Jonathan M. Schott 24.5 Epilepsy and disorders of

Jonathan M. Schott 24.5 Epilepsy and disorders of consciousness 5860 24.5.1 Epilepsy in later childhood and adulthood 5860

24.5 Epilepsy and disorders of consciousness CONTENTS 24.5.1 Epilepsy in later childhood and adulthood  5860 Arjune Sen and M.R. Johnson 24.5.2 Narcolepsy  5882 Matthew C. Walker 24.5.3 Sleep disorders  5886 Paul J. Reading 24.5.4 Syncope  5896 Andrew J. Larner 24.5.5 The unconscious patient  5901 David Bates 24.5.6 Brainstem death and prolonged disorders
of consciousness  5908 Ari Ercole, Peter J. Hutchinson, and John D. Pickard 24.5.1  Epilepsy in later childhood
and adulthood Arjune Sen and M.R. Johnson ESSENTIALS Epilepsy is a common, serious neurological disease, with a preva- lence 1% and a cumulative lifetime risk of 5%. An epileptic seizure is a transient occurrence of signs and/​or symptoms due to abnormal excessive or synchronous neuronal ac- tivity in the brain. Epilepsy is defined as a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures and by the neurobiological, cognitive, psychological, and social consequences of this condition. Traditionally epilepsy was diagnosed after a patient had two or more unprovoked seizures. However, a more modern definition of epilepsy would also include patients who have had an isolated seizure and have evidence for an enduring alteration in the brain that increases the likelihood of future seizures such as an ‘epileptiform’ electroencephalogram abnormality or an appropriate lesion on structural brain imaging (computed tomography or mag- netic resonance imaging). Epilepsy cannot, though, be diagnosed unless there has been at least one clinical event compatible with an unprovoked seizure. Pathophysiology Epileptic seizures are thought to arise at cortical sites. Focal (previ- ously referred to as partial) seizures begin in one part of the brain; generalized seizures infer widespread, bilateral cortical involve- ment from onset. Underlying mechanisms have been best defined for generalized absence seizures, where a thalamocortical circuit is responsible for generating synchronous burst firing of neur- ones. In different types of epilepsy, roles for specific ion channels
(e.g. voltage-​dependent calcium channel, (T-​channel)), recep- tors (e.g. GABAA-​receptors), and neurotransmitters (e.g. serotonin) have been suggested, but modern genetic research is increasingly implicating other aspects of synaptogenesis in the aetiology of epi- lepsy. Epilepsy may occur solely as the result of an inherited predis- position (formally referred to as ‘idiopathic epilepsy’ but increasingly referred to as ‘genetic epilepsy’), or as a consequence of a congenital or environmentally acquired brain injury. Genetic inheritance is complex for most genetic epilepsies, although important mendelian disorders are recognized. Clinical features—focal seizures Epileptic seizures can be variously classified in terms of their ana- tomical substrate (focal, multifocal, or generalized) or according to the extent of functional impairment, focal impaired awareness aware. Focal impaired aware seizures are not synonymous with temporal lobe seizures and may occur with focal seizures arising from elsewhere in the brain. Examples of focal aware seizures in- clude focal sensory or motor seizures, occipital lobe seizures with visual hallucinations, mesial temporal seizures including transient disturbances of memory such as déjà vu or other psychic phe- nomena, or lateral temporal seizures involving simple auditory hal- lucinations. Focal seizures with impaired awareness are those with altered or loss of conscious awareness. In the case of temporal lobe seizures various automatic activities or movement (automatisms) may occur (of which the patient is unaware). Temporal lobe focal impaired awareness seizures usually evolve slowly over seconds to minutes, whereas other focal seizures, such as those arising from frontal lobes, may have abrupt onset.

24.5.1  Epilepsy in later childhood and adulthood 5861 Clinical features—​generalized seizures These include (1) bilateral tonic–​clonic seizures—​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—​activity suddenly ceases (behavioral and speech arrest) for 10–​20 s, but without loss of posture. (3) Myoclonic seizures—​ brief, shock-​like contractions of muscle, occurring either in a gen- eralized or focal distribution. (4) Atonic seizures—​result in sudden loss of muscle tone and patients may crumple to the floor like a rag doll. (5) Tonic seizures—​associate with patients having sudden posturing of the arms or falling stiffly like a tree being felled. The terms ‘grand mal’ for tonic–​clonic seizures and ‘petit mal’ for ab- sence seizures should no longer be used. Status epilepticus—​defined as a single prolonged seizure or suc- cessional seizures without recovery of consciousness between attacks. The duration of continuous seizure activity that should be treated as status epilepticus has been recently redefined and is ex- plored more formally in this chapter. Investigation First seizures should be assessed from a general medical perspec- tive, with urgent and careful consideration given to the possibility of an underlying life-​threatening condition such as encephalitis. Acute underlying medical emergencies (stroke, encephalitis, meta- bolic precipitants, most particularly hypoglycaemia, arrhythmia, and forth) should be carefully excluded. All patients with a suspected first seizure must have an electrocardiogram (ECG). Subsequent key investigations are often electroencephalography and structural imaging (usually magnetic resonance imaging). The diagnosis of epilepsy confers important implications and should be made by an epilepsy-​competent service. Treatment Whether the patient requires anti-epileptic drugs or not is judged on the likelihood of having further seizures, For a patient with a single generalized tonic–​clonic seizure, no risk factors for seizures, normal electroencephalogram, and normal MRI brain imaging, their chance of further seizures is approximately 50% over the next two years, with the bulk of the risk falling within the first 6 months after the first seizure. If all such patients with a first seizure were treated, then approximately 50% of patients will have been treated unneces- sarily as they were not destined to have a further seizure. However, if a first seizure is associated with a clear epileptiform abnormality on the electroencephalogram, or occurred in the presence of an appropriate structural brain lesion (such as a tumour), treatment with antiepileptic drug therapy may be indicated. Epidemiological studies have shown that the presence of two or more seizures in- dicates a high risk of further seizures, and it is this epidemiological principle that informs the usual practice to treat following a second
epileptic seizure. Treatment decisions should be made by an epilepsy-​ competent service, and carefully considered and discussed with the patient. Patients with first seizures or epilepsy must be informed of driving regulations. The choice of anticonvulsant is informed by individual patient circumstances, as well as national and local guidelines such as those from the UK National Institute of Health and Clinical Excellence. Broadly, for generalized epilepsy (tonic–​clonic, absence, or myoclonic) sodium valproate is an appropriate first choice in men. In women of childbearing potential and generalized epilepsy, lamotrigine or levetiracetam are often considered as first-​line agents. For focal seiz- ures, with or without generalization, carbamazepine, lamotrigine, and levetiracetam are probably the drugs of choice. Many new antiepileptic drugs have been introduced over the last 20 years: each has an individual role and profile of unwanted effects. Antiepileptic drug therapy can pose specific problems in relation to pregnancy, drug withdrawal, driving and long-​term adverse effects (such as increased fracture risk) requiring expert management. Status epilepticus is a medical emergency and special consider- ations apply. Definitions An epileptic seizure is a transient occurrence of signs and/​or symp- toms due to abnormal excessive or synchronous neuronal activity in the brain. Epilepsy is therefore a disorder of neuronal networks and is defined as a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures and by the neurobio- logical, cognitive, psychological, and social consequences of this condition. The definition of epilepsy requires the occurrence of at least one epileptic seizure and evidence for an enduring alteration in the brain that increases the likelihood of future seizures such as an ‘epileptiform’ electroencephalogram (EEG) abnormality, an appro- priate lesion on structural brain imaging (CT or MRI), or the pres- ence of recurrent (two or more) unprovoked seizures. Excluded are febrile seizures and neonatal seizures (the latter are defined as those occurring in the first 4 weeks of life), and acute symptomatic seizures such as those arising from acute brain injury or hypoglycaemia. Epidemiology Incidence Most reported incidence rates for epilepsy lie between 40 and 70/​ 100 000. Age-​specific rates show a bimodal distribution, with the first peak in the first two decades, and a second peak in later life. In the developed world the incidence is highest in the older popu- lation and as populations age across the world, the prevalence of epilepsy will rise. Prevalence Prevalence figures for epilepsy lie between 4 and 10/​1000, with higher rates in low to middle income countries. Cumulative inci- dence (or lifetime prevalence) rates, excluding febrile seizures, are higher, producing a figure up to 5% in old age. Sex Males have slightly higher prevalence rates than females. Socioeconomic status Higher prevalence rates have been reported in the lower socio­ economic groups, in both developed and developing countries.

section 24  Neurological disorders 5862 Pathophysiology Inherent in any discussion of epilepsy mechanisms is the need to de- fine 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: focal seizures begin at one point in the cortex and generalized seizures infer widespread, bilateral, cortical involvement from the start. An interictal discharge occurs when a group of pyr- amidal neurons is synchronously activated. During the discharge, the cells develop a large and prolonged depolarization, which is termin- ated 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 re- sponsible for generating synchronous burst firing of neurons. The cir- cuit 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 mechan- isms of generalized convulsive seizures. Roles for GABAA-​receptors and altered serotoninergic neurotransmission have been suggested. Recently, inflammatory mechanisms have been implicated in both the occurrence of focal epilepsy following brain injury and in main- tenance of focal epilepsy, which may provide future opportunities for disease modification in epilepsy and potentially even prevention of epilepsy in high-​risk groups. Classification In 2010 the ILAE (International League against Epilepsy) revised the previously widely accepted 1981 classification of epilepsy. The new classification has been much more controversial than its predecessor and has struggled to gain universal acceptance. A further modification to try and ensure more clarity was made in 2017. Given these changes, the ILAE have therefore created an online guide to help with classifica- tion and terminology (https://​www.epilepsydiagnosis.org/​index.html) In essence, epilepsy can be divided into generalized epilepsy where there are discharges in both hemispheres, although these can be asym- metric, or focal epilepsy where discharges begin in one hemisphere and may spread or secondarily generalize to involve both hemispheres (Table 24.5.1.1). Traditionally focal seizures where consciousness was not impaired were termed ‘simple partial seizures’ and those where consciousness was impaired (or there was any loss of contact with environs) were termed ‘complex partial seizures’. In the 2010 classi- fication, the latter were termed focal dyscognitive seizures and such seizures are now termed focal impaired awareness seizures. However, although it has wide ranging implications (e.g. for driving) it can be very difficult to determine whether consciousness is affected during a focal seizure. While remaining a source of active discussion, many now term seizures which have a focal onset ‘focal seizures’ and then comment on whether, as best as can be determined, there is or is not loss of awareness. The 2017 classification tried to operationalise this while acknowledging that further delineation beyond a seizure having focal onset might be difficult. Previous simple partial seizures should now be referred to as focal aware seizures while complex partial/focal dyscognitive seizures should be termed focal impaired awareness seiz- ures. Secondary generalized seizures are now called 'focal to bilateral tonic clonic' and if it is not possible to determine the type of seizure this should be referred to as an unclassified seizure. The 2010 classification had proposed that generalized epilepsy be named ‘genetic generalized epilepsy’ rather than ‘idiopathic gener- alized epilepsy’. Clinicians have found this difficult as the underlying genetic basis for generalized epilepsy is still being disentangled and defining a condition as common as generalized epilepsy as ‘genetic’ might engender concern and stigmatization in patients. In the current chapter, ‘focal epilepsy’ will be used for seizures arising from a focus and ‘generalized epilepsy’ for seizures with bi-​ hemispheric origin. The terms ‘cryptogenic’, ‘symptomatic’, ‘petit mal’ and ‘grand mal’ should all now be avoided. Despite disagreements over terminology, every effort should be made to define each seizure type a patient experiences, even if in descriptive rather than technical language, to determine the underlying aetiology of the epilepsy and to classify a patient’s epilepsy as far as practicable. Clinical features Focal seizures Focal motor seizures Any part of the body can be affected by a focal motor seizure, ac- cording to the cortical site of origin of the discharge. Sometimes the seizure remains localized to the same area (e.g. the hand) and some- times it ‘marches’ along the motor cortex, producing successional Table 24.5.1.1  Summary of classification of epilepsy, 2017 I. Focal seizures A. Without impairment of consciousness or awareness (previously termed simple partial seizures)

1. With motor onset (automatisms, atonic, clonic, epileptic spasms, hyperkinetic, myoclonic, tonic)
2. With nonmotor onset (autonomic, behaviour arrest, cognitive, emotional, sensory) B. With impairment of awareness (previously termed complex partial seizures) C. Focal seizures evolving to bilateral tonic-clonic seizure (previously termed secondarily generalized seizure) II. Generalized seizures Motor (tonic-clonic, clonic, tonic, myoclonic, myoclonic-tonic-clonic, myoclonic-atonic, atonic, epileptic spasms) Nonmotor/absence (typical, atypical, myoclonic, eyelid myoclonia) III. Unknown onset Motor (tonic-clonic, epileptic spasms) Nonmotor (behaviour arrest) IV Unclassified (seizures where it is not possible to be more specific owing to inadequate information or inability to place in other categories) Motor (tonic-clonic, epileptic spasms) Nonmotor (behaviour arrest)

24.5.1  Epilepsy in later childhood and adulthood 5863 jerking of contiguous body parts (Jacksonian seizures). During the focal stage, consciousness is preserved. With secondary generaliza- tion (i.e. diffuse secondary 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, so isolated focal seizures of the foot, for example, are relatively un- common (the foot motor homunculus being relative small). Other focal motor disturbances reflecting epileptic discharges include ro- tation of the head and eyes contralaterally (from the dorsolateral prefrontal cortex), 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), but prolonged focal weakness following a seizure should not be automatically attributed to Todd’s paresis. Focal sensory seizures Seizures emanating from the sensory cortex produce paraesthesiae or numbness. The seizure can march in an analogous fashion to a motor seizure and, similarly, can then become generalized. When the tongue or face is involved, the symptoms are sometimes felt bilat- erally. 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 com- plex, 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 hal- lucinations may occur. Frontal lobe seizures Frontal lobe seizures are commonly nocturnal and frequently as- sociated 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, bicycling leg movements, and head movements. Rapid postictal recovery is common. Temporal lobe seizures The distinction between different types of focal seizures is blurred, based as it is on evidence of altered consciousness (Fig. 24.5.1.1). Olfactory, gustatory, and vertiginous sensations occur. The taste and smell sensations are sometimes pleasurable but often disagree- able. A metallic taste is common. Abdominal sensations also occur, which are typically ill-​defined, and may ascend to the chest and throat from the epigastrium. Psychic symptoms are more often as- sociated with focal seizures with loss of awareness. There may be intense pleasure or fear ushering in the attack. The patient can ex- perience a sense of loss of personal or environmental reality (de- personalization and derealization, respectively). There may be a sense of intense familiarity (déjà vu) or unfamiliarity (jamais vu). Pg1 Pg2 F3 Fz F4 F8 T3 O2 C3 C2 C4 C T4 T6 P4 Pz P3 T5 F7 O P 4 Fp1 Fp2 Fp2–F8 100 µV F8–T4 T4–T6 T6–O2 Fp1–F7 F7–T3 T3–T5 T5–O1 T4–C4 C4–Cz Cz–C3 C3–T3 T4–RSp RSp–LSp LSp–T3 1 s ECG1–ECG2 03/03/1992 LF = 0.5 Hz HF = 40 HZ File D: \LASER\pp001.P01 23:21:57 23:21:58 23:21:59 23:22:00 23:22:01 23:22:02 23:22:03 23:22:04 23:22:05 23:21:56 Fig. 24.5.1.1  Ictal spike and slow-​wave complex in a patient with focal impaired awareness seizures. The discharges are particularly apparent over the left temporal lobe (T3 to T5), but there are some independent discharges over the right temporal lobe (T4 to T6). Record kindly provided by Professor David Fish.

section 24  Neurological disorders 5864 Epileptic déjà vu is typically unpleasant. Epileptic anger is un- provoked and rapidly subsides and tends to associate with other features of temporal lobe epilepsy such as olfractory or gustatory halluncinations. Illusions are encountered, in the form of dis- ordered 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. Manual au- tomatisms, if unilateral, tend to be ipsilateral to the seizure focus. 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 earlier. Sometimes automatic movements are also seen with absence seizures. Other, rarer focal seizure types are confined to childhood. In be- nign 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. In Panayiotopoulous syn- drome, which occurs in otherwise unaffected children, seizures are characterized by predominantly autonomic symptoms and seizures may be prolonged. The EEG shows variable and moving foci, often with occipital predominance. Any of the focal epilepsies can lead to secondary generalization. Consciousness is lost, and a bilateral convulsive 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 Bilateral tonic-clonic seizures Some patients report a premonition for hours or even days before the attack. These symptoms are usually a vague sense of loss of well-​being and do not necessarily imply a focal origin for the attack. Similarly, a brief aura lasting a few seconds before the onset does not necessarily imply focal origin for the attack (although it should raise this possi- bility). The tonic phase of a convulsion is associated with contraction of axial and then limb muscles. If upright, the patient can fall heavily. Injury is common. Contraction of the jaw can lead to tongue injury and in this context the tongue is frequently lacerated laterally or the inside of the cheek may be bitten. Forcible contraction of the dia- phragm 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 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. Absence seizures Patients are 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 s and are accompanied by a 3 Hz spike-​and-​wave discharge on EEG recording (Fig. 24.5.1.2). 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 child- hood and usually cease in adult life, although 50% of patients will later develop tonic–​clonic seizures. In some absence seizures there may be additional features such as eyelid myoclonia, a particular feature of Jeavon’s syndrome. Myoclonic seizures Myoclonus consists of brief, shock-​like contractions of muscle, occurring in either a generalized or a focal distribution. Cortical myoclonus is usually less than 50 msec in duration. Many forms of myoclonus are not epileptic. Those associated with epilepsy are ac- companied by an ictal EEG discharge. In primary generalized epi- leptic myoclonus, the myoclonus is accompanied by diffuse cortical epileptic discharges and has an early morning preponderance, usu- ally occurring within the first hour of two after waking, and more likely to occur if the patient is tired or has taken alcohol to excess. Atonic/​tonic seizures Atonic seizures result in sudden loss of muscle tone. If the hypotonia 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. Tonic seizures, which may be seen in conditions such as tuberous sclerosis, consist of sudden stiffening and posturing of arms or of abrupt falls to the floor. A  possible clinical distinction is that in atonic seizures patients crumple like a rag doll while in tonic seiz- ures, they fall like a tree being felled. Status epilepticus Status epilepticus has recently been redefined. Traditionally status epilepticus was defined as a single seizure lasting more than 30 min or successional seizures without recovery of consciousness between. However, there is now an appreciation that if a seizure is longer than 5 minutes in duration, then it should be treated aggressively. In status epilepticus, the seizures are usually convulsive, but both focal impaired awareness 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 in- dividual seizure types may be a manifestation of several differing

24.5.1  Epilepsy in later childhood and adulthood 5865 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) and age of onset. Causes of epilepsy In most surveys, approximately 60% of epilepsy will have no cause other than a genetic predisposition with other causes distributed mainly among cerebral vascular disease, trauma, brain tumour, central nervous system infection, and developmental disorders. Genetically determined What constitutes an epilepsy gene is a matter of considerable debate. For some genetically determined disorders, epilepsy is only one feature of the condition (for example Tuberous Sclerosis). Many such disorders have features other than epi- lepsy and typically produce significant neurological disability. Examples include forms of progressive myoclonic epilepsy such as those associated with Lafora body disease, mitochondrial disorders, and Unverricht–​Lundborg disease. More relevant, in clinical terms, are those genetically determined conditions in which epilepsy is the sole or major manifestation. Generalized epilepsies The generalized epilepsies (now sometimes termed genetic gen- eralized epilepsies) account for about 30% of all epilepsy. For the vast majority of patients with generalized epilepsy, inheritance is complex and, to date, no common genetic variant has been unequivocally associated with generalized epilepsy, although a few de novo rare mutations associated with the condition have been described. However, our knowledge of genetic risk factors for generalized epilepsy is likely to be transformed in the next few years through the widespread utilization of whole genome sequencing. Focal epilepsies Similarly, genetic focal epilepsies may arise as a result of both men- delian inheritance and (more commonly) complex inheritance. Several forms of familial (mendelian) 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 four Fp2–F4 100 µV F4–C4 C4–P4 P4–O2 Fp1–F3 F3–C3 C3–P3 P3–O1 Fp2–F8 F8–T4 T4–T6 T6–O2 Fp1–F7 F7–T3 T3–T5 T5–O1 1 s 22:41:23 22:41:24 22:41:25 22:41:26 22:41:27 22:41:28 22:41:29 22:41:30 22:41:31 22:41:32 Pg1 Pg2 F3 Fz F4 F8 T3 O2 C3C2 C4 C T4 T6 P4 Pz P3 T5 F7 O P 4 26/11/1992 LF = 0.5 Hz HF = 40 Hz File D: \ LASER \ hs004.P01 Fp2 Fp1 Fig. 24.5.1.2  Electroencephalogram (EEG) of a typical absence seizure. The first 2.5 s of the record are entirely normal. The event begins with a large downward deflection which records eye closure, immediately followed in all channels by a spike-​and-​wave discharge at a frequency of three cycles/​s. The seizure terminates as abruptly as it began. Record kindly provided by Professor David Fish.

section 24  Neurological disorders 5866 and eight 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 noc- turnal 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 charac- terized by focal seizures with auditory, visual, psychic, or dysphasic symptoms. In some families the condition is linked to mutations in the leucine-​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 chromo- somes 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 fe- brile 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 are structural brain de- fects 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—​ periventricular and subcortical nodular heterotopia and focal cortical dysplasia. The associated epilepsy tends to arise during childhood and adolescence. The seizures 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 focal cortical dysplasia. MRI can detect particular signal changes in focal cortical dysplasia, although specialized sequences are often 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 epi- lepsy 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 anticonvul- sants 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 developing epilepsy in adulthood, particu- larly 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 po- tentially suggestive of frontal lobe tumour. Cerebrovascular disease The prevalence of epilepsy after stroke has been reported to lie be- tween 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–​5% of cases. Differences in rate between countries are often attributed to the variable prevalence of certain aetiologies (e.g. neurocysticercosis). Other tropical infections that have been con- sidered potential contributors to epilepsy prevalence include mal- aria, schistosomiasis, and trypanosomiasis. Epilepsy is a recognized feature of bacterial, tuberculous, and fungal meningitis and of viral encephalitis. Epilepsy may be 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. Seizures are more common in patients with familial Alzheimer’s disease and, while epilepsy was previously considered secondary to neuronal loss in hippocampal structures, there is now evidence that seizures contribute to the aetiopathogeneisis of that neuronal loss. Multiple sclerosis The prevalence of epilepsy in multiple sclerosis (MS) is probably of the order of 2%. Both generalized and focal seizures have been at- tributed to MS. Rarely, status epilepticus, and epilepsia partialis con- tinua have been recorded. Antibody-​mediated epilepsy It is increasingly recognized that certain antibodies associate with epilepsy. In particular, limbic encephalitis associated with anti- bodies to components of the voltage-​gated potassium channel com- plex or to the N-​methyl-​d-​aspartate (NMDA) receptor can associate with seizures. Antibodies to the leucine-​rich glioma-​inactivated 1 protein (LGI1; the same protein implicated in auditory epilepsy) can result in very specific seizure type consisting of brief jerks of the arm and face with dystonic posturing and preservation of aware- ness (see Video 24.5.1.1). So termed facio-​brachio dystonic seizures are considered almost pathognomonic of LGI1 associated disease and treatment with steroids can prevent the patient progressing to a limbic encephalitis. Treatment of antibody-​mediated epilepsy is primarily directed at immunomodulation with steroids, immuno- globulin, plasma exchange and possibly other agents including rituximab and cyclophosphamide. Treatment with antiepileptic medication alone is unlikely to be effective and patients with anti- body-​mediated epilepsy are more prone to developing rashes with antiepileptic medication than other people with epilepsy. Alcohol Alcohol lowers seizure threshold. Seizures may occur during binge drinking or during a period of withdrawal after alcohol excess. Long-​term alcoholism may predispose to chronic epilepsy, although the extent to which this is due directly to the alcohol itself or to

24.5.1  Epilepsy in later childhood and adulthood 5867 the consequences of alcoholism, such as brain injury, are unclear. Patients with epilepsy should be counselled not to drink to excess, in particular to not binge consume alcohol and to remain within government recommended limits on alcohol consumption. Metabolic disorders Seizures may occur in association with hypocalcaemia, hyper­ calcaemia, hypomagnesaemia, hypoglycaemia, hyponatraemia, and hypernatraemia. Severe renal and hepatic failure can both precipitate seizures. Certain drugs are considered to lower seizure threshold and are relatively contraindicated in patients with epilepsy. Examples include the tricyclic antidepressants, the phenothiazines, and isoniazid. Rapid withdrawal of barbiturates or benzodiazepines (perhaps particularly clonazepam) can trigger seizures in those without a history of epilepsy. Precipitants of epilepsy Recognized precipitants of epilepsy include inadequate sleep, al- cohol abuse and ingestion of certain drugs. In catamenial epilepsy the attacks are confined to around the menstrual period. Seizures confined to sleep are well recognized and sleep EEG recordings are characteristically more likely to register abnormal discharges than recordings made in the alert individual. In reflex epilepsy, attacks are triggered by a particular stimulus. Precipitants include photic stimulation, startle, noise, and movement. Rarer forms of reflex epilepsy have been linked to musical passages, reading, eating, showering in hot water and performance of certain mental tasks (e.g. Mah Jhong epilepsy). Differential diagnosis Syncope Misdiagnosis of syncope as epilepsy is common, and many refer- rals to ‘first seizure’ clinics are for people who have had a syncopal blackout rather than an epileptic seizure. Syncope is thus an im- portant differential diagnosis of seizures, and familiarity with the clinical features of syncope is mandatory if diagnostic errors are to be minimized. Syncope tends to occur from the standing pos- ture and after exposure to provoking factors such as seeing blood or pain. Most individuals who faint experience a characteristic set of symptoms before loss of consciousness. These include feelings of light-​headedness, mental slowing, fading of vision, altered hearing (particularly sound diminution), 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 convulsive or tonic seizures, the fall is precipitate and injury much more likely. Not uncommonly, in faints, there may be brief clonic jerks of the limbs or multifocal myo- clonus, 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 weak- ness, but these rapidly resolve. If, on the other hand, the upright posture is maintained (e.g. a soldier on parade) then stiffness of the limbs or repetitive generalized shaking may occur which are virtu- ally indistinguishable from the movements occurring with epilepsy. Usually, however, a true tonic–​clonic sequence does not occur in these circumstances. Incontinence of urine is common in syncope, and on its own does not differentiate between syncope and seizures. Micturition syncope Micturition syncope occurs predominantly in older males, but can affect any age group. The attacks are almost always nocturnal, often 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 man- oeuvre during a bout of prolonged coughing. Treatment is directed at the underlying chest condition. Driving restrictions beyond those for simple vasovagal attacks apply. Cardiac syncope Various cardiac abnormalities, all having in common the end re- sult of failing cardiac 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 add- ition to disorders of rhythm, abnormalities of ventricular con- tractility or obstruction of outflow can have a similar outcome, usually when increased output is required during a period of ex- ertion. 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 dis- ease, palpitations, dyspnoea, or chest pain in association with the attack and the finding of cardiac abnormalities on clinical exam- ination. This exemplifies the need for all patients with a presumed first seizure to have a thorough cardiological examination and an electrocardiogram (ECG). Separate from these mechanisms are cases of syncope associated with postural hypotension. Autonomic failure resulting in pos- tural hypotension is a feature of multiple system atrophy, certain neuropathies with autonomic fibre involvement, such as diabetes, and drug therapy (e.g. with phenothiazines and tricyclic antidepres- sants). 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 atrioven- tricular block or asystole. Occasionally, a pure vasodilator reaction occurs, with peripheral pooling of blood. Notably, while tachycardia is common with seizures, some pa- tients become bradycardic or even asystolic following seizures and

section 24  Neurological disorders 5868 in patients with frequent seizures and concerning symptoms (pro- longed cyanosis after an event) there should be a low threshold for cardiac monitoring. Detection of significant ictal arrhythmia war- rants discussion with the cardiologists about consideration of pace- maker insertion. 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 dif- ficulty. It is rare for patients with transient ischaemic attacks to lose consciousness. The attacks are not influenced by anticonvulsants but can be relieved by endarterectomy where there is an underlying sig- nificant 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 sen- sations (typically bilateral), ataxia, and dysarthria. Typically the pa- tient, 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, paraesthesiae, 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 diag- nostic difficulty. Narcolepsy and cataplexy Narcolepsy is defined as excessive daytime sleepiness, often occurring under unusual circumstances. The onset of sleep is usu- ally 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 sub- sequently 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 di- verge, and the facial muscles flicker. Despite this, the patient usually remains fully alert. The parasomnias Parasomnias are largely confined to children. They consist of either abnormal motor activity or excessive autonomic activity. Motor ac- tivity includes sleep myoclonus, bruxism and head banging. Sleep myoclonus produces repetitive leg contraction, typically dorsi- flexion 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 typic- ally occur in clusters, are often accompanied by various forms of vocalization. In most cases, the child is otherwise unaffected. 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. Dissociative seizures Dissociative seizures, also termed non​epileptic attacks or psycho- genic non​epileptic seizures, sometimes occur in isolation, or less frequently in those with epilepsy. They account for up to 20% of the patients referred to specialist epilepsy units, usually with a diagnosis of refractory epilepsy. The condition is more common in women than in men, although both sexes are affected. People with dissocia- tive seizures may have a past personal history of psychiatric disorder, a history of suicide attempt(s), evidence of sexual maladjustment, and current depressive symptoms. Certain features from the history should alert the physician to the diagnosis. The attacks more commonly take place with witnesses present. They develop gradually rather than suddenly, and the move- ments displayed are often unpredictable and bizarre. The eyes are usually closed during the attacks. Attempts to constrain the patient may be resisted, or there is other evidence for consciousness during the attack such as being able to squeeze the hand of a bystander if asked to or being able to recollect things during a period of reported loss of consciousness. Vocalization; incontinence, and tongue biting are commonly reported, and self-​injury is a recognized feature. Typically dissociative seizures are difficult to control. Obtaining a hand held video of an attack, which should only be done within the limits of safety, can be helpful, but in some cases videotelemetry is necessary to differentiate epileptic from non​epileptic seizures. Non​epileptic seizures are not voluntary and require treatment in their own right. That treatment should be psychologically rather than pharmacologically-​mediated. Early confirmation of the diag- nosis and referral to a skilled psychologist or psychiatrist is likely to improve outcome. 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 initiated the seizure and imaging may help determine the underlying structural process, where such exists. Cardiac examination and routine ECG should be undertaken in all patients with suspected epilepsy to avoid treatable structural or electrical abnormalities of the heart being missed. Electroencephalography (EEG) Certain caveats about the EEG must be understood before interpret- ation is attempted. Epileptiform discharges are encountered in be- tween 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 rou- tine EEG in adults with established epilepsy shows epileptiform ab- normalities in only 40 to 50% of cases. With repeat recording, with or without sleep records, the figure rises to 70–​80%. Therefore, some patients with unequivocal epilepsy will have persistently normal

24.5.1  Epilepsy in later childhood and adulthood 5869 or, at least, non​epileptic EEGs. Serial EEG recording is sometimes helpful in an attempt to define the origin of the seizure and to better delineate the seizure type. If photosensitivity is suspected (10% of in- dividuals with seizures occurring between 1 and 7 years are photo- sensitive), serial recordings are appropriate, as they also are in any individual with atypical status or in whom cognitive impairment might be due to subclinical epileptic activity. Where surgical inter- vention is being planned for epilepsy, routine and sleep recordings are followed by videotelemetry in order to record individual attacks. Magnetoencephalography (MEG) localizes focal epileptic discharges by measuring the changes in the extracranial magnetic fields that these discharges generate. The system costs around 25 times as much as a conventional EEG system and has limited availability. 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. For some patients, depth electrodes will be needed to establish the seizure source and define the epileptogenic zone. Depth electrodes are positioned stereotactically at sites determined by clinical and sur- face EEG criteria. Depth recordings are more accurate and sensitive in detecting focal discharges than scalp recording, but associate with a defined risk and careful consideration by a multidisciplinary team should be made before intracranial recording is performed. The EEG has also been used to attempt prediction of seizure recur- rence 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 re- cording. 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 abnor- malities 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 pro- cess, before the more widespread availability of MRI. MRI is advo- cated in all patients with epilepsy, other than for those epilepsies that are clearly generalised in onset (e.g. absence seizures, juvenile myoclonic epilepsy, and benign rolandic epilepsy) or when it is not practical to do so (e.g. severe learning disability, severe dementia). MRI MRI is both more sensitive and more specific than CT in detecting and defining brain lesions and abnormalities of the cerebral cortex thought to be relevant in the genesis of epilepsy, perhaps par- ticularly malformations of cortical development (Fig. 24.5.1.3). Protocols setting out to achieve high sensitivity and specificity re- quire T1-​weighted, thin-​slice volumetric sequences, T2 FLAIR (fluid-​attenuated inversion recovery), and high-​resolution T2 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 de- velopment, vascular malformations, tumours, and acquired cortical damage. MRI is particularly indicated in focal 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. MR spectroscopy (MRS), examining nuclei 31P and 1H, has been used for assessment of patients with focal seizures for possible sur- gery. Functional MRI is commonly used to localize the motor cortex before resection of adjacent neocortex, to lateralize language func- tion, and to help predict the consequences of temporal lobe resec- tion 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 path- ways. Although it has been assumed that the region with the most (b) (a) Fig. 24.5.1.3  (a) CT and (b) MRI: the readily visible cavernome on MRI is only just visible on CT.

section 24  Neurological disorders 5870 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 pa- tients with refractory focal epilepsy. FDG-​PET appears to be superior to standard MRI in the detec- tion 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) (Fig. 24.5.1.4). It appears that abnormalities in FMZVD are also linked to the pattern of recent seizure activity. 15O-​labelled water PET is likely 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 loca- tion of the seizure focus. Treatment: Drug therapy Choice of drug therapy Several principles can be stated in relation to drug therapy. Does the patient require anticonvulsants? The issue of whether isolated seizures should be treated remains un- resolved. 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 until at least investigations are complete. Were the EEG to show frank epileptiform discharge or the MRI show a salient lesion, further dis- cussions should be held about starting an antiepileptic drug. Similar discussions should take place after a second seizure even if investiga- tions are normal. It is important to engage the patient fully in these ini- tial discussions as antiepileptic medications are a long-​term treatment with potential side effects and good concordance with the medication is essential. For a patient who has very infrequent seizures, say five or more years apart, it may seem logical to withhold medication. Choice of anticonvulsant An algorithm can provide some guidelines regarding drug treat- ment (Fig. 24.5.1.5). For generalized seizures (tonic–​clonic, absence, or myoclonic) sodium valproate is the drug of choice in males with lamotrigine or levetiracetam being favoured in women of childbearing potential owing to the potential teratogenicity associated with sodium val- proate. Topiramate, zonisamide, and perampanel are also used in generalized epilepsy. Ethosuximdie can be very effective for absence seizures and clonazepam can help with myoclonic jerks. Myoclonus can be exacerbated by carbamazepine, gabapentin, pregabalin and, in some cases, lamotrigine. Absence seizures can be worsened by carbamazepine and gabapentin. For focal seizures, with or without generalization, carbamazepine, lamotrigine, and levetiracetam are first-​line agents. If one of these does not suit, then an alternative first-​line agent can be explored. Fig. 24.5.1.4  Positron emission tomography (PET) scan showing a region of probable cortical dysplasia in the right temporal lobe.
The [11C]fluamzenil volume of distribution (FMZVD) is an index of
γ-​aminobutyric acid A (GABAA)-​receptor density. Epilepsy diagnosis confirmed Generalised epilepsy (GGE/IGE) Focal epilepsy +/- secondary generalisation 1st line treatments: Valproate in men Lamotrigine/ Levetiracetam in women 1st line treatments: Carbamazepine Lamotrigine Levetiracetam If not seizure free: Alternative first line agent or Topiramate Perampanel Zonisamide If not seizure free: Alternative first line agent or Clobazam, Lacosamide, Oxcarbazepine, Perampanel, Topiramate, Zonisamide; Brivaracetam, Eslicarbazepine, Pregabalin, Gabapentin, Acetazolamide Clonazepam for myoclonus Ethosuximide for absence seizures Refer all pharmacoresistant focal epilepsy to an epilepsy surgery programme Vagal nerve stimulation can be considered in pharmacoresistant focal epilepsy (if not candidate for resection) or refractory generalised epilepsy Specific treatments, e.g. ketogenic diet should be considered in selected cases Fig. 24.5.1.5  Basic schema of treatment options in epilepsy.

24.5.1  Epilepsy in later childhood and adulthood 5871 There are a myriad of second-​/​third-​line agents, including clobazam, eslicarbazepine, gabapentin, lacosamide, oxcarbazepine, perampanel, pregabalin, topiramate, and valproate. Phenytoin and phenobar- bitone are not drugs of choice for long-​term prescribing in modern epileptology. Choice, especially of adjunctive therapy, is often influenced by comorbidity and side effect profile. In addition, determining which drug to try will be influenced by the patient’s age, sex (regarding the use of oral contraceptives and likelihood of pregnancy), reliability of adherence to a particular drug regimen and the patient’s own wishes. Dosage Although standard dose regimens tend to be quoted, many anticon- vulsants are sometimes effective in relatively low doses. Accordingly the drug is introduced in low dosage, which is then gradually in- creased according to need and tolerance. Sometimes only dosages that lead to toxic serum levels appear effective. Some patients tol- erate such toxic levels without difficulty. Failure of first drug Initially, a single appropriate medication should be commenced. Should that not be effective or associated with side effects, a second agent should be added and uptitrated. Once the second medication is at therapeutic dose, the first can be weaned away. One change at a time should be made wherever possible and all medications should begin at a low dose and titrate up slowly (start low, go slow principle). An exception to this is if a patient develops a rash with an anti-epileptic drug which generally mandates prompt withdrawal of the offending agent. Clobazam can be helpful to cover such drug withdrawal. Drug combinations If drugs given individually have failed then drug combinations should be considered, remembering that they may interact with each other. However, nowadays all patients who have pharmacoresistant epilepsy (incomplete seizure control despite adequate trial of two appropriate medications) should be referred to a specialist epilepsy centre for evaluation. This applies to generalized epilepsy and focal epilepsy. In all cases this is to help with diagnostic clarity and in patients with focal epilepsy to consider whether epilepsy surgery may be indicated. Generic prescribing In the United Kingdom, the Medicines and Healthcare Products Regulatory Agency (MHRA) have given guidance on generic pre- scribing. If possible, a patient should be initiated on a generic version of an antiepileptic drug and it is perhaps preferable to keep to that generic version when feasible. Some patients can only tolerate one formulation of a medication, be that generic or branded, and those patients should be enabled to continue on their preferred formulation. Controlled re- lease medications should remain as the same formulation. The problem of adherence Lack of adherence 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 ap- pears conducive to improved compliance. Drugs that are given once or twice a day are preferred to ones needing more frequent prescrip- tions. Slow-​release preparations allow drug regimens to be simplified. Mechanisms of action At a mechanistic level, epilepsy is often viewed as an imbalance be- tween excitatory and inhibitory neurotransmission with an excess of the former and a lack of the latter (Fig. 24.5.1.6). Antiepileptic drugs suppress seizures but are not antiepileptogenic, namely they do not alter the underlying process that causes the seizures. There are three main targets for antiepileptic medications, modu- lation of voltage-​gated ion channels, potentiation of GABA-​medi- ated inhibition, and reduction of glutamateric excitation. Several commonly utilized antiepileptic drugs act on voltage-​ gated sodium channels. Phenytoin, carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, and can all reduce the rate of recovery from inactivation of depolarized voltage-​dependent sodium chan- nels, thereby blocking sustained repetitive firing of action potentials in depolarized neurons. Lacoscamide also acts on sodium chan- nels although on slow inactivating channels, rather than the fast inactivating sodium channels that the others target. Topiramate, zonisamide, and valproate also act on sodium channels although these three medications have multiple sites of action, potentially ex- plaining their role in treating multiple seizure types. Voltage-​dependent calcium ion currents are thought to be of im- portance in the genesis of epileptic events. Ethosuximide acts by in- hibition of one class of voltage-​dependent calcium ion currents (T currents) and is a drug of choice for the treatment of absence seiz- ures. Similarly, valproate and zonismaide may also have an effect on T calcium channels and be effective in absence epilepsy. The now withdrawn retigabine targeted voltage-​gated potassium channels. The prime role of GABA-​mediated inhibition in the epileptic process implies that drugs that enhance GABAA-​receptor-​medi- ated inhibition will have anticonvulsant activity. Both barbiturates and benzodiazepines act by potentiating GABAA-​mediated in- hibition. The barbiturates bind to the β subunit to potentiate ac- tion of endogenous agonist GABA and prolong the opening time of the chloride ion channel. Benzodiazepines bind to the α sub- unit 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 while tiagabine pre- vents removal of GABA from the synaptic cleft by blocking GABA transport. Gabapentin acts presynaptically to promote GABA synthesis or release. Many other drugs including valproate and topiramate have also been implicated in influencing GABAergic function. 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 recep- tors including α-​amino-​3-​hydroxy-​5-​methylisoxazole-​proprionic acid (AMPA) and NMDA. The NMDA receptor is activated by glu- tamate or aspartate together with glycine. Blockade of the NMDA receptor results in antiepileptic effects. Felbamate probably acts, at least in part, through its effects on the NMDA receptor. However, the only currently available antiepileptic drug to specifically target glutamaterigc signalling is peramapnel which is a non​competitive AMPA anatagonist. Other modes of action include levetiracetam binding to synaptic vesicle protein 2A and medications, such as topiramate, zonisamide, and acetazolamide, being carbonic anhydrase inhibitors, and thereby

section 24  Neurological disorders 5872 attenuating excitatory neurotransmission through increased local bicarbonate concentration. Selected drugs See Table 24.5.1.2. Carbamazepine Carbamazepine is a first-​line drug for focal seizures. It can also be used in the treatment of convulsive seizures in generalized epilepsy, but may make absence seizures and myoclonus worse. It should be prescribed in controlled release formulation whenever possible. Dosage typically ranges from 400 mg/​day to 1600 mg/​day. A drug rash occurs in perhaps 3% of patients and demands drug withdrawal. The rash is particularly seen in the Han Chinese population, espe- cially those with the HLA-​B1502 allele. Other side effects include dizziness, blurring of vision, double vision, balance difficulties, and gastrointestinal disturbance. 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 conduc- tion and should not be given to patients with atrioventricular con- duction abnormalities unless they are already paced. The relationship between dosage and plasma concentrations is linear meaning that, unlike other antiepileptic medications, carbamazepine levels gener- ally correlate with efficacy and tolerability. Carbamazepine is a liver enzyme inducer and is potentially teratogenic. Lamotrigine Lamotrigine is licensed for both generalized and focal seizures. Lamotrigine too is a first-​line drug for focal epilepsy and for women with generalized epilepsy who are of child bearing poten- tial. Occasionally it exacerbates myoclonus. Doses seldom exceed 400 mg/​day, although up to 600 mg daily may be used. A drug rash occurs in about 3% of patients. Lamotrigine interacts with enzyme-​ inducing anticonvulsants, which lower its plasma level. Valproate enhances lamotrigine levels and therefore lamotrigine should only be introduced slowly in patients already taking valproate. The drug can be given once daily. Originally said to be non​teratogenic, recent studies suggest that this is not the case. Levetiracetam Levetiracetam is an increasingly used antiepileptic drug for both focal and generalized epilepsy. Levetiracetam is a first-​line agent for focal epilepsy and for generalized epilepsy in women of childbearing Propagated action potential Gabapentin Pregabalin Benzodiazepines Barbiturates Postsynaptic neuron Retigabine has now been withdrawn GABAA receptor AMPA receptor Retigabine Levetiracetam Brivaracetam Voltage-gated Na+ channel Na+ Depolarization Vesicular release SV2A GABA GAT-1 α2δ-subunit of Ca2+ channel Ca2+ K+ Also inhibits glial GAT-1 KCNQ K+ channel K+ Ethosuximide T-type Ca2+ channel Glutamate Cl– Na+ Ca2+ KCNQ K+ channel Inhibitory synapse Not illustrated: Vigabatrin → ↓ GABA degradation and drugs with multiple mechanisms: Topiramate → ↓ Na+ channels, ↓ AMPA/kainate receptors, ↑ GABAA receptors Felbamate → ↓ Na+ channels, ↑ GABAA receptors, ↓ NMDA receptors Valproate → ↑ GABA turnover, ↓ Na+ channels, ↓ NMDA receptors Excitatory synapse Retigabine Tiagabine Phenytoin Carbamazepine Oxcarbazepine Eslicarbazepine acetate Lamotrigine Lacosamide Zonisamide Perampanel Fig. 24.5.1.6  Mechanism of action of antiepileptic medications. Antiepileptic medications operate through a variety of molecular mechanisms with effects on both inhibitory (left hand side) and excitatory (right hand side) nerve terminals. AMPA, α-​amino-​3-​hydroxy-​5-​methyl-​4-​isoxazole propionic acid; GABA, γ-​aminobutyric acid; GAT-​1, sodium-​ and chloride-​dependent GABA transporter 1; SV2A, synaptic vesicle glycoprotein 2A. Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Neurology. Löscher, W. & Schmidt, D. (2012) Perampanel—​new promise for refractory epilepsy? Nat. Rev. Neurol. 8, 661–​2, copyright © 2012; modified with permission from Macmillan Publishers Ltd © Bialer, M. & White, H. S. Nat. Rev. Drug Discov. 9, 68–​82 (2010).

24.5.1  Epilepsy in later childhood and adulthood 5873 Table 24.5.1.2  Characteristics of commonly used antiepileptic drugs in adults Name Indication Initial dose Titration schedule Usual daily therapeutic dose Common side effects* Particular features Brivaracetam Adjunctive therapy in focal epilepsy 50 mg bd Initial dose is therapeutic. Maximum dose 100 mg bd 100–​200 mg daily Dizziness, fatigue, gastrointestinal disturbance, somnolence Derivative of Levetiracetam Cannot be used in combination with Levetiracetam. Can start at lower than therapeutic dose also and up-titrate Carbamazepine
(slow release generally preferred) Focal epilepsy Can help with convulsions in generalized epilepsy 200 mg
(100 mg in older patients) 200 mg every 2 weeks 400–​1200 mg Rash, dizziness, ataxia, blurring of vision, gastrointestinal difficulties, hyponatraemia Rash more common in Han Chinese(HLA-​B1502 allele) Enzyme inducer Monitor vitamin D Can exacerbate absences and myoclonus Clobazam Adjunctive therapy all types, but especially focal epilepsy 10 mg 10 mg every two weeks 20–​40 mg Drowsiness Behavioural change especially in patients with learning difficulties Can be used at times of vulnerability e.g. with intercurrent infection Clonazepam Myoclonus 1 mg 1 mg every
2 weeks 2–​8 mg Drowsiness Avoid abrupt withdrawal as risk of seizures Eslicarbazepine Adjunctive therapy in Focal epilepsy 400 mg nocte 400 mg every two weeks 800–​1200 mg Rash. Similar side effect to Carbamazepine but more prone to cause hyponatraemia Rash more common in Han Chinese (HLA-​B1502 allele) Enzyme inducer Monitor Vitamin D Ethosuximide Absence seizures 250 mg 250 mg every 2 weeks 1000–​1500 mg Ataxia, rash, blood dyscrasias, GI disturbance Only for absences Predominantly used in paediatric practice Gabapentin Adjunctive therapy in Focal epilepsy 300 mg 300 mg every 2 to 3 days 600–​1200 mg tds Dizziness, drowsiness Well tolerated, but efficacy perhaps less than mainstay AEDs Lamotrigine Focal epilepsy Generalized epilepsy 25 mg 25 mg every 2 weeks 100–​500 mg Rash is common (1 in 30 risk), GI disturbance, tremor, effect on sleep Interaction with valproate. Start 25 mg alternate days if patient taking valproate. Monitor levels in pregnancy May sometimes worsen myoclonus Levetiracetam Focal epilepsy Generalized epilepsy All seizure types 250 mg 250 mg every 2 weeks 1000–​3000 mg Irritability Effect on sleep No pharmacokinetic interactions Lacosamide Adjunctive therapy in Focal epilepsy 50 mg 50 mg every 2 weeks 100–​400 mg Nausea, dizziness, palpitations, effect on mood Check PR interval on ECG before starting Oxcarbazepine Adjunctive therapy in Focal epilepsy 300 mg daily 300 mg every two weeks 600–​2400 mg Rash. Similar side effect to Carbamazepine but more prone to cause hyponatraemia Enzyme inducer Monitor vitamin D Perampanel Adjunctive therapy in Focal epilepsy Generalized epilepsy 2 mg nocte 2 mg every
4 weeks 6–​12 mg Dizziness, balance difficulties, effect on mood Long half-​life Targets glutamatergic signalling Phenytoin All forms of epilepsy Now only started in emergency setting 300 mg nocte N/​A 300 mg day Higher doses are used Rash, gingival hypertrophy, hirsutism, diplopia, ataxia, GI disturbance, coarsening of facial features. In longer-​term neuropathy and adverse impact on bone health Not a drug of choice for long-​term prescribing Non​linear pharmacokinetics Enzyme inducer Monitor vitamin D (continued)

section 24  Neurological disorders 5874 Name Indication Initial dose Titration schedule Usual daily therapeutic dose Common side effects* Particular features Phenobarbital All forms of epilepsy Now only started in emergency setting 60 mg 15 mg every 2 weeks 60–​180 mg Rash, effect on cognition, effect on mood, ataxia Gradual introduction and slow withdrawal. Cognitive slowing can be significant hence now rarely initiated Monitor vitamin D Pregabalin Adjunctive therapy in Focal epilepsy 25 mg bd 25 mg every week 200–​600 mg Drowsiness, ankle oedema, weight gain, dry mouth Also anxiolytic and often prescribed for neuropathic pain Sodium Valproate Generalized epilepsy Also effective in focal epilepsy 200 mg to 300 mg bd 200 mg steps every 3 to 7 days 1000–​2500 mg Weight gain, hair changes, thrombocytopaenia, tremor, encephalopathy (check ammonia), liver dysfunction Particularly teratogenic Aim to avoid in women of childbearing potential May cause acute pancreatitis Monitor vitamin D Topiramate Adjunctive therapy in Focal epilepsy Generalized epilepsy 25 mg nocte 25 mg every 2 weeks 100–​500 mg Effect on cognition, effect on mood, paraesthesiae, weight loss, renal stones, Rarely rash Advise to hydrate well If patient presents with acute red eye, consider acute closed angle glaucoma Thought to be particularly teratogenic, although not as high risk as valproate Zonisamide Adjunctive therapy in Focal epilepsy Generalized epilepsy 25 mg nocte 25 mg every 2 weeks 100–​500 mg Rash, GI disturbance, effect on mood, effect on cognition, weight loss, paraesthesiae, weight loss, renal stones Advise to hydrate well Notes:

1. All drugs can cause idiosyncratic reactions and patients should be directed to the product inserts for the full side effect profile
2. Rash is seen with many antiepileptic drugs (AEDs). If a patient develops a rash with an AED, particularly within 12 weeks of starting the medication then medical attention should be sought promptly and consideration given to discontinuation of the drug
3. Many newer antiepileptic medications can associate with an adverse impact on mood and, potentially, unusual or even suicidal thoughts. Patients and carers must be counselled about this possible risk
4. In older people, typically starting and ceiling doses are halved as is the rate of titration. For all patients, medications are started at low dose and gradually escalate to try and minimize side effects
5. In patients taking enzyme-​inducing drugs or valproate, vitamin D levels should be checked and supplemented if the patient is deficient. It has been suggested that all people with epilepsy should take vitamin D supplementation.
6. All AEDs are potentially teratogenic. There is particular teratogenic risk with valproate and topiramate Table 24.5.1.2  Continued

24.5.1  Epilepsy in later childhood and adulthood 5875 potential. It is effective against all generalized epilepsy seizure types. Typical dosing is from 1000 to 3000 mg and sometimes up to 4000 mg daily. The drug has no known pharmacokinetic interactions, has high oral bioavailability, and is given in twice-​daily dosing. Rash is uncommon but does occur. The main disadvantages relate to mood and behavioural changes, with some patients reporting irritability. Other common side effects also include somnolence, asthenia, diz- ziness, and headache. Sodium valproate Sodium valproate is the first-​line treatment in males with generalized epilepsy and seems effective against all generalized epilepsy types as well as being effective in focal epilepsy. The dose ranges from 600 mg/​ day to 2500 mg/​day and it is given twice per day. A slow-​release prep- aration can be given once daily and chronospheres can be mixed with, for example, yoghurt to aid compliance in patients who are resistant to taking medications. Valproate is not enzyme inducing and, therefore, does not influence the metabolism of the oral contra- ceptive. Liver toxicity, ankle oedema and acute pancreatitis are recognized, although rare, hazards. Elevated serum liver enzyme activities are more common, but usually return to normal without the need for drug withdrawal. Thrombocytopenia can be observed. 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 de- gree, 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. Plasma levels are not a useful guide to efficacy. Valproate, particularly at doses above 800 mg daily is potently teratogenic, meaning that should not be given to women of child bearing potential unless alter- native antiepileptic drugs have been explored. Second-​ and third-​line agents Acetazolamide Use of this drug is largely confined to childhood epilepsies. Brivaracetam Brivaracetam is the most recently licensed antiepileptic medication. A derivative of levetiracetam, it does not require up-​titration and initial dose of 50 mg bd is therapeutic. Maximum dose is 100 mg bd. Potential side effects include dizziness, gastrointestinal difficulties, fatigue, and somnolence. It must not be administered concomitantly with levetiracetam. 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. Similarly abrupt withdrawal can result in seizures. The maximum tolerated dose is about 8 mg/​day. Clobazam Although it was thought that tolerance to clobazam can develop fairly readily, many patients continue to derive benefit from the medication on a long-​term basis. Typical dosing is from 10 to 40 mg daily with principal side effects being dizziness and drowsiness. It is often used intermittently at times of seizure vulnerability, for example, at times of intercurrent infection or when travelling on holiday or around the time of menses. Eslicarbazepine Eslicarbazepine is a derivative of carbamazepine and shares common features to carbamazepine and oxcarbazepine. It is licensed as ad- junctive therapy in focal epilepsy with total daily dose typically being between 400 and 1200 mg daily taken as a single bedtime dose. Side effect profile is similar to carbamazepine. Both eslicarbazepine and oxcarbazepine are more likely to associate with hyponatraemia than carbamazepine. Ethosuximide Ethosuximide is only used in 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–​1.5 g daily. Gabapentin Gabapentin is used as add-​on therapy for focal seizures with or without secondary generalization. Up to 4.8 g is given in three div- ided doses. The drug is generally well tolerated and has limited drug-​ drug interaction. Its anticonvulsant effect appears to be relatively weak, but it can be effective for some patients. Lacosamide Lacosamide causes slow inactivation of sodium channels and is an adjunctive therapy in focal epilepsy. Typical daily dosing is 100–​400 mg daily with main side effects being dizziness, headaches, gastro- intestinal disturbance, and double vision. Lacosamide can prolong the PR interval and a baseline ECG to evaluate any conduction dif- ficulties is mandatory before initiation of lacosamide. Although drug-​drug interactions are not reported, there does appear to be a pharmacodynamic interaction with sodium channel blockers such as carbamazepine and oxcarbazepine. Oxcarbazepine This drug is closely related to carbamazepine but is a less potent hepatic enzyme inducer. It is licensed as monotherapy or ad- junctive therapy in focal seizures with or without secondary gener- alization. Its side effect profile is similar to that of carbamazepine although it is more prone to cause hyponatraemia than carbamaze- pine. Patients who are hypersensitive to carbamazepine should not receive oxcarbazepine. The dosage range lies between 600 and 2400 mg daily, in adults. Perampanel Perampanel is the only currently licensed antiepileptic drug to target the AMPA receptors, thereby modulating glutamatergic transmis- sion. It was initially licensed as adjunctive therapy for focal epilepsy, but in 2015 was also granted a licence for generalized epilepsy. It is taken once daily with effective doses being between 4 to 12 mg nocte. Potential side effects include dizziness, lethargy, and an effect on mood. Pregabalin Similar to gabapentin, pregabalin binds to the α2δ subunit of the voltage-​dependent calcium channel in the central nervous system. It is used as adjunctive therapy in focal seizures with or without

section 24  Neurological disorders 5876 secondary generalization. It is thought to have anxiolytic effects and this may make it more suitable for some patients with psychological comorbidity. Typical doses in epilepsy prescribing range from 100 to 600 mg in two doses. Adverse effects include dizziness, drowsiness, weight gain, blurred vision, and ataxia. There are no interactions with other anticonvulsants. Topiramate This drug is licensed both for primary generalized tonic–​clonic seizures and as adjunct therapy for focal seizures. The total daily dose (given as a twice-​daily regimen) typically ranges from 100 mg to 500 mg daily. Nausea, anorexia, and weight loss are encoun- tered. Behavioural disturbances are reported, including emotional lability, mood change, and aggression. Topiramate can affect cog- nition, associating particularly with word finding difficulty. There is an increased incidence of renal stones in those taking the drug. Importantly, topiramate is thought particularly teratogenic, al- though risk is not as high as with high-​dose valproate. Zonisamide Zonisamide has multiple modes of action. Its effect appears to come through action at sodium and calcium channels. It is licensed as adjunctive therapy in patients with focal seizures with or without secondary generalization and can be effective in generalized epi- lepsy. Daily dosing is usually between 100 to 500 mg daily. The side effect profile is not dissimilar to topiramate with common side ef- fects including dizziness drowsiness, an effect on mood, an effect on thinking, weight loss, paraesthesiae, and renal stones. The drug is a sulphonamide and various toxic effects have been described including Stevens–​Johnson syndrome. It is teratogenic. Antiepileptic medications, now rarely used
in long-​term prescribing Felbamate Felbamate is licensed for use in focal seizures. The drug has serious side effects, including liver failure and aplastic anaemia, and should only be used by specialized centres and for patients in whom it is clear that the benefits outweigh the risks. Phenobarbital Phenobarbital is a very effective anticonvulsant but often badly tol- erated and again should not be a long-​term agent in modern epi- lepsy prescribing. Phenobarbitione affects cognition, mood, and behaviour adversely. 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 pheno- barbital is largely converted to phenobarbital by the liver and pheno- barbital is the main metabolite of primidone, although primidone’s other metabolite, phenylethylmalonamide, probably possesses anti- convulsant activity. Phenytoin Experience with phenytoin is vast and, despite its side effect pro- file and complex pharmacokinetics, large quantities of the drug continue to be prescribed. The drug is effective in both generalized tonic–​clonic seizures and focal seizures. However, owing to its mul- tiple long-​term side effects, phenytoin is not a drug of choice for chronic prescribing in modern epilepsy practice. Phenytoin has a long half-​life, and can be given once daily. Sedation is common. Toxic effects, generally dose related, include drowsiness, ataxia, con- fusion, blurred vision, and dizziness. Most patients who are intoxi- cated 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 fea- tures, 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 limited to 50 mg or even 25 mg at a time. Retigabine Retigabine was licensed as an adjunctive therapy in focal epilepsy. It modulates potassium channels. However, postmarketing surveil- lance revealed a blue discolouration to skin and retina. Consequently, retigabine has been withdrawn. Tiagabine Tiagabine is a GABA uptake inhibitor, resulting in increased syn- aptic GABA levels. The initial dose in adults is 4–​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. Exacerbations of seizures and cases of non​convulsive status epilep- ticus have been recorded. Vigabatrin Vigabatrin is an effective antiepileptic medication. Dosage should not exceed 3 g/​day. However, owing to its association with idiosynchratic retinal damage it is now not conventionally initiated in adults. Up to a third of patients develop concentric constriction of the visual fields, more marked nasally than temporally. The defect is often asymptom- atic initially and is irreversible. In patients who are still maintained on vigabatrin, regular visual field analysis is mandatory. Antiepileptic drugs continue to be developed and specific drugs for very targeted indications also exist, including stripentol in Dravet’s Syndrome and rufinamide in Lennox Gastaut syndrome. Cannabidiol is also being developed as a potential treatment, par- ticularly for epileptic encephalopathies in the first instance. Particular issues Enzyme induction Drugs that induce liver enzymes (e.g. phenytoin, phenobarbital, carbamazepine) 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, or an intrauterine device. The interactions between anticonvulsants are complex—​another reason for avoiding drug combinations where possible and ensuring patients on antiepilepsy drugs are managed and advised by experts. All the enzyme-​inducing anticonvulsants have the potential for accelerating vitamin D metabolism. Those individuals at risk for

24.5.1  Epilepsy in later childhood and adulthood 5877 developing vitamin D deficiency (e.g. due to poor nutrition) are at risk of developing osteomalacia or rickets when taking certain anti- convulsants. It is prudent to check vitamin D levels in patients taking enzyme-​inducing medication, or valproate, and prescribe supple- ments of vitamin D if the patient is found to be deficient. Drug monitoring Anticonvulsant levels are measured far too frequently and most drug levels do not correlate with efficacy or tolerability. There are specific circumstances where the measurement of drug levels is of value: • to ascertain compliance • to monitor dosage adjustment with phenytoin • to ascertain the unpredictable effect of combining anticonvulsant preparations. • in pregnancy for certain medications, particularly lamotrigine and levetiracetam Phenytoin undergoes saturatable hepatic metabolism. Regular moni- toring of the serum level is advisable, particularly after dose adjust- ment. Occasionally, measurement of the levels of carbamazepine and phenobarbital aids management, particularly where epilepsy control has been poor. Carbamazepine epoxide, a metabolite of carbamaze- pine, can sometimes be the cause of carbamazepine toxicity even when carbamazepine levels are in the therapeutic range: this can be a particular concern when carbamazepine is coprescribed with so- dium valproate, since valproate can increase the epoxide metabolite, and here measurement of carbamazepine epoxide levels can be im- portant. 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 Pregnancy and preconception counselling present special chal- lenges in the management of epilepsy and require expert guidance. In women who develop seizures in pregnancy, eclampsia must be actively excluded. Seizure frequency increases in pregnancy in about a 10% of pa- tients with epilepsy, but most patients who are seizure free at the start of pregnancy will remain seizure free during their pregnancy. It is no longer recommended that vitamin K be given in the last month of pregnancy in women on enzyme-​inducing drugs. Babies should receive i.m. vitamin K as per standard practice. Women who are taking antiepileptic drugs should plan in ad- vance of any future pregnancy when possible and take folic acid 5 mg daily for three months prior to conception and likely through the pregnancy itself. Women are vulnerable to seizures during labour owing to multiple potential provoking factors. They are advised to deliver in hospital, receive adequate analgesia, and be under the care of a specialist obstetric team. There is an increased risk of congenital malformations in women who have taken anticonvulsants during pregnancy (approxi- mately 4–​8% overall risk, compared to a background risk in the general population of 1–​3%). The critical period for development of the major malformations is in the first trimester. The potential teratogencity of antiepileptic drugs for a given woman will depend on the number of drugs taken, the doses of these drugs and the type of drugs being taken. It is generally recommended that women with epilepsy take folic acid 5mg daily for three months prior to conception and through at least the first trimester—particularly if they are taking valproate. Most evidence of teratogenicity has accumulated for phenytoin, phenobarbital, valproate, and carbamazepine. Data on the newer anticonvulsants is emerging. Lamotrigine and levetiracetam do ap- pear to have a favourable teratogenic profile while topriamte appears to have a higher risk than other modern antiepileptic drugs. Data are scarce for many of the more recent antiepileptic drugs. Valproate is the most teratogenic of all the antiepileptic medica- tions. That risk is dose dependent with a significant increase in risk with valproate doses above 800 mg daily. Valproate associates with an increased incidence of neural tube defects along with other mid- line abnormalities such as hypospadias, partial agenesis of the corpus callosum, and ventricular septal defects. The risk approaches 10%. There is evidence that exposure in utero to valproate increases the risk of neurodevelopmental delay and this may affect as many as 30 to 40% of pregnancies exposed to valproate. Use of valproate in women of childbearing potential is a special situation and requires expert opinion and close discussion with the patient. The European Medicines Agency and MHRA have recently strengthened their ad- vice in this regard. They now recommend that all women taking val- proate for epilepsy who are capable of becoming pregnant have at least annual specialist review to consider alternatives to valproate. Should valproate continue then the woman and her treating specialist are required to adhere to the stipulations of the 'prevent' programme which, for example, recommends long term user independent contraception for women who take valproate and could conceive. Monitoring of lamotrigine levels can be helpful as lamotrigne levels can fall precipitously on conception or through the pregnancy. Having a baseline lamotrigine level in women who are seizure free prior to conception allows the clinician to treat to the level and in- crease dosing if required. If the dose of lamotrigine has been ad- justed owing to low levels, then generally women should return to their preconception dosing within 24–​48 hours after delivery. The epilepsy risk in the offspring of an affected patient is around 5% for generalized epilepsy, but may vary according to the precise underlying genetic aetiology. Breastfeeding Breastfeeding is recommended. The concentration of antiepileptic medication in breast milk is very low. If the mother is on a barbit- urate or a benzodiazepine, sedation of the baby is possible. If breast- feeding then ceases abruptly, a withdrawal reaction can occur in the infant with tremor and agitation. Importantly, breastfeeding should be done in a safe environment, such that were the mother to have a seizure while breastfeeding the chance of injury to her or the baby is minimized. Drug withdrawal Generally medication is continued until a minimum of 3–​5-​year period free of seizures has been established. Factors known to pre- dispose to recurrence of epilepsy after drug withdrawal include neurological abnormalities on examination, an underlying struc- tural 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 chil- dren than in adults. Any drug withdrawal should be gradual, for example over three to six months. Absence seizures in patients with childhood absence epilepsy, but not in juvenile absence epilepsy,

section 24  Neurological disorders 5878 usually remit spontaneously in late adolescence. Juvenile myoclonic epilepsy has a greater tendency to recur after drug withdrawal. Driving In the United Kingdom, driving must cease for six months after any type of seizure, providing that the patient has been assessed by an appropriate specialist and no relevant abnormalities found on inves- tigation. If a nocturnal pattern of sleep seizures has been established for one year and there have never been any seizures from wakeful- ness, driving can then continue even if nocturnal seizures are still occurring. If there has been a seizure from wakefulness, the pattern of nocturnal seizures alone must be established for three years be- fore a return to driving. Patients with simple focal seizures alone for more than a year who have no impairment in their ability to act during a seizure and who have never had any other type of seizure may also be eligible to continue to drive. The Driver and Vehicle Licensing Agency (DVLA) prefers patients not to drive during a period of drug withdrawal, and for six months after the withdrawal has been completed. For drivers of large goods vehicles, a five-​year period of seizure freedom must be established, and the criteria de- fined earlier again met. Furthermore, a continuing liability to epi- lepsy must be excluded. All patients with a suspected first seizure should be asked to stop driving until formal evaluation has occurred. In cases where there is uncertainty, discussions should be held with the DVLA about a patient’s possible eligibility to continue to drive. Advice regarding driving alters periodically although the DVLA or other licensing body always remain the final arbiters with regards to driving. Status epilepticus Status epilepticus has very recently been redefined to try and better capture that time is critical and that aetiology is important. The proposed new formal definition is ‘Status epilepticus is a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures (after time point t1). It is a condition, which can have long-​term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures’. In generalized tonic–​clonic status epilepticus, t1 is typically 5 min- utes and t2 typically 30 minutes. The new definition also includes four axes (seimiology, aetiology, EEG correlates, and age) to help in determining possible aetiologies and thereby hopefully help clinical management. Precipitants of status epilepticus include sudden anticonvul- sant withdrawal and alcohol abuse. Although noncompliance and subtherapeutic drug levels may cause status epilepticus, several studies have established that most individuals with epilepsy who present in status have therapeutic drug levels at or around the time of presentation. At least half of the cases occur in the absence of pre- vious epilepsy and, if refractory, is termed New Onset Refractory Status Epilepticus (NORSE). Status in the absence of previous epi- lepsy is followed by unprovoked seizures in about half the cases. Status epilepticus is a condition with high morbidity and mor- tality. The mortality figures for status epilepticus have varied substantially from series to series. In one 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%. 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 also be difficult to recognize, often presenting as coma. Immediate management of the patient must be directed at safety and resuscitation. The patient should be moved away from possible hazards, such as broken glass, an airway established, and oxygen administered. Lorazepam is probably the drug of choice. It is given in a dose of up to 0.1 mg/​kg intravenously (usually a 4 mg bolus, repeated once after five minutes) at the rate of 2 mg/​min. Alternatives include di- azepam (Diazemuls) given intravenously in a dose of 10–​20 mg at a rate of 5 mg/​min. Buccal midazolam may also prove of value where immediate intravenous access is difficult (e.g. in young children and in appropriately supervised non​hospital settings). Simultaneous with the administration of benzodiazepines, blood glucose should be checked and, if necessary, 50 ml of 50% glucose should be administered intravenously. 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. Thiamine can produce an anaphylactic response. In addition to plasma glucose measurement, blood should be taken for urea, elec- trolytes (including calcium and magnesium), acid–​base balance, liver function tests, and full blood count. A serum sample should be stored in case anticonvulsant, alcohol, or toxin levels are required subse- quently. 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 to a dose of 15–​20 mg/​kg in 0.9% sodium chloride should be given at a maximum rate of 50 mg/​min into a large vein can- nulated for single use. An alternative is fosphenytoin, a water-​soluble drug, which is metabolized to phenytoin with a half-​life of 8–​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 pheny- toin but causes less phlebitis and less hypotension, and is better toler- ated. Nowadays levetiracetam is often loaded in the acute setting with data suggesting that the loading dose should likely be between 20 to 60mg/kg. Valproate may also be considered (20 to 30mg/kg). If phenytoin/levetiracetam infusion is unsuccessful, and seizures continue, the patient should be transferred to the intensive care unit and phenobarbital can be considered, given at a loading dose of up to 10 mg/​kg intravenously at a rate not faster than 100 mg/​min. Should seizures persist then anaesthesia will be required with one or more of midazolam, propofol, or thiopentone initially. In super-​ refractory status epilepticus, multiple agents are utilized including levetiracetam, lacosamide, and topiramate as antiepileptic agents and ketamine as an anaesthetic agent. Every effort should be made to identify a cause including full metabolic testing, MRI brain imaging, cerebrospinal fluid analysis, analysis for toxins, and evaluation for mitochondrial disease. All patients with super-​refractory status epilepticus should be evalu- ated for a possible neuroinflammatory/​autoimmune cause to their

24.5.1  Epilepsy in later childhood and adulthood 5879 status epilepticus and treated with immunomodulation (steroids, IVIg, plasma exchange). Patients should ideally be on a neurointensive care unit and must be on an intensive care unit (ITU) with access to regular EEG moni- toring. Intially the aim is for the patient to enter EEG burst suppres- sion and EEG is critical to determining when it may be possible to begin to wean anaesthetic agents. Perhaps most critical to optimal management of patients with re- fractory status epilepticus is good systemic care and full engagement with the intensive care team. Meticulous attention to haemodynamic control, ventilation, feeding, skin care, metabolic parameters, and infection will all help improve outcome. Mortality and epilepsy Patients with epilepsy have an increased risk of death compared with age-​ and sex-​matched controls. Seizures may be fatal owing to injury or drowning. Comorbidity, including psychological comorbidity, is higher in patients with epilepsy and this too can contribute to mortality. Sudden unexpected death in epilepsy (SUDEP) predominates in younger age groups and in those with more severe epilepsy. It is more common in those with poor adherence to medication and if there is concomitant alcohol excess. The median incidence in patients with refractory epilepsy has been estimated at 3.6/​1000. The precise physiological mechanism of SUDEP is not known, but it is recommended that the concepts of SUDEP are discussed with patients with epilepsy at or soon after diagnosis. Surgery Despite optimal treatment, some 30% of patients with epi- lepsy continue to have attacks. For a proportion of patients with pharmacoresistant focal epilepsy resective surgery of the epilepto- genic zone can be considered. A prerequisite in patient selection for surgery is accurate localization of the epileptic discharges and understanding of circumstances where a resection might prove det- rimental in terms of functional deficit. Patients with pharmacoresistant focal epilepsy (pharmacoresis­ tance being defined as ongoing seizures despite adequate trials of two appropriate antiepileptic agents) should be referred promptly to a specialist epilepsy centre for assessment. Localization techniques incorporate seizure semiology, imaging, electrophysiological re- cording, neuropsychometry, and neuropsychiatric evaluation. Mesial temporal lobe epilepsy, secondary to hippocampal scler- osis, is the most common cause of medically refractory focal seiz- ures in adults. Improvements in imaging have revolutionized the care of these patients as the structural abnormality can be better visualized. MRI characteristics of mesial temporal sclerosis include atrophy or increased signal on T2-​weighted images. The presence of atrophy is the best predictor for a good surgical outcome. Besides visual inspection, measurement of hippocampal volume and tech- niques for measuring the T2 signal change are used to improve sen- sitivity. 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 sen- sitivity 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. Similarly, improvements in MRI criteria have allowed better recognition of areas of focal cortical dysplasia and assist in planning the extent of cortical resection. Continuous surface EEG monitoring is usually undertaken as part of the work-​up for patients being considered for surgical inter- vention. The technique, however, has limitations. It often fails to de- tect seizure activity arising in areas distant from surface electrodes, such as the orbitofrontal cortex and may falsely lateralize foci, par- ticularly in the presence of large lesions. For improving EEG local- ization intracranial recording may be 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 (Fig. 24.5.1.7). In optimal cases, resection of hippocampal sclerosis can offer up to a 70% chance of seizure remission, although longer-​term studies suggest that remission persists in about 50% of cases. Disabling neurological complications after surgery, such as hemianopia, hemi- paresis, or dysphasia, occur in about 1–​2% of patients. Depression and psychosis are recognized complications of temporal lobectomy. Other less commonly performed surgical procedures include neo- cortical resections (e.g. for focal cortical dysplasia), 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. It is rarely performed in adults. As an alternative hemispherotomy has been devised, attempting a complete deaffer- entation of hemispheric neural connections with maximal preser- vation of cerebral tissue. Division of the corpus callosum (typically Fig. 24.5.1.7  Intracranial recording (electrocorticography) can be performed by placing a grid of electrodes over the surface of the brain (as shown here) or by placing depth electrodes into the substance of the brain. Intracranial recording is much more accurate than scalp recording in defining the seizure onset zone. Stimulation through an intracranial grid can also help to delineate eloquent cortex. © Oxford Medical Illustrations, Oxford University Hospitals NHS Trust.

section 24  Neurological disorders 5880 anterior corpus callosum) is sometimes performed in patients with severe secondary generalized epilepsy who have disabling drop attacks. Multiple subpial transection disconnects horizontally coursing cortical fibres over 5 mm apart while preserving vertically oriented projection fibres. Although the procedure was designed to reduce postoperative neurological deficit, it is probably less effective in seizure control compared with cortical resection and again is only very occasionally suggested in adult practice. Stimulation therapies Vagal nerve stimulation (VNS) is achieved through the implant- ation 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 nu- clei, which have been shown to influence cerebral seizure suscep- tibility. In patients with chronic refractory focal seizures who are not amenable to surgical resection, VNS implantation may be con- sidered. VNS is also now indicated for pharmacoresistant general- ized epilepsy. VNS associates with a reduction in the frequency and intensity of seizures, rather than their elimination. Effectiveness also appears to increase with the passage of time. VNS devices also have a magnet that can be swiped across the pulse generator to give an extra stimulation if the start of a seizure is recognized. The ASPIRE SR device has been developed which can automatically detect a rise in heart rate that can be seen associated with a seizure and deliver an extra stimulation without needing ac- tivation by the magnet while more recently the SenTiva VNS device has become available which offers many more programming op- tions. Another modification of the VNS is the transcutaneous VNS device which does not require implantation and electrode placement around the vagus nerve, but rather stimulates the auricular branch of the vagus non​invasively. Deep brain stimulation (DBS) for epilepsy is also being actively developed. The SANTE trial has provided evidence that DBS may be effective in some patients and will likely enter the panoply of surgical treatment options for epilepsy in the near future. Careful patient se- lection for the appropriate surgical intervention and a holistic multi- disciplinary approach to potential surgical candidates is essential. Comorbidity in epilepsy Patients with epilepsy are prone to multiple comorbidities, particu- larly cognitive difficulties, psychological difficulties, and psycho- social difficulties. Systemic illness is also more common in patients with epilepsy. Cognitive difficulties and epilepsy The principal cognitive problem that patients with epilepsy report is memory difficulties. This may relate to the underlying cause of the epilepsy, the seizures or, sometimes, the medication. Standard neuropsychometric assessment may not reveal much deficit as many patients with active epilepsy exhibit accelerated long-​term forgetting. Consequently, patients may perform quite well over testing periods for a few hours, but memory declines more quickly than the general population over the next week or so. Clinically this may manifest by patients watching the same movie two weeks after first seeing the film and not recollecting that they have seen the film before. Many novel antiepileptic medications are ‘cognitively-​neutral’ demonstrating minimal adverse impact on cognition. Older drugs such as phenobarbitone can significantly affect cognition. Valproate can associate with hyperammonemic encephalopathy, which can be improved by lactulose to clear the gut. Topiramate and zonisamide can also affect cognition, the former associating with word finding difficulties. Patients with cognitive difficulties and epilepsy may require re- ferral to a clinical psychologist to help identify specific areas of cog- nitive impairment that might require attention. Psychiatric aspects of epilepsy A substantial proportion of patients with poorly controlled epilepsy are likely to have psychiatric symptoms. One-​third of patients will develop depression and the rate of suicide is increased in patients with epilepsy. 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 be- fore or with the seizure, but psychotic afterwards. Typically, postictal psychosis occurs following a latent period of one to two days after the seizure. Additional psychiatric morbidity is encountered as an interictal phenomenon. In addition, an adverse psychiatric outcome may follow epilepsy surgery. Antiepileptic medications, particularly modern antiepileptic medications (levetiracetam, lacosamide, perampanel, topiramate, zonisamide) may have an adverse impact on mood. However, cer- tain antiepileptic medications may be mood stabilizing (carbamaze- pine, lamotrigine, valproate) or anxiolytic (pregabalin). Mood difficulties in patients with epilepsy are often inadequately addressed. Modern antidepressants (escitalopram, citalopram, sertraline) tend not to reduce seizure threshold and patients may also benefit from talking therapies. Psychosis or severe psycho- logical difficulties should be managed by psychiatrists experienced in the management of patients with epilepsy. Psychosocial impact of epilepsy Even in the 21st century epilepsy, which was described in Babylonian texts, remains a deeply stigmatized condition. Given its prevalence, this is perhaps surprising. However, epilepsy is generally an episodic condition and therefore can remain a ‘hidden’ disease. The unpredictability of seizures, need for regular treat- ment, driving and potentially employment restrictions all con- tribute to the psychosocial impact upon the person with epilepsy and also their family and friends. It is beholden on those helping in the management of patients with epilepsy to strive to enable pa- tients to achieve their full potential in all spheres. The role of specialist nurses and the general practitioner Optimal management of people with epilepsy requires close liaison across all sectors of care. Studies suggest that an epilepsy specialist nurse, working either in general practice or in association with a hospital clinic, can make a tangible difference to patient care. Where joint care is to be achieved between general practice and hospital, it is vital that there is good quality communication and record

24.5.1  Epilepsy in later childhood and adulthood 5881 keeping. Giving files that document vital information, including their drug regimen, to the patient is valuable. As in other conditions, Patients prefer the continuity of care achievable through seeing the same doctor at each consultation and are more likely to engage with medical advice under those circumstances. Prognosis The prognosis for people with epilepsy who are sufficiently stable to be followed in the community is considerably better than for a hospital-​based population. Fig. 24.5.1.8 records the percentage of patients in remission (defined as being seizure free for five years). Factors that influence outcome adversely include a combination of focal impaired awareness and bilateral 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 a hospital, a specialist nurse, and a 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 develop- ments, issues relating to pregnancy, the question of non​epileptic seizures, diagnostic uncertainties, and the potential for surgery for many patients with poorly controlled epilepsy make the case for epilepsy clinics staffed by neurologists expert in the management of epilepsy. FURTHER READING Arruda F, et  al. (1996). Mesial atrophy and outcome after amygdalohippocampectomy or temporal lobe removal. Ann Neurol, 40, 446–​50. Berg AT, Shinnar S (1994). Relapse following discontinuation of anti-​ epileptic drugs: a meta-​analysis. Neurology, 44, 601–​8. Berg AT, et al. (2010). Revised terminology and concepts for organ- ization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–​2009. Epilepsia, 51, 676–​85. Betjemann JP, Lowenstein DH (2015). Status epilepticus in adults. Lancet Neurol, 14, 615–​24. Binnie CD, Stefan H (1999). Modern electroencephalography: its role in epilepsy management. Clin Neurophysiol, 110, 1671–​97. Blümcke I, et al. (2011). The clinicopathologic spectrum of focal cor- tical dysplasias: a consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission. Epilepsia, 52, 158–​74. Crawford P, et al. (1999). Best practice guidelines for the management of women with epilepsy. Seizure, 8, 201–​17. Dedeurwaerdere S, et al. (2012). Finding a better drug for epilepsy: antiinflammatory targets. Epilepsia, 53, 1113–​8. Dichter MA (1994). Emerging insights into mechanisms of epilepsy: implications for new antiepileptic drug development. Epilepsia, 35 Suppl 4, S51–​7. Duncan JS (1997). Imaging and epilepsy. Brain, 120, 339–​77. Fisher RS, et  al. (2005). Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and International Bureau for Epilepsy (IBE). Epilepsia, 46, 470–​2. Fisher R, et al. (2014). ILAE official report: a practical clinical defin- ition of epilepsy. Epilepsia 55, 475–​82. Fisher R, et al. (2017). Operational classification of seizure types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology. Epilepsia, 58, 522–30. Goldstein LH (1990). Behavioural and cognitive–​behavioural treat- ment for epilepsy: a progress review. Br J Clin Psychol, 29, 257–​69. Irani S, et al. (2011). Faciobrachial dystonic seizures precede Lgi1 anti- body limbic encephalitis. Ann Neurol, 69, 892–​900. Johnson MR (2011). The genetic contribution to epilepsy: the known and missing heritability. In: Shorvon SD, Andermann F, Guerrini R (eds) The causes of epilepsy, pp. 63–​7. Cambridge University Press, Cambridge. Keezer MR, et al. (2015). Comorbidities of epilepsy: current concepts and future perspectives. Lancet Neurol, S1474–​42. Kotsopoulos IA, et al. (2002). Systematic review and meta-​analysis of incidence studies of epilepsy and unprovoked seizures. Epilepsia, 43, 1402–​9. Krishnamoorthy ES, Brown RJ, Trimble M (2001). Personality and psychopathology in non-​epileptic attack disorder:  a prospective study. Epilepsy Behav, 2, 418–​22. Lempert T, Bauer M, Schmidt D (1994). Syncope:  a videometric analysis of 56 episodes of transient cerebral hypoxia. Ann Neurol, 36, 233–​7. Manford M, et al. (1992). The national general practice study of epi- lepsy applied to epilepsy in a general population. Arch Neurol, 49, 801–​8. Mattson RH, et al. (1985). Comparison of carbamazepine, phenobar- bital, phenytoin, and primidone in partial and secondarily general- ized tonic–​clonic seizures. NJEM, 313, 145–​51. Percentage in remission 80 60 40 20 0 Years after diagnosis 5 6 10 15 20 Fig. 24.5.1.8  Probability of seizure recurrence after a first epileptic seizure. The top curve indicates the percentage of patients achieving a 5-​year period of remission at any time during the 20-​year period of follow-​up. The middle curve refers to those patients in remission for at least the last 5 years at the time of sampling. The difference between the top and middle curves represents those patients who have relapsed after achieving a 5-​year remission. The bottom curve indicates the probability of being in remission while not taking anticonvulsants. The curves flatten off, indicating that remission becomes less likely the longer the seizures persist. Data from the National General Practice Study of Epilepsy, reproduced by kind permission.