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A 29-year-old woman came for evaluation. • The previous evening, her husband, who was in the next room, heard unusual sounds and found her lying on the bed looking dazed. She was confused for a few minutes but quickly returned to normal. • On questioning, she recalls an unwitnessed event about 1 month previously; at that time, she awoke feeling mildly confused, had sore muscles, and discovered she had bitten her tongue. • How should she be evaluated and treated? NEJM 2008;359:166 What is epilepsy? What is epilepsy? – Epilepsy is a disorder in which the person two or more epileptic seizures. Classification of Epileptic Seizures Classification of seizures (International League Against Epilepsy ILAE) Partial seizures 57% Generalized seizures 40% 3% Unclassified seizures Classification of epileptic seizures (ILAE) I. Partial seizures II. Generalised A. simple partial B. complex partial C. partial seizures evolving to generalised seizures (sometimes called secondarily generalised seizures) A. absence B. myoclonic C. clonic D. tonic E. tonic-clonic F. atonic III. Unclassified Epileptic Seizures • Includes all those seizures that cannot be classified because of incomplete data or because they defy classification into the above categories Simple partial seizures Somatosensory. Tingling of contralateral limb, face, or side of body Central fissure Postcentral gyrus Precentral gyrus Focal motor. Tonic-clonic movements of upper (or lower) limb. LEG TRUNK ARM ARM FACE Visual. Sees flashes of light, scotomas, unilateral or bilateral blurring Contraversive. Head and eyes turned to opposite side Auditory. Hears ringing, hissing or noises Autonomic. Sweating, flushing or pallor, and/or epigastric sensations Complex partial seizures Impairment of consciousness: cognitive, affective symptoms Formed auditory hallucinations. Hears music, etc FRONTAL LOBE Dreamy state; blank, vacant expression; déjà vu; jamais vu; or fear d Ž j ˆ PARIETAL LOBE POSTERIOR TEMPORAL GYRUS OCCIPITAL LOBE Formed visual hallucinations. Sees house, trees that are not there Bad or unusual smell Superior temporal gyrus Dysphasia Psychomotor phenomena. Chewing movements, wetting lips, automatisms (picking at clothes) Absence seizure Between seizures patient normal Seizure: Vacant stare, eyes roll upward, eyelids flutter (3/sec), cessation of activity, lack of response Tonic-clonic seizures A. Tonic phase Incontinence B. Clonic phase C. Post-ictal confusional fatigue Cyanosis Epileptic cry Cyanosis Generalised stiffening of body and limbs, back arched Eyes blinking Salivary frothing Clonic jerks of limbs, body and head Limbs and body limp Status epilepticus • A condition characterized by an epileptic seizure that is so frequently repeated or prolonged as to create a fixed and lasting condition • A medical emergency that requires prompt and appropriate treatment Some epilepsy triggers In rare cases patients may have one specific trigger that brings on a seizure, for example: Flashing visual stimuli Looking at a particular kind of pattern Hearing a particular piece of music Reading Epilepsy Syndromes: Examples • Benign epilepsy of childhood with centrotemporal spikes: – Localization-related, idiopathic epilepsy – Age of onset: 3-13 years – Simple partial onset and generalizing to tonicclonic seizures – No associated illnesses – EEG findings are diagnostic. – Aetiology is genetic. – Prognosis is excellent. Epilepsy Syndromes: Examples • Juvenile myoclonic epilepsy – Generalized, idiopathic with age-related onset – Onset during teenage years – Consists of myoclonic, absence and generalised tonic-clonic seizures – Specific gene locus in chromosome 6p21.2-p11 has been proposed – Treatment is very specific: valproate Epilepsy Syndromes: Examples • Infantile spasms (West’s syndrome) – Generalised, symptomatic and/or Idiopathic – Ages of 4-12 months – Characterized by a quick spasm that consists of flexion at the neck, waist, arms and legs. May occur a hundred times a day – Impairment in psychomotor development – 20% die before 5 years of age; of the survivors 75%-93% are mentally retarded; 25% of these will develop Lennox-Gastaut syndrome Epilepsy Syndromes: Examples • Lennox-Gastaut Syndrome – Generalized, idiopathic and/or symptomatic – Devastating disorder in children (1-8 years) with mixed types of seizures and progressive mental retardation – Seizures include tonic, tonic-clonic, atypical absence, myoclonic and atonic seizures – Cognitive deficit is present and may be associated with behavioural problems – Prognosis is poor and response to AED therapy generally unsatisfactory Incidence of seizure types Generalised tonic-clonic 23.0% Complex partial 36.0% Other generalised 8.0% Absence 6.0% Simple partial 14.0% Myoclonic 3.0% Unclassified 3.0% Partial unknown 7.0% Causes of epilepsy ? Disruption of the balance between excitation and inhibition Excess excitation Lack of inhibition epileptic seizures epileptic seizures Formation of epileptic seizures Hughlings Jackson An abnormal synchronous and sustained activity (overexcitation) in a group of nerve cells Epileptogenic focus Interictal activity Recruitment of surrounding, normal nerve cells into a synchronous pattern of larger abnormal activity Ictal activity Epileptic seizure Predisposing factors Disturbed levels of body water/electrolytes: – ‘water intoxication’/hyponatraemia – dehydration/hypernatraemia – hypocalcaemia – hypomagnesia Disturbed levels of blood glucose: – hypoglycaemia Altered blood gases: – reduction in oxygen supply to the brain, via e.g. asphyxia, heart attack, head injury, stroke Raised body temperature: – febrile convulsions Predisposing factors Altered sleep patterns: – sleep deprivation Hormonal disturbance: – thyroid disturbance – sex hormones Toxicity: – accumulation of toxic waste due to renal failure – congenital metabolic disorders e.g. phenylketonuria – poisoning or drug overdose Etiological categories of epilepsy Idiopathic – No identifiable cause, assumed to have a probable genetic basis Cryptogenic – No cause is found, but there may be an undiscovered physical cause which has yet to be found Symptomatic – A cause for the condition can be found (e.g. head injury, scarring due to infections in the brain, stroke, brain tumor). Aetiology of epilepsy Degenerative brain disorder 3.5% Infection 2.5% Neoplasm 4.1% Idiopathic and cryptogenic epilepsy 65.5% Vascular injury 10.9% Trauma 5.5% Congenital causes 8.0% Symptomatic seizures in different age groups 100 90 80 70 60 50 40 30 20 10 0 Others Degenerative Cerebrovascular Brain tumour Trauma Infection Development 0–4 5–14 15–24 25–44 45–64 65+ Diagnosis of epilepsy Diagnosis/evaluation of a seizure • History taking • Electroencephalography (EEG) • Brain images (CT scan, MRI) EEG morphologies Normal a) K-complex b) Lambda complex c) Mu rhythm d) Spike e) f) g) Sharp waves Repetitive spikeand-wave activity Sleep spindle h) Vertex sharp wave i) Polyspike discharge Specific EEG wave types EEG activation techniques • • • • • • Hyperventilation Photic stimulation EEG during sleep/awakening EEG after sleep deprivation Ambulatory EEG monitoring Other sensory stimuli Epidemiology • Prevalence of epilepsy is approximately 6 to 8 per 1000 population in the United States. • Affects about 45 million people worldwide. Epidemiology: prognosis effect of treatment 110 Untreated Treated % seizure free 100 90 80 70 60 50 40 0 3 6 12 months after first seizure 18 24 Epidemiology: prognosis Predictors of remission: • young age at onset • young age at diagnosis • generalized seizures • normal neurological examination • idiopathic etiology Epilepsy and quality of life • • • • • Burden of epileptic seizures Chronic drug treatment Pregnancy Employment Driving Treatment • • • • • • • • Treatment of underlying causes Not to treat Trigger avoidance Drug therapy Surgery Vagus nerve stimulation Ketogenic diet Complementary therapies Common surgical procedures Procedure Indication Hemispherectomy Children with severe unilateral epilepsy syndromes such as Rasmussen’s syndrome; such epilepsies usually have some preexisting loss of motor function on the contralateral side. Subpial transection Partial-onset seizures arising from a region of cortex that is nonresectable. Focal resection 1. Sub-dural grid used to localise the site of seizure onset 2. Frontal lobectomy of non-dominant hemisphere (red area indicates the extent of resection) Vagus nerve stimulation VNS lead transmits signals from the generator to the vagus nerve Generator is implanted under the skin in the upper left chest Ketogenic diet • A high fat/low carbohydrate diet • Tried occasionally in children with severe epilepsy syndromes such as Lennox-Gastaut syndrome and generalised myoclonic seizures. The aim is to achieve a state of body chemistry called ‘ketosis and acidosis’. Complementary therapies • Relaxation – Many complementary therapies involve relaxation. Yoga, meditation or other relaxation therapy might help some people to avoid seizures being brought on by stress. • Aromatherapy – Aromatherapy massage can be very relaxing and is liked by many people. Finding a qualified therapist is important as some of the essential oils used can be dangerous. Complementary therapies • Acupuncture – Probably not effective in the control of seizures, but it can be effective in reducing stress and anxiety. Again, a qualified therapist would be recommended. • Biofeedback – Some people can learn a technique which may delay a seizure or prevent them from happening – People with partial seizures are able to learn and use it to prevent the initial seizure from spreading to become generalised. It is most appropriate for people with the kind if partial seizures that start with ‘aura’-type symptoms – E.g. Someone whose simple partial seizures take the form of tingling in the arm may find that rubbing the arm can sometimes stop the seizure developing into a tonic-clonic type Drug therapy AED - History 1857 Bromides 1912 Phenobarbital Ethosuximide 1937 Phenytoin 50ies Carbamazepine 1960 Benzodiazepine 70’s Valproate 1989 Zonisamide Vigabatrin 1990 Lamotrigine Oxcarbazepine 1991 Felbamate 1993 Gabapentin 1995 Topiramate 1996 Tiagabine 1999 Levetiracetam Generations of AEDs Standard Phenytoin (PHT), Pfizer (Dilantin) Carbamazepine (CBZ), Novartis (Tegretol) Sodium valproate (VPA), Sanofi Synthelabo (Depakine) Ethosuximide (ESM), Pfizer Barbiturates Phenobarbital (PB) Primidone (PRM) New Felbamate (FBM), Carter-Wallace Vigabatrin (VGB), Aventis(Sabril) Lamotrigine (LTG), GSK(Lamictal) Gabapentin (GBP), Pfizer(Neurontin) Topiramate (TPM), Janssen-Cilag(Topamax) Tiagabine (TGB), Sanofi Synthelabo(Gabatril) Oxcarbazepine (OCBZ), Novartis(Trileptal) Benzodiazepines Clonazepam (CZP) Clobazam (CLB) Zonisamide (ZNS), Athena Standard AEDs: efficacy against common seizure types and syndromes Seizure type Agent Partial 2o generalised Tonicclonic Absence Myoclonic LennoxGastaut Infantile spasms CBZ + + + – – 0 0 VPA + + + + + + + PHT + + + – – 0 0 ESM 0 0 0 + 0 0 0 PB + + + 0 ?+ ? ? PRM + + + 0 ? ? ? CZP + + + ? + ?+ ?+ CLB + + + ? + + ?+ Key: + proven efficacy, ?+ probable efficacy, 0 ineffective, – worsens control ? effect unknown New AEDs: efficacy against common seizure types and syndromes Seizure type Agent Partial 2o generalised Tonicclonic Absence Myoclonic LennoxGastaut Infantile spasms LTG + + + + + + ?+ GBP + + ?+ 0 ?– ? ? VGB + + ?+ – – ? + OCBZ + + + – – 0 0 TPM + + + ? + + ? TGB + + ? ? ? ? ? FBM + + ?+ ?+ ? + ? Key: + proven efficacy, ?+ probable efficacy, 0 ineffective, – worsens control, ? effect unknown Tolerability – – – – – Dose-related side effects Idiosyncratic side effects Chronic side effects Drug interactions Teratogenicity Modes of action – Decreased excitation – via blockade of sodium channels, interaction with voltage-sensitive calcium channels or blockade of glutamate receptors. – Increased inhibition – via an increase in the concentration of GABA in the synaptic cleft. Blocking presynaptic glutamate release Treated epileptic neurone Untreated epileptic neurone Synaptic vesicle (glutamate neurotransmitter) AED blocks Na+ and Ca2+ channels Na+ + Na Na+ + Na 2+ Ca + Na Ca2+ Ca2+ 2+ Ca 2+ Ca 2+ Ca Presynaptic neurone + Na Presynaptic neurone Glutamate released in response to Na+ and Ca2+ influx into the presynaptic neurone Stabilised presynaptic neurone Modes of action AEDs that inhibit sodium channels AEDs that inhibit voltagedependent calcium channels Standard New Standard New Phenytoin Carbamazepine Valproate Phenobarbital Lamotrigine Oxcarbazepine Topiramate Zonisamide Ethosuximide Zonisamide Blocking postsynaptic glutamate receptors AED blocks non-NMDA receptor, reducing ion flow Ca2+ Na+ Ca2+ Na+ Mg2+ K+ AED blocks NMDA receptor, reducing ion flow NMDA receptor + Na+ K Non-NMDA receptor Key Postsynaptic neurone Glutamate Glycine Modes of action AEDs acting at NMDA receptors AEDs acting at non-NMDA (AMPA/kainate) receptors Standard New Standard New – Felbamate Phenobarbital Topiramate GABA transmission and its interaction with AEDs Presynaptic neurone Postsynaptic neurone Chloride ion channel GABAA receptors 1. In the resting presynaptic neurone, GABA is stored in vesicles. 2. The membrane of the postsynaptic neurone has chloride ion channels, which are normally closed. There are GABAA receptors located on the chloride channels. GABA transmission and its interaction with AEDs (continued) Benzodiazepines and barbiturates bind at GABAA receptors and so potentiate GABA-mediated inhibition. Topiramate enhances GABAA receptor function. Hyperpolarisation 3. Arrival of an electrical impulse causes the vesicles to fuse with the presynaptic membrane and so release GABA into the synaptic cleft. 4. Binding of GABA and GABAA receptors causes the chloride channels to open; this enables an influx of Cl- into the postsynaptic neurone. This influx of negatively charged ions hyperpolarises the postsynaptic membrane, in this way making ‘firing’ of the postsynaptic neurone even more difficult than usual. GABA transmission and its interaction with AEDs (continued) Subsequently, GABA is removed form the synaptic cleft by reuptake via special sites in the presynaptic neurone and glial cells. Following reuptake, it is broken down by the enzyme GABA-transaminase (GABA-T) and converted to succinate. Tiagabine inhibits the reuptake of GABA Vigabatrin increases brain levels of GABA by irreversibly inhibiting GABA-transaminase Modes of action AEDs that influence GABA transmission Standard New Valproate Barbiturates Benzodiazepines Topiramate Tiagabine Vigabatrin