EPILEPSY Shrouded in mystery Surrounded by prejudice, bias, fear Visitation by evil spirit Importance uncontrolled; life-long; ? Cause; ?

use; ? Rx profound psychopathological consequence J. Caesar; Napoleon; Nobel; Peter the great; Myths in Epilepsy and Sexual Functions Seizures episodic event xterised by discharges of aggregates of hyperexcitable cerebral neurones + motor; sensory; autonomic; psychic symptoms + impairment of consciousness.

Epilepsia- (greek) to be attacked; seized; grabbed Epilepsycontinuing tendency to Sx chronic sx 2 stereotyped unprovoked attacks STATUS EPILEPTICUS Single episode of seizure lasting at least 30 mins or two or more seizure in a 30 mins period without returning to baseline mental state in between. Serial seizure two or more seizure with returning to baseline mental state in between. EPILEPSIA PARTIALIS CONTINUA Partial seizure Epileptic encephalopathy; sustained epileptic activity contributing to progressive cerebral dysfunction without overt electrographic seizure pattern (Engel 2001). Epidemiology world-wide; commonest non-infectious > in developing; (4-5 X); 37/1000 dev.ing (Osuntokun) 1.3 9 devd dx of chn + young adults: < 20 in 2/3 risk factors: febrile convulsion ; head injury; post-meningitis; communicable dx immunisation lack; perinatal NNJ ; family hx. EPIDEMIOLOGY CONT. The lifetime likelihood of experiencing at least 1 epileptic seizure is about 9%, the lifetime likelihood of receiving a diagnosis of epilepsy is almost 3%.

 the prevalence of active epilepsy is only 0.8%. AETIOLOGY Ancient Greek: Moon sickness / Holy sickness (supernatural) Hippocrates (450BC) - natural phenomenon. Three different theories 1. Possession by Spirit / Demons Rx: prayer / fasting - mark 9 v17-29 Prevention spitting (view in force at time of Christ) AETIOLOGY OF EPILEPTIC SEIZURE Congenital disorders Degenerative diseases Genetic Idiopathic Infectious/fever Metabolic Neoplastic Perinatal/gestational Toxic Traumatic Vascular

Clinical features and Classification ILAE (International league against epilepsy) Int. class. Of Epileptic Sx 1969 ; 1981. clinical sx type; EEG sx type; interictal EEG. Partial/focal/localisation-related Generalised Unclassified sleep/neonatal sx

Partial /focal Seizures (aura +) Simple partial no impairment of consciousness

Complex partial impairment of consciousness +

 Partial sx with secondary generalisation Aura Motor twitching of extremities Sensory paraesthesia of extremities Behavioural / Psychic Autonomic- rising epigastric sensation - diaphoresis - internal heat - blurring of vision (miosis) - palpitation Prim Gen.TCSx (no aura) 6 major categories: (1)absence seizures, (2) tonic seizures, (3) clonic seizures, (4) myoclonic seizures, (5) primary generalized tonic-clonic seizures, (6) atonic seizures. Classif. of Epilepsies & Epileptic syndromes 1985/1989 Anatomical /Aetiological / structural / metabolic Precipitant - age an epileptic syndrome is a group of signs and symptoms that share a common pathogenesis, prognosis, and response to treatment.

EPILEPTIC SYNDROME 2 major categories: localization-related syndromes and generalized-onset syndromes. Physicians would ideally classify their patients' seizures by using the classification for seizure types and make a syndromic diagnosis if possible. Localization-related epilepsies and syndromes Idiopathic with age-related onset Benign childhood epilepsy with centrotemporal spikes Childhood epilepsy with occipital paroxysms Symptomatic Generalized epilepsies and syndromes Idiopathic with age-related onset Benign neonatal familial convulsions Benign neonatal convulsions Benign myoclonic epilepsy of infancy Childhood absence epilepsy (pyknolepsy)

Juvenile absence epilepsy Juvenile myoclonic epilepsy (JME) Epilepsy with grand mal seizures on awakening Idiopathic and/or symptomatic infantile spasms Lennox-Gastaut syndrome Epilepsy with myoclonic astatic seizures Epilepsy with myoclonic absences Symptomatic Classification- cont. Undetermined whether focal / generalised . sleep related GTCS Special Syndromes situation related Sx Catamanial Febrile Isolated Sx Status Epilepticus PATHOGENESIS Complex & varied according to aetiology, syndrome and focality Modified by age, sex, hormonal,or other factors Abnormal neuronal and network excitability. Basic Mechanism Genetics: - important in prim. gen. Sx ? autosomal dominant with age spp penetrance 1 parent - 4% ; 2 parents 20 30% 1 Identical twin - 80%; non-identical twin10- 20% Microdysgenesis abnormal cortical maturation Instability of Resting membrane potential abn. k+ conductance ; defect in Calcium channels; Deficiency in mitochondrial ATPase Shrinkage of perineural space. Basic Mechanism IONIC CONDUCTANCE: 3 distinct pathologic events in seizures: a) Initiation > Na / Ca conductance depolarisation > Neuronal firing b) Maintenance - same as above c) Arrest - > K / Cl conductance hyperpolarisation - < Neuronal firing

 BasicMechanism NEUROTRANSMITTERS Interplay of Excitatory VS inhibitory synaptic activity / neurotransmitters e.g GABA receptors in AD febrile seizures + syndrome 1. overriding of excitatory neuronal activity (Glutamate/Aspartate/Ach opens Na channels) 2. suppress. of inhibitory event (GABA defect Cl) G.Acid GABA (G.A decarboxy.- B6 co-factor) 3. Adenosine reg. release of excitatatory Amino Acid. Differential Diagnosis Syncope Migraine Narcolepsy T.I.A Hypoglycaemia TGA (Transient Global Amnesia) Hysteria Breath holding spells in children Hyperventilation / Panic attacks Pseudo seizure Toxic effects of drugs PseudoSeizure Unpatterned jerks Attention seeking behaviour Occurs when medical attendants are present. Eyes closed unlike true seizures with opened eyes and tonic eye deviation Normal Prolactin level Syncope / Seizures Upright posture Regains consciousness on lying supine No body injury Negative phenomenon (No jerking) No sphincteric dysfn No post ictal confusion / Todds palsy

ECG abnormal

Any posture Supine posture not influence LOC Injury likely Positive phenomenon (Jerking likely) Sphincteric dysfn likely Post-ictal confusion / Todds palsy likely EEG abnormal Investigations EEG EEG supports the diagnosis; classify the Sx type; provides evidence for existence of E syndrome. 30% normal in Epileptics 20% abnormal EEG in Normal individuals sharp / slow wave abnormalities Hypsarrhythmia (slow mountainous) - Infantile sx 3 cycl / s. spike and slow wave discharges (absence) EEG 30% normal in epileptic; 20% abnorm. in normal >diagnostic yield: > sleep deprivation + depth EEG Nasopharyngeal / foramen ovale / Sphenoidal / Epidural / Subdural / cortical (ECG) / intracerebral (ICH). ( MRI is supplanting depth studies) video monitoring (telemetry). Ambulatory EEG Electroencephalogram (EEG) is a tool for evaluating the physiological state of the brain. offers excellent spatial and temporal resolution to characterize rapidly changing electrical activity of brain activation captures voltage potentials produced by brain cells while communicating. In an EEG, electrodes are implanted in deep brain or placed on the scalp over multiple areas of the brain to detect and record patterns of electrical activity and check for abnormalities. Scalp EEG Data Acquisition Investigations 2) neuroimaging techniq.: structural / functional Structural: CT scan / MRI abnormal structure - tumor; strokes; AVMs,infective lesioncysticerci CT scan: success in detecting lesions: PS-30% MRI highly sensitive and specific in PS -100%

 MRI MRI best tool for imaging in E. produces better spatial resolution, excellent images of the temporal fossae which is not visualized well by CT, reveals isodense lesions on CT. no radiation exposure;save in pregnancy MTS visualization rate approach 80 100% cf maximum of 5% with CT Investigations Cranial radiograph (1%); air encephalogram no longer used ; angiography used pre-op Functional Neuroimaging abnorm. of brain fn hypo/hyper metab+changes neurotransmitter level. Radionucleide study - PET/SPECT normal physiological and functional changes PET: - measures aspect of cerebral function negligible clinical role; MRI > useful clinically. Investigations SPECT - cf PET but uses different radioisotope magnetic resonance spectroscopy + fnal MRI S. Prolactin level pseudoSx baseline; 0, 5,10 minutes

electrolytes; glucose; Ca2+,Mg2+, hepatic/ renal dx screen for toxin in blood / urine - risk gp. Lumbar Puncture Meningitis / Encephalitis Treatment Multimodal education of the patient. treatable not curable; avoidance of ppt factors address varieties of psychol. + social issues Rx underlying condition-cause/ contributing factors suppression of recurrent Sx AEDs/surgery. Rx - special situatn preg; occ. grps - driver Rx plans must be individualized Treatment 1) Avoidance of ppt factors: avoid situations lowering Sx threshold, alcohol. sleep deprivation normal sleep schedule; 2) Social / psychological support 95% of epileptic chn are in ordinary school ; 75% of adults have normal job; 8% sacked. Cost of treatment is enormous 3) Rx underlying conditions metabolic cause: reverse the abn. prevent recurrence. AEDs unnecessary.

 Treatment 4) suppression of recurrent chr. Sx prophylaxis AEDs attenuate Sx activities; not prevent formation of Sx focus - mainstay of Rx Treatment Treat pt with Seizures NOT Seizures in the patient

AIM: Control Sx Improve quality of life activity limitations drive/swim Treatment policies Monotherapy vs renaissance of polytherapy Phasing in of medication (except phenytoin /phenborb) Treatment Policies drug interaction-hepatic stimulation- Contraceptives Gradual withdrawal / > /<. duration of Rx 2 3 years from time of last Sx Stop treatment : Normal EEG / Gen. Sx. Precipitant identified / < Severity Evaluation of AEDs: Efficacy; safety; drug-drug interactions; patients compliance, cost effectiveness, optimise quality of life. POTENTIAL MECH. OF ACTION OF AEDS

Increase action of GABA

Decrease action of excitatory Amino Acids.

Increase action of adenosine

modify ionic conductances MECHANISM OF ACTION OF AED Blockers of repetitive activation of sodium channel - Phenytoin, carbamazepine, oxcarbazepine GABA enhancers - Phenobarbital, benzodiazepines Glutamate modulators - Topiramate, lamotrigine, felbamate T-calcium channel blockers - Ethosuximide, valproate N- and L-calcium channel blockers - Lamotrigine, topiramate, zonisamide, valproate H-current modulators - Gabapentin, lamotrigine Blockers of unique binding sites - Gabapentin, levetiracetam Carbonic anhydrase inhibitors - Topiramate, zonisamide Rational AEDs 1857 K+ bromide std Rx in 1881 1912 phenobarbitone replaced Brin 1930 1937 phenytoin Trimetha/dimetha-dione Ethosuximide-Abs 1974 Carbamazepine psychotropic prop., positive effect on attentiveness /cognition; anti-depressant, mania/bipolar depression hyperexcitability/aggressive states (Episodic discontrol syndrome) POTENTIAL MECH. OF ACTION OF AEDs PHY; CBZ; Val; lamotrigine: inhibit Na chnls PHY also inhibits Ca chnls. Benzodiazep/barbiturat. interact GABA rcpts Benzodiazepine inhibit uptake of adenosine Val. > GABA : > synths (> GAD);catabolism (inhibit GABA-T Gabapentin > GABA level = > synthesis/release; also < glutamate synthes Ethosuximide / Val: inhibit Ca2+ channel in thalamus. Carbamazepine 1974 1st dev in 1950 as a behavioural agent for bipolar affective disorder struct. cf trycyclic antidep. psychotropic prop., +ve effect on attentiveness /cognitn anti-depressant, mania/bipolar depression hyperexcitability/aggressive state(Episodic DC Blocks Na channels and NMDA. 10,11 epoxide weak anticonvulsant metabolite. Autoinduction(4w). Plasma life: 50 H vs 5 24H Na+ Valproate

1978 *Na valproate branched chain f. acid (carboxylic acid) 1st used in epilepsy in 1964. mech of action speculation. inhibits GABA breakdown, or > synthesis. Opens K channel causing hyperpolarisation. AEDs - Phenytoin 1937 *phenytoin similar to Barbiturate acts on Na and K channels, has effect on GABA receptors; Potent enzyme inducer. Trimethadione/Dimethadione/*Ethosuximide- Absence Seizures Anticonvulsive treatments for specific types of seizures

Absence seizures: ethosuximide. are valproic acid, lamotrigine, or topiramate. Do not use carbamazepine, gabapentin or tiagabine Tonic or atonic seizures: valproic acid, lamotrigine, topiramate or felbamate . Myoclonic seizures:The best medications for JME and myoclonic seizures are valproic acid, lamotrigine, and topiramate. Anecdotal evidence suggests that zonisamide and levetiracetam might be helpful in JME. Primary generalized tonic-clonic seizures: This seizure type responds to valproic acid, topiramate, or lamotrigine. Partial-onset seizures: Carbamazepine is considered first-line therapy. However, in special populations, lamotrigine, oxcarbazepine, and topiramate might be better choices. Adjunctive therapy with levetiracetam, tiagabine, gabapentin, or pregabalin might be a choice if the first or second monotherapy trial with first line treatments failed. Treatment of status epilepticus The ideal AED effective, quick acting, non-lipophilic and no tendency to accumulate, Restore homeostasis 15 mins Airway / Intubation - 100% 02; B.P Blood for glucose, E, C, U, Ca. IVF N/S; glucose 50ml/50% + Thiamine 100mg Rx hyperthermia. Stop convulsion Diazepam 10mg I.V repeat with every Sx up to 50mg. phenytoin 20mg/Kg I.V Paraldehyde + phenobarb 260 mg I.V Diagnostic evaluation identify cause Hx, O/E , inv. (run concurrently with above) ? Structural/metabolic abnormality Cosmetic side effects of antiepileptic drugs

Antiepileptic drugs and hormonal contraceptives Enzyme-inducing drugs

Phenytoin Phenobarbital Primidone Carbamazepine Oxcarbazepine (Topiramat)

High doses hormonal contraceptives

Not enzyme-inducing drugs

Valproate Vigabatrin Lamotrigine Gabapentin Tiagabine Levetiracetam Pregabalin Zonizamide

Adverse reactions of AEDs idiosyncratic / dose-related cerebellar toxicity ataxia; nystagmus folate deficiency megaloblastic A Phenytoin : hirsutism; gingival hyperplasia; gen lymphadenopathy alopecia - valproate Status Epilepticus

Restore homeostasis 15 mins Airway / Intubation - 100% 02; B.P Blood for glucose, E, C, U, Ca. IVF N/S; glucose 50ml/50% + Thiamine 100mg Stop convulsion Diazepam 10mg I.V repeat with every Sx up to 50mg. phenytoin 20mg/Kg I.V

Paraldehyde + phenobarb 260 mg I.V Diagnostic evaluation identify cause Hx, O/E , inv. (run concurrently with above) ? Structural / metabolic abnormality Prognosis - poor Evidence of diffuse cerebral disease Early onset Partial or mixed type Progressive neurological dx T. sclerosis Long duration of Sx Severe epileptic syndrome- West, L.G.S. Poly-pharmacy before Sx free. Refactory Epilepsy persistent epileptiform EEG Prognosis -good good control / remission / prognosis Adult onset - idiopathic Sx Infrequent gen. Sx. Situational Sx with known precipitant mild attacks. Benign syndrome - Benign Rolandic E Good initial response to AEDs. MonoRx b/4 Sx free. normal EEG . petit mal. No treatment long interval b/t attacks > 9 12 mths; B. Rolandic epilepsy; chn with only aura. ? Simple Partial Sx Whom to treat Accepted risk factors for treatment: 1) abnorm. neurologic o/e ; subnormal intellig. 2) Sx presenting as status epilepticus; 3)postictal Todds palsy 4)strong family hx of Sx. 5) multiple Sx type either PS or G 6) 1 Sx + EEG changes. 7) 2 Sx + interval < 12 months.

 8) idiopathic Sx in a driver occupational grp. When to stop AEDs Normal EEG / Gen. Sx. Precipitant identified / < Severity 70% chn (outgrow); 60% adults stop (remission) Duration of Rx: stop when Sx free for > 2 yrs. Withdraw slowly over 3 6/12. decision discussed with pt +knowledge of risks, economic costs and side effect of continued Rx. Seizure Relapse There is 30-40% risk of relapse and 20% of those remaining on AEDs also likely relapse. Factors predictive of SX relapse ff withdrawal Age > 16 years Hx of Sx after initiation of AED - breakthr Sx, Focal Sx; TCS; Myoclonic Sx; Abnormal EEG Adverse reaction of AEDs S/E idiosyncratic / dose-related cerebellar toxicity ataxia; nystagmus folate deficiency megaloblastic A hirsutism;gingival hyperplasia;gen. Lpathy-Ph alopecia valproate Folate def : < in speed of nerve impulses Death Stevens-johnson ; aplastic anaemia; hepatic failure. Pancreatitis; thrombocytopenia; altered appearance, obesity, drowsiness, cognitive and behavioural dysfunction. Other treatment Options Ketogenic diet: The ketogenic and medium chain triglycerides introd by Wilder -1921 high in fat , low in CHO resulted in ketosis and acidosis (cf starvation exerts anticonvulsant effect) Intracellular acidosis < neuronal excitability and prevent Sx discharges Intermittent Vagus N stimulation adjunct for refractory Sx >release of inhibitory neorotransmitter; < Aspartate; > serotonin and dopamine Vagus nerve stimulator in the neck - implanted , programmable, pacemaker like device connected by 2 stimulating electrodes to the left vag.N- safe;well tolerated; transient

hoarseness Vagus Nerve Stimulator Surgery in Epilepsy most pts are Rxed medically >70% controlled on monoRx, a further 10% can be significantly improved by use of newer drugs 59% experienced complete Sx remission, 19% very rare recurrence postop; 19% still had Sx but the reduction in frequency was clinically significant. 2% remained unchanged Temporal lobe resection; lesionectomy ; selective amygdalohippocampectomies Pregnancy - causes

endocrine effect on CNS: Estr < ; Prog > Sx susceptibility

variation in pharmacokinetics; dilutional (45% >B.V 3rd trim.; > D elimination - > unbound fraction changes in compliance. Malabsorbtion. Fetal hydantoin syndrome fetal abnormalities 5-6% cf 2-3% in the healthy mothers teratogenic effect ; > with > medications. Fetal hydantoin syndrome Facial dysmorphism; cleft lip/palate; cardiac defects and digital hypoplasia; nail dysplasia. Also with CBZ/val (1-2% NTD cf 0.5 to 1%) lowest effective monoRx 1st trim. folate 1-5mg/d Haemorrhage in the new born transient /reversible vit K def 50% of newborn newborn < 24Hrs Rx mother oral vit K 20 mg dly in last 2/52; infant 1 mg at birth; fresh frozen plasma (2 clotting factors < 5%).

Abn PT/PTT-baby; (mother0)blocks vit K transport across PL. (Fetal) Perinatal mortality 1.2 x norm Chn of epileptic women > x2 dev Sx later in life cf chn non epileptic ? drug Rx or genetic predisposition Breast feeding+; ? lethargy and poor feeding THE END THANK YOU