Prof.Mohammad Salah Abduljabbar Seizures & Epilepsy Prof.Mohammad Salah Abduljabbar

Outline Definitions Pathophysiology Aetiology Classification Diagnostic approach Treatment Quiz

Definition A chronic neurologic disorder manifesting by repeated epileptic seizures (attacks or fits) which result from paroxysmal uncontrolled discharges of neurons within the central nervous system (grey matter disease). The clinical manifestations range from a major motor convulsion to a brief period of lack of awareness. The stereotyped and uncontrollable nature of the attacks is characteristic of epilepsy.

Definition Seizure (Convulsion) Epilepsy Clinical manifestation of synchronised electrical discharges of neurons Epilepsy Present when 2 or more unprovoked seizures occur at an interval greater than 24 hours apart

Definition Provoked seizures is a seizures induced by somatic disorders originating outside the brain E.g. fever, infection, syncope, head trauma, hypoxia, toxins, cardiac arrhythmias

Definition Status epilepticus (SE) Idiopathic SE Symptomatic SE Continuous convulsion lasting longer than 30 minutes OR occurrence of serial convulsions between which there is no return of consciousness Idiopathic SE Seizure develops in the absence of an underlying CNS lesion/insult Symptomatic SE Seizure occurs as a result of an underlying neurological disorder or a metabolic abnormality

Aetiology of seizures Epileptic Idiopathic (70-80%) Cerebral tumor Neurodegenerative disorders Neurocutaneous syndromes Secondary to Cerebral damage: e.g. congenital infections, HIE, intraventricular hemorrhage Cerebral dysgenesis/malformation: e.g. hydrocephalus

Aetiology of seizures Non-epileptic Febrile convulsions Metabolic Hypoglycemia HypoCa, HypoMg, HyperNa, HypoNa Head trauma Meningitis Encephalitis Poisons/toxins

Aetiology of Status Epilepticus Prolonged febrile seizure Most common cause Idiopathic status epilepticus Non-compliance to anti-convulsants Sudden withdrawal of anticonvulsants Sleep deprivation Intercurrent infection Symptomatic status epilepticus Anoxic encephalopathy Encephalitis, meningitis Congenital malformations of the brain Electrolyte disturbances, drug/lead intoxication, extreme hyperpyrexia, brain tumor Prolonged febrile seizure: -lasting for more than 30min, particularly in a child younger than 3, is the most common cause of SE Sudden withdrawal of anticonvulsants: -Especially benzodiazepines and barbiturates

Pathogenesis The 19th century neurologist Hughlings Jackson suggested “a sudden excessive disorderly discharge of cerebral neurons“ as the causation of epileptic seizures. Recent studies in animal models of focal epilepsy suggest a central role for the excitatory neurotransmiter glutamate (increased) and inhibitory gamma amino butyric acid (GABA) (decreased)

Pathophysiology Still unknown Some proposals: Excitatory glutamatergic synapses Excitatory amino acid neurotransmitter (glutamate, aspartate) Abnormal tissues — tumor, AVM, dead area Genetic factors Role of substantia nigra and GABA

Pathophysiology Excitatory glutamatageric synapses And, excitatory amino acid neurotransmitter (glutamate, aspartate) These are for the neuronal excitation In rodent models of acquired epilepsy and in human temporal lobe epilepsy, there is evidence for enhanced functional efficacy of ionotropic N-methyl-D-aspartate (NMDA) and metabotropic (Group I) receptors Chapman AG. Glutatmate and Epilepsy. J Nutr. 2000 Apr; 130(4S Suppl): 1043S-5S

Pathophysiology Abnormal tissues — tumor, AVM, dead area These regions of the brain may promote development of novel hyperexcitable synapses that can cause seizures

Pathophysiology Genetic factors At least 20 % Some examples Benign neonatal convulsions. Juvenile myoclonic epilepsy. Progressive myoclonic epilepsy.

Classification of seizures

Epilepsy - Classification The modern classification of the epilepsies is based upon the nature of the seizures rather than the presence or absence of an underlying cause. Seizures which begin focally from a single location within one hemisphere are thus distinguished from those of a generalised nature which probably commence in a deeper structures (brainstem? thalami) and project to both hemispheres simultaneously.

Seizures Partial Electrical discharges in a relatively small group of dysfunctional neurones in one cerebral hemisphere Aura may reflect site of origin + / - LOC Generalized Diffuse abnormal electrical discharges from both hemispheres Symmetrically involved No warning Always LOC

Partial Seizures Simple Secondary generalized Complex 1. w/ motor signs 2. w/ somato-sensory symptoms 3. w/ autonomic symptoms 4. w/ psychic symptoms 1. simple partial --> loss of consciousness 2. w/ loss of consciousness at onset 1. simple partial --> generalized 2. complex partial 3. simple partial --> complex partial Simple partial In simple partial seizures, consciousness is not impaired. Patients can present with motor, somatosensory, special sensory, autonomic or psychic symptoms complex A complex partial seizure describes a seizure where consciousness is impaired. A partial seizure may begin with a simple seizure, conversely, its onset may coincide with the impairment of consciousness. It may be presented with or without an aura. 2ndary generalized Partial sezure evolve to secondarily generalized seizures May be gen. Tonic-clonis, tonico or clonic

Focal (partial) seizures Simple partial seizures Motor, sensory, vegetative or psychic symptomato- logy Typically consciousness is preserved

Simple partial seizures with motor signs Focal motor w/o march Focal motor w/ march Versive Postural Phonatory Focal motor may remain strictly focal OR they may spread to contiguous cortical areas producing a sequential involvement of body parts in an epileptic march - Jacksonian seizure Versive : head turning to one side usually contraversive to the discharge

Simple partial seizures with motor signs Sudden onset from sleep Version of trunk Postural Left arm bent Forcefully stretched fingers Looks at watch Note seizure Simple partial seizure with versive motor signs and postural motor signs usually arising from sleep; version of trunk to R L arm bent at elbow, finger forcefully stretched R arm beats on arm of chair to warn the nurse tonic contraction of face and eyes jerking of head and L shoulder turns back to normal position support head with R hand look at watch for note seizure in calender

Simple partial seizures with sensory symptoms Somato-sensory Visual Auditory Olfactory Gustatory Vertiginous Areas of cortex subserving sensory function, described as pins and needles / numbness Visual: flashing lights - structured visual hallucinatory phenomena e.g. persons, scenes. Auditory: crude aud sensations - highly integrated functions e.g. music Olfactory: unpleasant odours Gustatory sensations: pleasant / odious taste often described as metallic Vertiginous: sensations of falling in space, floating

Simple partial seizures with sensory symptoms Vertiginous symptoms “Sudden sensation of falling forward as in empty space” No LOC Duration: 5 mins

Simple partial seizures with autonomic symptoms Vomiting Pallor Flushing Sweating Pupil dilatation Piloerection Incontinence borborygmi

Simple partial seizures with autonomic symptoms Stiffness in L cheek Difficulty in articulating R side of mouth is dry Salivating on the L side Progresses to tongue and back of throat

Simple partial seizures with psychic symptoms Dysphasia Dysmnesic Cognitive Affective Illusions Structured hallucinations Psychic: disturbance of higher mental function Dysmnesic symptoms: deja-vu or jamais-vu, forced thinking - panoramic vision ( a rapid recollection of episodes from his/her past life) Cognitive: dreamy states, distorsions of time sense. Detachment or depersonalisation Affective: Anger and Fear which is apparently unprovoked and abates rapidly

Simple partial seizure with pyschic symptoms Dysmnesic symptoms “déjà-vu” Affective symptoms fear and panic Cognitive Structured hallucination living through a scene of her former life again

Complex Partial Seizures Simple partial onset followed by impaired consciousness with or without automatism With impairment of consciousness at onset with impairment of consciousness only with automatisms

Partial Seizures evolving to Secondarily Generalized Seizures Simple Partial Seizures to Generalised Seizures Complex Partial Seizures to Generalised Seizures Simple Partial Seizures to Complex Partial Seizures to Generalised Seizures

Generalized seizures Absence Myoclonic Clonic Tonic Tonic-clonic Atonic Generalized seizure: Atonic1: lack of normal tone Tonic1: under continuous tension Clonic1: rhythmic contractions and relaxations of a muscle in rapid succession Myoclonic1: single or repetitive sudden twitching or spasm of a muscle or a group of muscles

Generalized seizures (convulsive or non-convulsive) Absences Myoclonic seizures Clonic seizures Tonic seizures Atonic seizures

Absence seizures Sudden onset Interruption of ongoing activities Blank stare Brief upward rotation of eyes Duration: a few seconds to 1/2 minute Evaporates as rapidly as it started

Absence seizures Stops hyperventilating Mild eyelid clonus Slight loss of neck muscle tone Oral automatisms Slight impairment of mental performance: Heard what was spoken to her before the seizure stopped, but has probably not understood it qte right “are you there” and “is it there” sound very close to each other in Danish

Myoclonic seizures Sudden, brief, shock-like Predominantly around the hours of going to or awakening from sleep May be exacerbated by volitional movement (action myoclonus)

Myoclonic seizures Symmetrical myoclonic jerks

Clonic seizures Repetitive biphasic jerky movements Repetitive vocalisation synchronous with clonic movements of the chest (mechanical) Venous injection of diazepam Passes urine

Tonic seizures Rigid violent muscle contraction Limbs are fixed in strained position patient stands in one place bends forward with abducted arms deep red face noises - pressing air through a closed mouth

Tonic seizures Elevates both hands Extreme forward bending posture Keeps walking without faling Passes urine Usually: patient stands in one place bends forward with abducted arms deep red face noises - pressing of air through a closed mouth

Tonic-clonic seizures (grand mal) Tonic Phase Sudden sharp tonic contraction of respiratory muscle: stridor / moan Falls Respiratory inhibition cyanosis Tongue biting Urinary incontinence Clonic Phase Small gusts of grunting respiration Frothing of saliva Deep respiration Muscle relaxation Remains unconscious Goes into deep sleep Awakens feeling sore, headaches

Tonic-clonic seizures Tonic stretching of arms and legs Twitches in his face and body Purses his lips and growls Clonic phase EEG show generalized sharp waves spikes decrease in frequency

Atonic seizures Sudden reduction in muscle tone Atonic head drop

Epilepsy syndrome Epilepsy syndromes may be classified according to: Whether the associated seizures are partial or generalized Whether the etiology is idiopathic or symptomatic/ cryptogenic Several important pediatric syndromes can further be grouped according to age of onset and prognosis EEG is helpful in making the diagnosis Children with particular syndromes show signs of slow development and learning difficulties from an early age

Table 1. Modified ILAE Classification of Epilepsy Syndromes Category Localization-related Generalized Idiopathic Benign epilepsy of childhood with centrotemporal spikes (benign rolandic epilepsy) Benign occipital epilepsy Benign myoclonic epilepsy in infancy Childhood absence epilepsy Juvenile absence epilepsy Juvenile myoclonic epilepsy Symptomatic (of underlying structural disease) Temporal lobe Frontal lobe Parietal lobe Occipital lobe Early myoclonic encephalopathy Cortical dysgenesis Metabolic abnormalities West syndrome Lennox-Gastaut syndrome Cryptogenic Any occurrence of partial seizures without obvious pathology Epilepsy with myoclonic absences West syndrome (with unidentified pathology) Lennox-Gastaut syndrome (with unidentified pathology)

(cond’) Table 1. Modified ILAE Classification of Epilepsy Syndromes Special syndromes Febrile convulsions Seizures occurring only with toxic or metabolic provoking factors Neonatal seizures of any etiology Acquired epileptic aphasia (Landau-Kleffner syndrome)

Three most common epilepsy syndromes: Benign childhood epilepsy Childhood absence epilepsy Juvenile myoclonic epilepsy Three devastating catastrophic epileptic syndromes: West syndrome Lennox-Gastaut syndrome Landau Kleffner Syndrome

Benign childhood epilepsy with centrotemporal spike (Benign Rolandic Epilepsy) Typical seizure affects mouth, face, +/- arm. Speech arrest if dominant hemisphere, consciousness often preserved, may generalize especially when nocturnal, infrequent and easily controlled Onset is around 3-13 years old, good respond to medication, always remits by mid-adolescence Idiopathic (with age-related onset) – normal neuro exam, development and neuroimaging, typically nocturnal, usually stop in adolescence, family history 40% 1. Benign childhood epilepsy with centrotemporal spike (aka benign rolandic epilepsy) a. Age of onset 2-13 yrs, accounts for 11.5-25% of childhood epilepsy (autosomal dominant with variable penetrance). Always remits by mid-adolescence. b. Typical seizure affects mouth, face, +/- arm. Speech arrest if dominant hemisphere, consciousness often preserved, may generalize especially when nocturnal, infrequent and easily controlled c. Interictal EEG normal background, midtemporal and central high-amplitude spikes and sharp waves, increased in sleep, can be unilateral (less often) or bilateral but independent (more often). Ictal EEG shows unilateral sharps which can occasionally be bilateral. Sharps can be occipital in <5 yo.

Childhood absence epilepsy School age ( 4-10 years ) with a peak age of onset at 6-7 years Brief seizures, lasting between 4 and 20 seconds 3Hz Spike and wave complexes is the typical EEG abnormality Sudden onset and interruption of ongoing activity, often with a blank stare. Precipitated by a number of factors i.e. fear, embarrassment, anger and surprise. Hyperventilation will also bring on attacks. Juvenile myoclonic seizure Around time of puberty Myoclonic ( sudden spasm of muscles ) jerks → generalized tonic clonic seizure without loss of consciousness Precipitated by sleep deprivation

West’s syndrome (infantile spasms) Triad: infantile spasms arrest of psychomotor development hypsarrhythmia Spasms may be flexor, extensor, lightning, nods, usually mixed. Peak onset 4-7 months, always before 1 year. Lennox-Gastaut syndrome Characterized by seizure, mental retardation and psychomotor slowing Three main type: tonic atonic atypical absence Landau- Kleffner syndrome ( acquired aphasia ) Prognosis related to underlying cause, response to treatment. ACTH or steroids West Lennox-Gastaut syndrome Three main type: tonic atonic atypical absence Begins age 1-8 yo, seizures can be tonic-axial, atonic, absence, myoclonic, GTC, usually frequent sz, frequent status epilepticus, seizures difficult to control. EEG abnormal background, slow spike and wave (<3Hz), often multifocal abnormalities. Usually has mental retardation.

Diagnosis in epilepsy Aims: Differentiate between events mimicking epileptic seizures E.g. syncope, vertigo, migraine, psychogenic non-epileptic seizures (PNES) Confirm the diagnosis of seizure (or possibly associated syndrome) and the underlying etiology

Epilepsy Differential Diagnosis The following should be considered in the diff. dg. of epilepsy: Syncope attacks (when pt. is standing; results from global reduction of cerebral blood flow; prodromal pallor, nausea, sweating; jerks!) Cardiac arrythmias (e.g. Adams-Stokes attacks). Prolonged arrest of cardiac rate will progressively lead to loss of consciousness – jerks! Migraine (the slow evolution of focal hemisensory or hemimotor symptomas in complicated migraine contrasts with more rapid “spread“ of such manifestation in SPS. Basilar migraine may lead to loss of consciousness! Hypoglycemia – seizures or intermittent behavioral disturbances may occur. Narcolepsy – inappropriate sudden sleep episodes Panic attacks PSEUDOSEIZURES – psychosomatic and personality disorders

Diagnosis in epilepsy Approach: History (from patient and witness) Physical examination Investigations

History Event Past medical history Developmental history Localization Temporal relationship Factors Nature Associated features Past medical history Developmental history Drug and immunization history Family history Social history Localization: aspects involved e.g. motor, sensory? Any specific site e.g. one limb involved, or generalized involvement? Temporal relationship: number of episode? Diurnal pattern? Duration? Onset and offset? Progression? Persistency? Factors: precipitating? Nature: consciousness impaired? Type of sensory/ motor/ psychic/ emotional disturbances observed/ experienced? Associated features: Prodrome? Aura? Postictal state? Colour of patient? Focal neurological sign?

Physical Examination General Neurological Other system as indicated esp. syndromal or non-syndromal dysmorphic features, neurocutaneous features Neurological Other system as indicated E.g. Febrile convulsion, infantile spasm

Epilepsy – Investigation The concern of the clinician is that epilepsy may be symptomatic of a treatable cerebral lesion. Routine investigation: Haematology, biochemistry (electrolytes, urea and calcium), chest X-ray, electroencephalogram (EEG). Neuroimaging (CT/MRI) should be performed in all persons aged 25 or more presenting with first seizure and in those pts. with focal epilepsy irrespective of age. Specialised neurophysiological investigations: Sleep deprived EEG, video-EEG monitoring. Advanced investigations (in pts. with intractable focal epilepsy where surgery is considered): Neuropsychology, Semiinvasive or invasive EEG recordings, MR Spectroscopy, Positron emission tomography (PET) and ictal Single photon emission computed tomography (SPECT)

Investigations I. Exclusion of differentials: Bedside: urinalysis Hematological:CBP Biochemical: U&Es, Calcium, glucose, ABGs Radiological: CXR, CT head Toxicological: screen Microbiological: LP (Always used with justification)

Investigations II. Confirmation of epilepsy: Dynamic investigations : result changes with attacks E.g. EEG Static investigations : result same between and during attacks E.g. Brain scan

Electroencephalography (EEG) EEG indicated whenever epilepsy suspected Uses of EEG in epilepsy Diagnostic: support diagnosis, classify seizure, localize focus, quantify Prognostic: adjust anti-epileptic treatment

International 10-20 System of Electrode Placement in EEG

Electroencephalography (EEG) EEG interpretation in epilepsy Hemispheric or lobar asymmetries Periodic (regular, recurring) Background activity: Slow or fast Focal or generalized Paroxysmal activity: Epileptiform features – spikes, sharp waves Interictal or ictal Spontaneous or triggered

Electroencephalography (EEG) Certain epilepsy syndromes have characteristic or suggestive features E.g. Infantile spasms Hypsarrhythmia Childhood absence epilepsy Generalized 3-Hz spike-wave Juvenile myoclonic epilepsy Generalized/ multifocal 4-5 Hz spike-wave and polyphasic-wave Benign occipital epilepsy Unilateral/ bilateral occipital sharp/ sharp-slow activity that attenuates on eye opening Lennox-Gastaut syndrome Generalized/ bianterior spike-wave activity at <2.5 Hz

Electroencephalography (EEG) E.g. Brief absence seizure in an 18-year-old patient with primary generalized epilepsy

Electroencephalography (EEG) Note: Normal in 10-20% of epileptic patients Background slowed by: AED, diffuse cerebral process, postictal state Artifact from: Eye rolling, tremor, other movement, electrodes Interpreted in the light of proximity to seizure

Neuroimaging Structural neuroimaging Functional neuroimaging

Structural Neuroimaging Who should have a structural neuroimaging? Status epilepticus or acute, severe epilepsy Develop seizures when > 20 years old Focal epilepsy (unless typical of benign focal epilepsy syndrome) Refractory epilepsy Evidence of neurocutaneous syndrome

Structural Neuroimaging Modalities available: Magnetic Resonance Imaging (MRI) Computerized Tomography (CT) What sort of structural scan? MRI better than CT CT usually adequate if to exclude large tumor MRI not involve ionizing radiation I.e. not affect fetus in pregnant women (but nevertheless avoided if possible)

Functional Neuroimaging Principles in diagnosis of epilepsy: When a region of brain generates seizure, its regional blood flow, metabolic rate and glucose utilization increase After seizure, there is a decline to below the level of other brain regions throughout the interictal period

Functional Neuroimaging Modalities available: Positron Emission Tomography (PET) Single Photon Emission Computerized Tomography (SPECT) Functional Magnetic Resonance Imaging (fMRI) Mostly used in: Planning epilepsy surgery Identifying epileptogenic region Localizing brain function

Venn Diagram

Seizure Therapy Seizure Specific Treatments General Treatment Reassurance and Education Anticonvulsant Surgery

Education & Support Information leaflets and information about support group Avoidance of hazardous physical activities Management of prolonged fits Recovery position Rectal diazepam Side effects of anticonvulsants

Treatment The majority of pts respond to drug therapy (anticonvulsants). In intractable cases surgery may be necessary. The treatment target is seizure-freedom and improvement in quality of life! The commonest drugs used in clinical practice are: Carbamazepine, Sodium valproate, Lamotrigine (first line drugs) Levetiracetam, Topiramate, Pregabaline (second line drugs) Zonisamide, Eslicarbazepine, Retigabine (new AEDs) Basic rules for drug treatment: Drug treatment should be simple, preferably using one anticonvulsant (monotherapy). “Start low, increase slow“. Add-on therapy is necessary in some patients…

Treatment If pt is seizure-free for three years, withdrawal of pharmacotherapy should be considered. Withdrawal should be carried out only if pt is satisfied that a further attack would not ruin employment etc. (e.g. driving licence). It should be performed very carefully and slowly! 20% of pts will suffer a further sz within 2 yrs. The risk of teratogenicity is well known (~5%), especially with valproates, but withdrawing drug therapy in pregnancy is more risky than continuation. Epileptic females must be aware of this problem and thorough family planning should be recommended. Over 90% of pregnant women with epilepsy will deliver a normal child.

Anticonvulsants Suppress repetitive action potentials in epileptic foci in the brain Sodium channel blockade GABA-related targets Calcium channel blockade Others: neuronal membrane hyperpolarisation Na channel blockade: phenytoin, carbamazepine, lamotrigine GABA-related targets: benzodiazepines interact with specific receptors on GABAa receptor-chloride ion channel macromolecular complex Ca channel blockade: ethosuxamide inhibits low-threshold Ca currents especially in thalamic neurons that act as pacemakers to generate rhythmic cortical discharge Other mechanisms: Valproic acid - neuronal membrane hyperpolarisation possibly by enhancing K channel permeability

Anticonvulsants Drugs used in seizure disorders Absence seizures Tonic-clonic and partial Absence seizures Myoclonic seizures Status Epilepticus Infantile Spasms Cabamazepine Ethosuximide Corticotropin Valproic acid Short term control Prolonged therapy Phenytoin Valproic acid Corticosteroids Clonazepam Valproic acid Clonazepam Infantile spasms: corticotropin and corticosteroids are commonly used but cause cushingoid side effects. Diazepam Phenytoin Lorazepam Phenobarbital

Adverse Effects Teratogenicity Overdosage toxicity Neural tube defects Fetal hydantoin syndrome Overdosage toxicity Life-threatening toxicity Hepatotoxicity Stevens-Johnson syndrome Abrupt withdrawal Neural tube defects (spina bifida) associated with valproic acid Fetal hydantoin syndrome - phenytoin Overdosage: most of the commonly used anticonvulsants are CNS depressants - respiratory depression Life threatening toxicity fatal hepato. - valproic acid greatest risk to children <2 yrs of age and patients taking multiple anticonvulsant drugs Lamotrigin - skin rashes and life-threatening Stevens Johnsons syndrome Abrupt withdrawal - increased seizure frequency and severity

Medical Intractability No known universal definition Risk factors High seizure frequency Early seizure onset Organic brain damage Established after adequate drug trials Operability Intractability can be established after: 2-3 of the established newer first and second line AED, as monotherapy at least one in combination max tolerated dose High seizure frequency: daily / weekly episode brain damage: the more severe the brain damage, the greater the likelihood of seizure persistence Assess operability using imaging studies

Surgery Curative Palliative Catastrophic unilateral or secondary generalised epilepsies of infants and young children Sturge-Weber syndrome Large unilateral developmental abnormalities Palliative Vagal nerve stimulation Large unilateral developmental abnormalities such as cortical dysplasias and porencephalic cysts

Surgical Treatment A proportion of the pts with intractable epilepsy will benefit from surgery. Epilepsy surgery procedures: Curative (removal of epileptic focus) and palliative (seizure-related risk decrease and improvement of the QOL) Curative (resective) procedures: Anteromesial temporal resection, selective amygdalohippocampectomy, extensive lesionectomy, cortical resection, hemispherectomy. Palliative procedures: Corpus callosotomy and Vagal nerve stimulation (VNS).

Surgical Outcome Medical Intractability A well-localised epileptogenic zone EEG, MRI Low risk of new post-operative deficits

Status Epilepticus A condition when consciousness does not return between seizures for more than 30 min. This state may be life-threatening with the development of pyrexia, deepening coma and circullatory collapse. Death occurs in 5-10%. Status epilepticus may occur with frontal lobe lesions (incl. strokes), following head injury, on reducing drug therapy, with alcohol withdrawal, drug intoxication, metabolic disturbances or pregnancy. Treatment: AEDs intravenously ASAP, event. general anesthesia with propofol or thipentone should be commenced immediately.

References Stedman’s Medical Dictionary. MDConsult: Nelson’s textbook. Illustrated Textbook of Pediatrics. Video atlas of epileptic seizures – Classical examples, International League against epilepsy. Guberman AH, Bruni J, 1999, Essentials of Clinical Epilepsy, 2nd edn. Butterworth Heinemann. Manford M, 2003, Practical Guide to Epilepsy, Butterworth Heinemann.