsy; in most cases, this requires two or more unprovoked seizures separated by at least 24 hours. Provoked seizures are distinct from epilepsy and occur in up to 5% of people at some point in their lifetime; causes include head injury, stroke, infection, fever, alcohol withdrawal and metabolic derangements.

Types of seizure

The two main types of seizure are illustrated in Fig. 11.1. Primary generalized seizures diffusely involve both cerebral hemispheres at onset and consciousness is usually lost. Partial (focal) seizures have a discrete cortical origin and the clinical features reflect the function of the affected area. Abnormal electrical activity can often be recorded during a seizure using scalp electrodes (discussed below).

Primary generalized seizures

This type of seizure appears to originate from abnormal oscillations in thalamocortical loops (reciprocal connections between the thalamus and cerebral cortex). There may be convulsions as a result of the bilateral cortical involvement, but the clinical features are quite variable and there are several well-recognized patterns (e.g. absence, tonic, clonic, myoclonic, tonic-clonic and atonic). Usually it is not possible to identify a structural brain lesion in people with primary generalized epilepsy and most cases are classified as idiopathic. This means that the cause is not known, but there is assumed to be an underlying genetic basis.

Partial (focal) seizures

This type of seizure arises from a discrete focus such as a cortical malformation or tumour. In simple partial seizures there is a disturbance of motor, sensory, cognitive or autonomic function without loss of consciousness. In complex partial seizures, the focal symptoms are accompanied by disturbance of normal awareness or responsiveness. Complex partial seizures commonly originate in the temporal lobe. They are frequently preceded by an aura (Latin: breeze or soft wind) such as a strange sensation or an unpleasant smell.

A secondarily generalized seizure occurs when a partial seizure spreads to involve both cerebral hemispheres. This may be preceded by focal symptoms (e.g. involuntary limb movement or head turning), but these can be missed if generalization is rapid. The presence of localizing neurological signs after the seizure (such as weakness) provides an important clue that there is a discrete (focal) cortical origin.

Key Points

The epilepsies are a group of neurological disorders caused by abnormal electrical activity in the brain. Epilepsy is the tendency to have recurrent, unprovoked seizures.

Epilepsy is the most common serious neurological disorder worldwide, affecting 1% of the general population. Provoked seizures are distinct from epilepsy and occur in up to 5% of people.

Seizures can be classified as partial (focal) or generalized. Partial seizures are further classified as simple or complex, depending on whether or not conscious awareness is altered.

Primary generalized seizures are usually classified as idiopathic, meaning that the cause is unknown, but there is assumed to be an underlying genetic basis.

Partial seizures arise from a discrete cortical focus such as a tumour or malformation. They may spread to involve both cerebral hemispheres and become secondarily generalized.

An abnormal interictal EEG trace is found in approximately 50% of people with clinically definite epilepsy, rising to 80% with provocation (sleep deprivation, hyperventilation, etc).

General aspects

There are numerous epilepsy syndromes with differences in seizure type, age at onset, presumed aetiology and EEG findings (Clinical Box 11.1). They can be classified in different ways such as mode of onset (generalized versus focal) or age at presentation. Many epilepsy syndromes arise in childhood and some have highly characteristic features (Clinical Boxes 11.2, 11.3 & 11.4).

Clinical Box 11.1: Electroencephalography (EEG)

Electrical recording from the scalp can be used to look for epileptiform discharges from the cerebral cortex to support a clinical diagnosis of epilepsy (Figs 11.2 & 11.3). An abnormal interictal trace is recorded in around 50% of people with clinically definite epilepsy, but the diagnostic yield can be increased to 80% by sleep deprivation, hyperventilation or intermittent photic stimulation (flickering light). In some cases it is not possible to record epileptiform discharges, even during a seizure (for instance, if the seizure focus is too deeply seated to be picked up by scalp electrodes). The false positive rate is 0.5% in adults and 4% in children.

Fig. 11.2 Placement of scalp electrodes for electroencephalography (EEG).
Electrodes are placed in standard positions for recording electrical traces from the surface of the brain [Fp, frontopolar; F, frontal; C, coronal; P, parietal; T, temporal; O, occipital; Z, midline; odd numbers, left; even numbers, right]. From Fitzgerald: Clinical Neuroanatomy and Neuroscience 5e (2006) with permission.

Fig. 11.3 EEG trace during a generalized tonic-clonic (convulsive) seizure.
**(A)** Normal interictal recording; **(B)** Generalized seizure activity in all electrode positions; **(C)** Generalized convulsive (tonic-clonic) activity; **(D)** Immediate postictal period with slow waveform pattern throughout; **(E)** Resumption of normal waveforms. From Fitzgerald: Clinical Neuroanatomy and Neuroscience 5e (2006) with permission.

Clinical Box 11.2: Focal motor seizures

These are simple partial seizures that originate in the primary motor cortex and cause convulsions in the opposite half of the body. There is no loss of consciousness, by definition. The seizure typically begins with involuntary movements in one part of the body (e.g. the great toe, thumb or corner of the mouth). As the wave of abnormal electrical activity spreads across the motor strip, clonic (jerking) movements gradually progress to involve more of the body. This is called the Jacksonian march. After the seizure there may be contralateral weakness for up to 48 hours, referred to as Todd’s paresis.

Clinical Box 11.3: Rolandic epilepsy

The commonest childhood epilepsy syndrome is benign epilepsy with centrotemporal spikes. The alternative term Rolandic epilepsy refers to the seizure focus in the region of the central sulcus, which was referred to historically as the fissure of Rolando. This syndrome is characterized by focal motor seizures (simple partial seizures) with speech arrest and hypersalivation (drooling), often with secondary generalization. Rolandic epilepsy usually presents below the age of ten and is regarded as benign since it often disappears during puberty.

Clinical Box 11.4: West’s syndrome

West’s syndrome (or infantile spasms) is a seizure disorder with progressive cognitive decline that is associated with a specific interictal EEG pattern called hypsarrhythmia (consisting of random high-voltage spikes and waves). West’s syndrome begins in the first year of life and is characterized by abrupt, shock-like episodes called salaam attacks, in which there is sudden flexion of the upper limbs, neck and hips with the knees drawn up against the body. It is frequently associated with a developmental or perinatal brain injury such as anoxia or encephalitis.

Tonic phase (30 seconds)

Intense neuronal discharges from the cerebral cortex cause the entire body to become rigid (Fig. 11.4A). Spasm of the laryngeal and respiratory muscles forces air out of the chest, often producing an epileptic cry. The eyes deviate upwards and the patient falls stiffly to the ground, remaining in a state of tonic muscular contraction. Breathing ceases temporarily, leading to cyanosis.

Fig. 11.4 Clinical appearances of a generalized tonic-clonic seizure.
**(A)** The tonic phase lasts around 30 seconds. The entire body becomes rigid, respiration ceases and the patient becomes cyanotic; **(B)** The clonic (jerking) phase is characterized by violent symmetrical convulsions, often associated with laboured breathing and frothing at the mouth, typically lasting around 60 seconds.

Clonic phase (60 seconds)

This is characterized by violent, symmetrical convulsions, with muscular contraction and relaxation (Fig. 11.4B). Breathing is noisy and poorly coordinated, with salivation that appears as ‘frothing at the mouth’. The face may be pink and congested or cyanosis may persist if ventilation is poor. Tongue biting and other injuries sometimes occur and the patient may be incontinent of urine. As the clonic phase comes to an end the jerking movements gradually subside.

Postictal coma (up to 30 minutes)

As the seizure ends, breathing and colour return to normal but the patient remains unconscious. This is probably due to the large-scale release of neurochemicals during the seizure including opiates and the inhibitory neurotransmitter GABA (gamma-aminobutyric acid). On waking there may be postictal confusion, agitation or somnolence, together with muscular stiffness and headache.

Absence seizures

This is another type of primary generalized seizure (formerly known as petit mal) that commonly occurs in childhood absence epilepsy. Absences are characterized by brief (5–10-second) episodes in which the patient becomes unaware of their surroundings. These occur unpredictably, with abrupt onset and offset. During an absence the patient stops whatever he or she is doing and becomes unresponsive, but maintains normal posture and muscle tone. The expression is blank, sometimes with fine flickering of the eyelids or face. There is no aura or postictal confusion and patients are often unaware that anything has happened. Frequent absences may cause severe disruption to concentration and impaired school performance.

Key Points

Numerous epilepsy syndromes (e.g. benign Rolandic epilepsy, West’s syndrome) can be recognized based upon differences in seizure type, age at onset, aetiology and EEG findings.

Seizure disorders fall into three main aetiological groups: symptomatic (with a known structural, metabolic or genetic cause), idiopathic (probably genetic), and cryptogenic (probably symptomatic).

The most common type of ictal event is a generalized tonic-clonic seizure, characterized by separate tonic (rigid) and clonic (jerking) phases followed by postictal coma.

Complex partial seizures are common in temporal lobe epilepsy. They are often preceded by an aura and may be accompanied by automatic behaviours (automatisms).

Absence seizures are a type of primary generalized seizure seen in childhood absence epilepsy and are characterized by 5–10-second periods of ‘unresponsiveness’ with abrupt onset and offset.

Genetic factors in epilepsy

The risk of epilepsy is 2–3 times greater in those with an affected parent, sibling or child and the concordance rates are significantly higher in identical twins. In most cases the heritable component is complex and polygenetic, involving multiple genes interacting with environmental variables, but single-gene disorders are also described.

Inherited seizure disorders

Approximately 2% of epilepsy syndromes show a clear pattern of Mendelian inheritance. This is most often autosomal dominant with variable penetrance, but examples of autosomal recessive, X-linked and mitochondrial inheritance have also been described. Most known mutations affect ion channels (sodium, potassium, calcium or chloride) and these disorders are referred to as channelopathies. This is assumed to alter the balance of excitatory and inhibitory influences and may be associated with focal or generalized seizures.

There are very few single-gene conditions in which epilepsy is the main feature. An example is the syndrome of benign familial neonatal seizures, an autosomal dominant voltage-gated potassium channelopathy which tends to spontaneously remit in adulthood. Another is autosomal dominant nocturnal frontal lobe epilepsy, caused by mutations in the nicotinic acetylcholine receptor gene. A separate group of conditions cause a progressive myoclonic epilepsy syndrome, with shock-like myoclonic jerks and gradual intellectual decline.

Key Points

The risk of epilepsy is 2–3 times higher in those with an affected parent, sibling or child and is also significantly more common in identical twin pairs.

Inheritance is likely to be complex and polygenetic and most of the genes are unknown. Simple Mendelian forms of epilepsy do exist but are uncommon (less than 2% of cases).

Some inherited forms of partial and generalized epilepsy are caused by abnormalities in ion channels for sodium, potassium, calcium or chloride (ion channelopathies).

Diagnosis and management

The diagnosis of epilepsy is clinical and requires a detailed eyewitness account of the episodes. If EEG is performed, this may provide evidence to support the clinical diagnosis. Video recording combined with EEG (referred to as telemetry) may be particularly helpful in difficult cases (Fig. 11.5). Epilepsy can usually be managed pharmacologically, but a neurosurgical procedure may be suitable in a minority of cases. In some patients, the less invasive option of a vagus nerve stimulator may be considered (Clinical Box 11.5).

Clinical Box 11.5: Vagus nerve stimulation

Some patients with epilepsy may benefit from stimulation of the tenth cranial nerve. A vagus nerve stimulator is implanted under general anaesthetic in the neck region and is attached to a subcutaneous pacemaker unit in the upper chest. This is usually carried out in people with pharmacoresistant seizures, halving seizure frequency in up to 50% of patients, but the exact mechanism of action is not known.

Fig. 11.5 Patient undergoing video telemetry in epilepsy.
The EEG trace **(A)** and video sequence **(B)** capture an ictal event, characterized by involuntary orofacial movements. From Specchio, N et al: Epilepsy and Behavior: Ictal yawning in a patient with drug-resistant focal epilepsy: Video/EEG documentation and review of literature reports. Epilep Behav 2011 Nov; 22(3):602–605 with permission.

Anti-epileptic drugs (AEDs)

Two thirds of patients can be managed effectively with anti-epileptic drugs and adequate control is usually achieved with a single agent (monotherapy). Some of the important side effects of anti-epileptic drugs are discussed in Clinical Box 11.6.

Clinical Box 11.6: AED side effects

Some common and important side effects of anti-epileptic drugs are illustrated in Fig. 11.6. Most are central nervous system depressants, so they tend to cause drowsiness and impaired concentration. Many have a toxic effect on the cerebellum, especially when serum levels are high, causing dysarthria (slurred speech), diplopia (double vision) and ataxia (incoordination). Other agents have specific side effects including allergic reactions, skin rashes, gum hypertrophy, acne or hirsuitism. As a group, anti-epileptic agents are known to be teratogenic (Greek: teras, monster) increasing the risk of birth defects from 2% to 6%. Sodium valproate carries the greatest risk, but teratogenicity is also increased in patients receiving more than one anti-epileptic agent (polytherapy).