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).

Fig. 11.6 Side effects of anti-epileptic drugs.

Mechanisms of action

A minority of anti-epileptic agents are the product of rational drug design, based upon knowledge of cellular events in epileptogenesis. Most are discovered fortuitously or by systematic screening of a large number of candidate compounds in an animal model of epilepsy. For this reason the mode of action is not always clear, but most agents fall into one of four main categories (discussed below).

Sodium channel antagonists

Inhibition of voltage-gated sodium channels is the most common mechanism. This interferes with the depolarization phase of the action potential, which is mediated by a fast inward sodium (Na⁺) current. Many agents prolong channel inactivation by preferentially binding to sodium channels in their inactivated state. This increases the refractory period of the neuronal membrane (see Ch. 6). Repetitive neuronal firing at high frequencies is specifically reduced (activity-dependence), minimizing interference with normal brain activity. Examples of agents that block sodium channels include: phenytoin, carbamazepine, sodium valproate and lamotrigine.

Calcium channel antagonists

These agents inhibit voltage-gated calcium channels, which contribute to membrane depolarization and action potential generation (in the neuronal cell body) and transmitter release (at the axon terminal). Calcium channels also act as pacemakers, supporting oscillating patterns of activity between the cortex and thalamus. This is important in the generation of absence seizures, for which the calcium channel antagonist ethosuximide is effective. Drugs which antagonize calcium channels include: sodium valproate, gabapentin, phenytoin and lamotrigine.

GABA potentiators

These drugs increase activity at inhibitory synapses (see Ch. 7). Some act via post-synaptic GABA_A receptors which are linked to a chloride ion channel; this stabilizes the neuronal membrane via an inward chloride (Cl^–) current. These include (i) benzodiazepines (e.g. clonazepam, diazepam) which increase the frequency of channel opening and (ii) barbiturates (e.g. primidone, phenobarbital) which increase the duration of channel opening. Others act at metabotropic (G-protein-coupled) GABA_B receptors which influence second messenger cascades; this causes longer-lasting hyperpolarization of the neuronal membrane by opening potassium channels. Several anti-epileptic agents increase the amount of GABA available by modulating its synthesis (sodium valproate), reuptake (tiagabine), release (gabapentin) or breakdown (vigabatrin).

Glutamate modulators

Glutamate receptor antagonists have a powerful anti-epileptic effect in animal models, but are not suitable for clinical use. This is because of the unacceptable side effects that would be caused by widespread interference with excitatory neurotransmission. Nevertheless, several well-established anti-epileptic drugs have some effect on the synthesis, release, reuptake or degradation of glutamate (e.g. topiramate, felbamate, lamotrigine).

Failure of anti-epileptic drugs

Seizure control is inadequate in 30% of patients. An important factor is non-compliance and large studies in the UK and USA have shown that two thirds of patients regularly fail to take their medication. This can be improved by patient education and modified-release (once daily) preparations.

Pharmacoresistance

Focal (partial) seizures are more likely to be drug resistant, especially in temporal lobe epilepsy. Resistance may develop with progression of the underlying disease or as a result of alterations in ion channels and receptors. Another cause is upregulation of multi-drug transporter proteins which are present at the blood–brain barrier and eject lipophilic molecules from the brain. A similar mechanism underlies resistance to chemotherapeutic agents in certain cancers. One of the best known drug resistance proteins is p-glycoprotein; others include the multi-drug-resistance-associated proteins (MRPs) and breast cancer resistance protein (BCRP).

Surgery in epilepsy

Approximately 10% of patients with drug-resistant focal epilepsy might benefit from a neurosurgical procedure. Before any surgical intervention, detailed preoperative assessment is carried out including psychometric testing and functional brain imaging, to assess the potential impact of surgery on memory, language and intellect (Fig. 11.7).

Fig. 11.7 Preoperative assessment prior to epilepsy surgery.
This patient has a large cystic lesion in the left cerebral hemisphere. The image shows a functional MRI (fMRI) scan in the axial plane during a word generation task used to determine if radical epilepsy surgery is likely to lead to post-operative language impairment. There is increased regional cerebral blood flow in the inferior frontal and posterior temporal regions in the right cerebral hemisphere suggestive of language reorganization to the unaffected (right) side of the brain in this patient which predicts a more favourable outcome following surgery (NB language is normally represented in the left cerebral hemisphere in 95% of right-handed people and 70% of those who are left-handed; see Ch. 3). From Bargalló, Núria: Eur J Radiol 2008 67(3): 401–408 with permission.

Types of procedure

The aim of surgery in epilepsy is usually to (i) remove a causative lesion or (ii) interrupt white matter pathways to prevent seizures from spreading.

Partial or complete removal of a lobe (lobectomy) may be appropriate for a focal lesion. The most commonly performed procedure is temporal lobectomy with hippocampectomy, in order to treat drug-resistant temporal lobe epilepsy.

Division of the corpus callosum (callosotomy) can be used to prevent interhemispheric spread of seizures. Resection of an entire cerebral hemisphere (hemispherectomy) or surgical ‘disconnection’ of the cerebral cortex (functional hemispherotomy) is occasionally performed for severe unilateral disease (Clinical Box 11.7).

Clinical Box 11.7: Rasmussen’s encephalitis

This is a very rare inflammatory brain disease of childhood that is characterized by severe, unilateral seizures with progressive intellectual decline. Contralateral hemiplegia and hemianopia develop over a number of years as one hemisphere is progressively destroyed (Fig. 11.8). The aetiology is uncertain, but is thought to be autoimmune in origin. Anti-epileptic drugs are ineffective and surgical resection of the affected hemisphere is often the only option.

Fig. 11.8 Rasmussen’s encephalitis.
T1-weighted axial MRI scan showing marked unilateral atrophy which is particularly prominent in the frontal lobe. From Gibbs, JW et al: Physiological analysis of Rasmussen’s encephalitis: patch clamp recordings of altered inhibitory neurotransmitter function in resected frontal cortical tissue. Epilep Res 1998 June; 31(1):13–27 with permission.

The outcome of surgery is excellent in three quarters of cases and up to 70% of patients with well-circumscribed lesions can expect to be left seizure free. In the small number of cases requiring hemispherectomy the cure rate may be as high as 95%.

Key Points

Two thirds of patients can be managed effectively with anti-epileptic drugs (AEDs) and in most cases this can be achieved with a single agent (monotherapy).

The major types of AED are: sodium channel antagonists (e.g. phenytoin, sodium valproate); calcium channel antagonists (e.g. ethosuximide); and GABA potentiating agents (e.g. benzodiazepines, barbiturates). Some agents also modulate glutamate neurotransmission.

Anti-epileptic drugs have a number of side effects including drowsiness, reduced concentration and cerebellar ataxia. Incidence of birth defects is also increased, particularly with sodium valproate.

Seizure control is inadequate in 30% of patients. This may reflect pharmacoresistance in some cases, but an important contributing factor is non-compliance.

Approximately 10% of drug-resistant focal epilepsy might benefit from a surgical procedure to remove a causative lesion or prevent the spread of seizure activity.

Neuropathology of epilepsy

There are no specific pathological features in primary generalized epilepsy. In focal epilepsy the three common findings are: hippocampal sclerosis, cortical malformations and benign tumours.

Hippocampal sclerosis

Hippocampal sclerosis is the most common pathological finding in focal epilepsy, accounting for 65% of cases. The typical MRI findings are unilateral volume loss on T1-weighted images and increased signal (hyperintensity) on T2-weighted images (Fig. 11.9). Resected surgical specimens usually appear shrunken and may feel firm or sclerotic when they are sliced (Greek: sklerōs, hard).

Microscopic features

Examination of the specimen under the microscope shows marked loss of neurons in the pyramidal cell layer of the hippocampus, accompanied by glial scarring (Fig. 11.10). Neuronal loss is most pronounced in the CA1 subfield, a region that is selectively vulnerable to a range of pathological processes including hypoxia, ischaemia and excitotoxic injury (see Ch. 8). In severe cases there may be widespread loss of hippocampal neurons, but those within the CA2 subfield and dentate gyrus tend to be resistant.

Fig. 11.10 Pathological features of hippocampal sclerosis.
**(A)** Micrograph of a normal human hippocampus (stained with Luxol fast blue/cresyl violet) showing the main anatomical structures [DG = dentate gyrus; CA1-3 = subfields of Ammon’s horn; Sub = subiculum]; **(B)** Immunohistochemistry for the neuronal marker NeuN in a patient with hippocampal sclerosis showing neuronal loss in the CA1 subregion; **(C)** The same specimen stained with Luxol fast blue (a myelin stain) which shows collapse of the CA1 subfield; **(D)** Astrogliosis (glial ‘scarring’) in the same case, which is most obvious in CA1, demonstrated using antibody-labelling for the astrocytic marker GFAP (glial fibrillary acidic protein).

Another common finding is granule cell dispersion. The granule cell layer is thicker than usual and its normally rounded neurons become spindle-shaped, reminiscent of migrating nerve cells. This is thought to be due to the birth and migration of new neurons, triggered by seizure activity. Changes in hippocampal connectivity (in particular, a phenomenon called mossy fibre sprouting) are discussed below in the context of partial seizure mechanisms. In 10% of cases a second lesion such as a malformation or tumour is also found (‘dual pathology’).

Aetiology of hippocampal sclerosis

Retrospective studies in adults with hippocampal sclerosis have identified an initial precipitating insult (during childhood) in up to 90% of cases. This is most often a febrile convulsion, a fever-associated seizure that occurs in up to 5% of normal children under the age of 5 years (with no further problems in the vast majority of cases). In a small proportion of children, regular spontaneous seizures develop after a variable latent period (usually <10 years). The phenomenon has been replicated in animal models, providing evidence that temporal lobe epilepsy might be caused by damage to the immature brain (the concept that ‘seizures beget seizures’).

Another possibility is that a pre-existing developmental abnormality of the hippocampus is responsible for both the febrile convulsions in childhood and the development of epilepsy in later life. This idea is supported by the finding of subtle hippocampal abnormalities in relatives of people with hippocampal sclerosis (who do not have epilepsy themselves).

Malformations of cortical development

This is a group of neuronal migration disorders characterized by abnormal development of the cerebral cortex, termed cortical dysplasia. This accounts for approximately 20% of cases in epilepsy surgical specimens and is an important cause of pharmacoresistant partial seizures. There are several types (some of which are discussed in Clinical Box 11.8) but the most common form is focal cortical dysplasia.

Clinical Box 11.8: Cortical migration disorders

This group of disorders is characterized by abnormal lamination and folding of the cerebral cortex. The pattern of surface convolutions is simplified and the cortex is abnormally thick. The most severe form is lissencephaly in which the surface of the brain is smooth (Greek: lissos, smooth). Two thirds of cases are caused by mutations or deletions affecting the LIS1 or XLIS (DCX) genes on chromosomes 17p and Xq respectively, which are involved in microtubule binding and cell motility. In subcortical band heterotopia (or double cortex syndrome) a thick band of abnormal grey matter is found beneath the cerebral cortex. This is caused by germline deletions in the DCX/XLIS gene and occurs almost exclusively in females. Cortical migration disorders are often associated with epilepsy and cognitive impairment.

Focal cortical dysplasia (FCD)

In this condition the affection region of the cerebral cortex is thickened and the junction with the subcortical white matter is blurred (Fig. 11.11A). The microscopic structure of the cortex is disturbed, with malorientated neurons and abnormal cell types (Fig. 11.11B):

Fig. 11.11 Focal cortical dysplasia (FCD).
**(A)** Brain specimen showing an area of abnormal cortical architecture (*) with blurring of the normally sharp boundary between the cerebral cortex (stained pink) and subcortical white matter (stained blue). This is a combined preparation using haematoxylin and eosin with Luxol fast blue; **(B)** Micrograph of FCD (routine haematoxylin and eosin staining) showing the disorganized cortical structure with abnormal (dysplastic) cells. The presence of balloon cells is best confirmed with immunohistochemistry (antibody labelling) by demonstrating large, swollen cells that express both neuronal and glial proteins. From Burger: Surgical Pathology of the Nervous System and its Coverings 4e (Churchill Livingstone 2002) with permission.

Balloon cells are large, rounded cells with intermediate features between neurons and glia; the presence of balloon cells is diagnostic of focal cortical dysplasia.

Dysplastic neurons have abnormal, bizarrely shaped cell bodies and dendrites, in addition to abnormal orientation and positioning within cortical laminae.

Giant neurons are large pyramidal cells with an otherwise normal morphology. They can be found throughout the dysplastic cortex.

Epileptiform discharges have been obtained in electrode recordings from dysplastic cortex in human surgical specimens and appear to arise from abnormal neurons. Interestingly, the foci of dysplasia are indistinguishable from cortical ‘tubers’ in tuberous sclerosis (Clinical Box 11.9).

Clinical Box 11.9: Tuberous sclerosis

This is an autosomal dominant condition affecting 1 in 6000 live births. There are two causative genes, TSC1 and TSC2 (located on chromosomes 9 and 16 respectively), which take part in cytoplasmic signalling pathways involved in cell growth and development. Features of tuberous sclerosis include epilepsy and developmental delay together with characteristic skin lesions (Fig. 11.12). The risk of certain cardiac, renal and glial tumours is also increased. Brain imaging shows multiple cortical tubers which represent areas of focal cortical dysplasia.

Fig. 11.12 Facial angiofibromas (‘adenoma sebaceum’) in a patient with tuberous sclerosis.
This is one of many neurocutaneous syndromes with manifestations in both the skin and nervous system. From McIntosh, N et al: Forfar and Arneil’s Textbook of Pediatrics 7e (Churchill-Livingstone 2008) with permission.

Glioneuronal tumours

Two tumours with a predilection for the mesial temporal lobe commonly cause drug-resistant focal epilepsy: dysembryoplastic neuroepithelial tumour (DNT) and ganglioglioma. These are both classified as ‘low-grade’ tumours, meaning that they are benign and slow-growing (see Ch. 5).

Microscopic examination shows a mixture of immature neurons and glial cells. In DNT, the main glial component consists of oligodendroglia-like cells (OLCs) (Fig. 11.13). The characteristic elements in ganglioglioma are ganglion cells, large neurons with rounded cell bodies and large nuclei. In 50% of cases binucleate ganglion cells can be found. Epileptiform discharges sometimes originate from abnormal neurons within the tumour itself and in other cases result from disturbance to the perilesional cortex, which is often removed together with the tumour.

Fig. 11.13 Microscopic appearances of dysembryoplastic neuroepithelial tumour (DNT).
Rows of cells with round nuclei (oligodendroglia-like cells or OLCs) can be seen lining up on either side of a large, mucin-filled lake. A ‘floating neuron’ with a large nucleus and prominent nucleolus is present with the mucin lake. Astrocytic cells (with a spidery appearance) can also be identified. This overall pattern is referred to as the ‘specific glioneuronal element’ and is diagnostic of DNT. (Routine haematoxylin and eosin staining.)

Key Points

There are no specific pathological features in primary generalized epilepsy. In focal epilepsy the three common findings are: hippocampal sclerosis, cortical malformations and benign tumours (such as DNT and ganglioglioma).

Hippocampal sclerosis is the most common pathology encountered in epilepsy surgical specimens, accounting for 65% of cases. There is neuronal loss and gliosis in Ammon’s horn (particularly the CA1 subfield) accompanied by mossy fibre sprouting and granule cell dispersion.

In 90% of cases of HS there is evidence of an initial precipitating insult (e.g. a febrile convulsion) with a variable latent interval before seizure onset (usually <10 years).

It is not clear if the early-life event damages the hippocampus or if a pre-existing developmental abnormality is responsible for both the febrile convulsions and the subsequent epilepsy.

Partial seizure mechanisms

It was traditionally assumed that epilepsy resulted from a simple imbalance between excitatory and inhibitory influences in the brain (Fig. 11.14). It is now regarded as a network phenomenon that arises from abnormal synchronized discharges in large neuronal assemblies. Reseach (in animal models) has shown associated changes in connectivity, receptors and ion channels.

Fig. 11.14 The classical concept that epilepsy results from an imbalance between excitatory and inhibitory influences is now known to be a gross over-simplification.

Animal models of epilepsy

Experimental models of epilepsy are extremely important for the development and screening of novel anti-epileptic drugs and for the investigation of partial seizure mechanisms.

Acute seizure models

There are a number of acute models that can be used to induce seizures in non-epileptic experimental animals. One option is to use a chemoconvulsant substance (e.g. picrotoxin, kainic acid, pilocarpine, strychnine, penicillin or pentylenetetrazole) which can be administered in different ways such as subcutaneous injection or direct application to the cortical surface. Another is to use focal electrical stimulation, such as the maximal electroshock (MES) method in which mice or rats receive an electrical stimulus that is just strong enough to cause maximal seizure activity. This is widely used in the screening and assessment of potential anti-epileptic drugs.

Acute seizure models are used to simulate a range of epilepsies including generalized tonic-clonic, myoclonic and absence seizures. Prolonged stimulation (e.g. with pilocarpine) may induce status epilepticus (seizure activity lasting more than 30 minutes; see Clinical Box 11.10). This leads to changes in the medial temporal lobe that are similar to those seen in human temporal lobe epilepsy.

Clinical Box 11.10: Status epilepticus

A patient is said to be in status epilepticus if seizure activity persists for more than 30 minutes. This may be the result of a single prolonged seizure or serial seizures with no intervening recovery of consciousness. The seizures may be of any type. Complex partial status epilepticus (or epilepsia partialis continua) sometimes presents with bizarre behavioural disturbances that may mimic a psychiatric disorder. Generalized convulsive status epilepticus is a medical emergency with a mortality of 10–20%. This may be due to hyperthermia, metabolic derangement, prolonged hypoxia or acute brain injury. If seizure control cannot be gained with intravenous anticonvulsant agents then general anaesthesia may be required.

Chronic seizure models

Chronic seizure models are useful not only to investigate the acute events involved in seizure onset and termination, but also the interictal events, including long-term changes in synaptic connections, receptor subunit composition and peptide expression.

A popular animal model of temporal lobe epilepsy is called kindling, which alludes to the process of starting a fire. In this method, an electrode is used to deliver a repetitive, low-frequency electrical stimulation to the medial temporal region of a rodent (e.g. within the amygdala or hippocampus; see Ch. 3). The current is not sufficient to cause a seizure, but sustained electrical stimulation over a period of time eventually leads to epileptiform discharges, together with a long-lasting susceptibility to further stimulation or even spontaneous seizures. It is thought that repetitive stimulation leads to abnormal recruitment of synaptic strengthening mechanisms (long-term potentiation or LTP) that are involved in learning and memory (see Ch. 7).

Genetic seizure models

A number of genetic models of chronic epilepsy also exist. These include naturally occurring animals that are genetically predisposed to epileptic seizures: either spontaneously or as a result of various types of stimulation (e.g. audiogenic epilepsy, which is triggered by sudden loud noises). These are available in numerous species including mice, rats, gerbils and dogs and the range of seizure types is wide. There are also various transgenic or genetic knockout mice models of epilepsy (e.g. inhibitory neuropeptide ‘knockout’ mice that have spontaneous epileptic seizures).

Electrical basis of epilepsy

Electrical recordings in animal models of epilepsy have identified abrupt shifts in the resting membrane potential of hippocampal neurons: the paroxysmal depolarization shift (PDS). An inward sodium current (mediated by voltage-gated ion channels) is followed by a prolonged, calcium-dependent depolarization. The PDS lasts ten times longer than a normal action potential and is associated with an intense burst of nerve impulses. It is terminated by calcium-sensitive potassium channels which repolarize the neuronal membrane. A prolonged period of after-hyperpolarization then follows (see Ch. 6). When a paroxysmal depolarization shift occurs simultaneously in several million cortical neurons it can be detected by scalp electrodes as an interictal spike. If the abnormal activity spreads over a large enough cortical area (more than a few centimetres in the human brain) it may develop into a seizure.

Key Points

Experimental models of epilepsy are important for the development and screening of new anti-epileptic drugs and for investigating partial seizure mechanisms.

Acute seizure models (e.g. using chemoconvulsant agents or maximal electroshock stimulation) can be used to induce seizures in non-epileptic experimental animals.

Chronic seizure models (e.g. the kindling model of temporal lobe epilepsy) allow the study of interictal events and long-term changes in neurons, synapses and receptors.

Genetic epilepsy models are available in a range of species, some of which are naturally occurring and others that have been specially bred (e.g. transgenic mice).

Recordings in animal models of epilepsy show that interictal spikes are associated with calcium-mediated paroxysmal depolarization shifts in the neuronal membrane.

Pathophysiology of epilepsy

Much of the experimental work on epileptogenesis has focused on the mesial temporal region, from which 60% of seizures originate. The main contributing factors are discussed in the following sections.

Increased excitation/decreased inhibition

Seizures can be provoked in animal models by blocking inhibitory (GABAergic) neurotransmission and in 80% of cases the abnormal discharges originate in the hippocampus. Loss of inhibition may therefore contribute to temporal lobe epilepsy in humans.

The activity of hippocampal neurons within the dentate gyrus is normally restrained by a population of inhibitory interneurons called basket cells. Basket cells are in turn excited by mossy cells, located in the hilum of the dentate gyrus. A proposed mechanism contributing to temporal lobe epilepsy is the selective death of hilar mossy cells, reducing excitatory drive to basket cells and releasing hippocampal neurons from their normal state of inhibition: the dormant basket cell hypothesis.

Alterations in connectivity

The axons of dentate granule cells (mossy fibres) normally extend into the hilum of the dentate gyrus and synapse on CA3 pyramidal neurons. In hippocampal sclerosis new axons arise from the granule cell layer in a process referred to as mossy fibre sprouting. Importantly, these new processes form aberrant, potentially self-excitatory connections within the granule cell layer that may promote seizure activity (Fig. 11.15). Abnormal connectivity of inhibitory interneurons might also contribute to epileptogenesis by encouraging synchronized bursting in groups of excitatory neurons (Fig. 11.16). This might help to explain why powerful inhibitory agents exacerbate some forms of epilepsy.

Fig. 11.15 Mossy fibre sprouting in hippocampal sclerosis.
Immunohistochemistry for the neuropeptide dynorphin shows newly sprouted mossy fibres emerging from the granule cell layer (dashed line). These may form aberrant, self-excitatory connections (inset).

Fig. 11.16 Abnormal synchronization may be triggered by inhibitory neurons.
Powerful activity in an inhibitory interneuron with divergent projections may inhibit several excitatory neurons simultaneously **(A)** leading to synchronous discharge as they all recover at the same moment **(B)**.

Changes in receptors and ion channels

A number of seizure-associated alterations have been observed at the neuronal cell and receptor level, including changes in the pattern of action potential firing. This has led to the concept of the epileptic (bursting) neuron. It appears that previously normal pyramidal neurons can change their behaviour during epileptogenesis to become ‘bursters’. This probably results from alterations within ion channels (or changes in their subunit composition) in the neuronal cell body. Synchronization can also be facilitated by the addition or strengthening of direct intercellular bridges between neurons called gap junctions (see Ch. 7).

Changes in inhibitory peptides

The hippocampus is richly supplied by axon terminals releasing inhibitory neuropeptides including neuropeptide Y, somatostatin, enkephalins and dynorphin. These are co-released with classical neurotransmitters and have powerful anti-convulsant properties. This is mediated by changes in second messenger cascades and increase or decrease in cytosolic substrates such as cyclic AMP (cAMP). Genetically engineered ‘knockout’ animals with reduced or absent expression of inhibitory peptides show markedly reduced seizure threshold or spontaneous seizures and there is evidence for alterations in neuropeptide expression in human epilepsy.

The role of astrocytes

Astrocytes may play a direct role in epileptogenesis, contributing to the generation of brief, high-frequency discharges called very fast oscillations (VFOs). This is thought to depend upon the presence of gap junctions between astrocytes. These allow depolarizing currents to pass freely between cells, generating oscillations at frequencies of 80–200 Hz. These oscillations (also called ripples) are normal in the hippocampus, but pathological in the neocortex and have been detected prior to focal seizure activity. Oscillations have also been recorded in human brain tissue removed during epilepsy surgery and gap junction inhibitors have been shown to possess anti-convulsant properties in animal models.

Key Points

Epilepsy is a ‘network phenomenon’, caused by abnormally synchronized electrical discharges originating in interconnected groups or assemblies of cortical neurons.

Epileptogenic networks show many pathological changes including: increased excitation, decreased inhibition, changes in receptors and ion channels or loss of peptide inhibition.

Astrocytes may play a direct roll in epileptogenesis, contributing to the development of very fast oscillations or ripples (80–200 Hz) mediated by gap junctions.

Mechanism of absence seizures

Unlike most forms of primary generalized epilepsy, the mechanism in absence seizures is well understood. It is due to derangement of a rhythmic pattern of oscillations that normally occurs between the cortex and thalamus during sleep. This creates the typical spike and wave discharge seen on the EEG (Fig. 11.17).

Fig. 11.17 Spike and wave discharges in absence seizures.
The abnormal discharges emerge from a normal background EEG trace at a typical frequency of 3 Hz (cycles per second).

The thalamic relay and sleep

The thalamus acts as the ‘gateway’ to the cerebral cortex and contains specific thalamocortical relay nuclei for all sensory modalities apart from olfaction (see Ch. 3). Thalamocortical neurons projecting to the primary sensory areas of the cortex can be said to operate in two modes:

During wakefulness (Fig. 11.18A) they are tonically active, transmitting sensory information to the cortex. Excitatory noradrenergic and cholinergic projections from the diffuse neurochemical systems of the brain stem (see Ch. 1) contribute to their excitation.

Fig. 11.18 The thalamocortical relay (A) during wakefulness and (B) during sleep.

During sleep (Fig. 11.18B) thalamocortical sensory relay neurons are quiescent. This is due to reduced peripheral afferents (in a dark, quiet environment) and decreased activity in the diffuse projections from the brain stem.

Sleep-associated hyperpolarization (inhibition) of thalamocortical neurons triggers a rhythmic pattern of oscillations between thalamus and cortex. This normally appears on the EEG as the sleep spindle, characterized by regular bursts of activity at a frequency of 12–14 Hz (cycles per second).

Origin of thalamic bursting

The sleep spindle depends upon a hyperpolarization-dependent cation channel which is expressed by thalamocortical neurons. The resting membrane potential for thalamocortical neurons is –60 mV and the reversal potential (see Ch. 6) for the hyperpolarization-dependent channel is –30 mV. Opening of the hyperpolarization-dependent channel therefore causes depolarization of thalamocortical cells (from –60 mV to –30 mV).

Co-recruitment of a second hyperpolarization-dependent channel, a T-type calcium channel, enables calcium as well as sodium to enter thalamocortical neurons. This triggers a burst of action potentials both in the thalamic neurons and in the cortical regions to which they project. Once the membrane of the thalamocortical neuron is fully depolarized (to –30 mV) both hyperpolarization-dependent channels close. The membrane is then repolarized to its resting value of –60 mV (by a calcium-sensitive potassium channel) and the oscillating cycle of depolarization and repolarization begins again.

Origin of absences

In absence seizures, inappropriate activation of the sleep spindle mechanism is believed to occur when thalamocortical relay neurons are hyperpolarized in the waking state (thereby triggering the hyperpolarization-dependent channels). This creates a burst of thalamocortical oscillating activity that blocks transmission of information to the cerebral cortex, since the thalamic ‘gateway’ is temporarily closed. The cortex is therefore briefly deprived of peripheral sensory input, manifesting as an ‘absence’.

Inhibition comes from the reticular nucleus of the thalamus which utilizes the inhibitory neurotransmitter GABA (Fig. 11.19). This nucleus appears to be stimulated by a hyperexcitable focus in the primary somatosensory cortex. In keeping with this idea, absence seizures can be triggered by cortical excitation in animal models, but only if thalamocortical connections are intact. This also explains why the calcium-channel antagonist ethosuximide is effective in the treatment of absence seizures.

Fig. 11.19 Mechanism of absence seizures.
It is thought that the inhibitory reticular nucleus may be stimulated by a hyperexcitable focus in the primary sensory cortex. This powerfully inhibits the thalamus and triggers the sleep spindle oscillations inappropriately in the waking state.

Key Points

Childhood absence seizures are a form of primary generalized epilepsy characterized by spike and wave discharges on the EEG at a frequency of 3 Hz.

Absence seizures are thought to represent inappropriate activation of the sleep spindle in the waking state, triggered by hyperpolarization of thalamocortical relay neurons.

This leads to activation of two hyperpolarization-dependent channels in the thalamus (a cation channel and a T-type calcium channel) which sets off the abnormal thalamocortical oscillations.

Inhibition (hyperpolarization) comes from the reticular nucleus of the thalamus which may in turn by activated by discharge from a hyperexcitable region in the primary sensory cortex.

The thalamocortical model of absence seizures explains many of the key features, including the effectiveness of the calcium-channel antagonist ethosuximide.

Sudden death in epilepsy

The overall mortality rate in people with epilepsy is 2–3 times higher than that of the general population. In some cases this is due to progression of an underlying disease process (such as a brain tumour) but may also be the result of accidental injury, drowning or suicide.

Seizures are not generally life-threatening, provided that the airway is protected and that oxygenation is adequate. However, the risk of sudden death is 20–30 times higher than in non-epileptic controls and there is a well-recognized syndrome of sudden unexpected death in epilepsy (SUDEP). This excludes deaths due to status epilepticus (see Clinical Box 11.10) and can only be diagnosed when the following criteria are met (see also Fig. 11.20):

Fig. 11.20 Sudden unexpected death in epilepsy (SUDEP): checklist for diagnosis.

Sudden unexpected death in a person known to have epilepsy.

No evidence of accidental injury or drowning.

No alternative cause of death identified at autopsy.

SUDEP is most commonly seen in young adults with poorly controlled tonic-clonic seizures. It is more common in males and is associated with the use of multiple anti-epileptic drugs, poor compliance and alcohol misuse.

Cause of death

The mechanism of death in SUDEP is uncertain, but cardiorespiratory abnormalities are known to occur in temporal lobe epilepsy, including: cardiac dysrhythmias (disturbances of heart rhythm), apnoea (cessation of respiration) and hypoxaemia (low blood oxygen levels). In particular, there is evidence that seizures originating from the insula and amygdala (which have powerful visceral and autonomic projections; see Ch. 3) may lead to episodes of asystole (cardiac standstill).

Key Points

The mortality rate in people with epilepsy is 2–3 times higher than that of the general population, attributable to accidental deaths, underlying disease processes, status epilepticus and SUDEP.

Status epilepticus is a continuous state of seizure activity that lasts for at least 30 minutes without recovery of consciousness. Convulsive status epilepticus is a medical emergency with a mortality of 10–20%.

Diagnosis of SUDEP requires a post-mortem examination (showing no alternative cause of death) and excludes accidental death and status epilepticus.

The cause of death in SUDEP is uncertain but may reflect inhibition or disturbance of brain stem cardiac or respiratory centres, leading to respiratory or cardiac arrest.

Psychological aspects

The differential diagnosis for epileptic seizures is wide (Fig. 11.21) and includes non-epileptic attacks of psychological origin (Clinical Box 11.11). There are a number of other psychological aspects to consider in patients with epilepsy, including a significant impact on leisure activities and occupation and an association with psychiatric illness.

Clinical Box 11.11: Psychogenic (non-epileptic) attacks