Epilepsy /Seizures

1. Epilepsy /Seizures • CONVULSION • FEBRILE CONVULSION • STATUS EPILEPTICUS • SERIAL SEIZURES • SIMULATED • ISOLATED • CATAMANIAL Sx.

2. EPILEPSY Shrouded in mystery • Surrounded by prejudice, bias, fear • Visitation by evil spirit • Importance • uncontrolled; • life-long; • ? Cause; • ? Rx • profound psychopathological consequence • J. Caesar; Napoleon; Nobel; Peter the great;

3. 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 • Epilepsy–continuing tendency to Sx • chronic sx 2 stereotyped unprovoked attacks

4. 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.

5. AETIO – PATHOGENESIS BASIC MECHANISM • 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 • Holy prophet Mohammed (PBOH) • Prevention  spitting • (view in force at time of Christ)

6. Aetio-pathogenesis • 2. phlegm build up in Artery to head. • (Vein - bld; Artery –air) • Four body humors / liquid • bld; phlegm; red / black gall • Galeno-100 AD. • Rx: torniquet; amputation ; trepaning • 3. Infection: Various poisons / toxins • Rx: seizures (cf fever) - shake it out • prevention: stay off.

7. 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 twin–10- 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.

8. 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

9. BasicMechanism • NEUROTRANSMITTERS • Interplay of • Excitatory VS inhibitory synaptic activity / neurotransmitters • 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.

10. POTENTIAL MECH. OF ACTION OF AED’S Increase action of GABA Decrease action of excitatory Amino Acids. Increase action of adenosine modify ionic conductances

11. 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

12. Partial /focal Seizures (aura +) • Simple partial no impairment of consciousness ▪ Complex partial impairment of consciousness + ▪ Partial sx with secondary generalisation

13. Aura • Motor – twitching of extremities • Sensory – paraesthesia of extremities • Behavioural / Psychic – • Autonomic- rising epigastric sensation • - diaphoresis • - internal heat • - blurring of vision (miosis) • - palpitation

14. Prim Gen.TCSx (TAGAM) (no aura) • Tonic • Absence - (petit mal) • Generalised Tonic Clonic (Grand mal) • Akinetic / Atonic • Myoclonic

15. Classif. of Epilepsies & Epileptic syndromes 1985/1989 • Anatomical /Aetiological / structural / metabolic • Precipitant - age • Localisation – related idiopathic / symptomatic / cryptogenic • Generalised Epilepsies & syndromes I/S/C • Epilepsies & syndromes.

16. Classification- cont. • Undetermined whether focal / generalised . sleep related GTCS • Special Syndromes • situation related Sx • Catamanial • Febrile • Isolated Sx • Status Epilepticus

17. 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

18. PseudoSeizure • Unpatterned jerks • Attention seeking behaviour • Occurs when medical attendants are present. • Eyes closed unlike true seizures with opened eyes and tonic eye deviation • Sphinctericdysfn unlikely • INJURY / TONGUE BITING unlikely

19. Upright posture Regains consciousness on lying supine No body injury Negative phenomenon (No jerking) No sphincteric dysfn No post ictal confusion / Todd’s palsy ECG abnormal Any posture Supine posture not influence LOC Injury likely Positive phenomenon (Jerking likely) Sphincteric dysfn likely Post-ictal confusion / Todd’s palsy likely EEG abnormal Syncope / Seizures

20. 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)

21. 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

22. Investigations • 2) neuroimaging techniq.: structural / functional • Structural: CT scan / MRI – abnormal structure - tumor; strokes; AVMs,infective lesion-cysticerci • CT scan: success in detecting lesions: PS-30% • MRI – highly sensitive and specific in PS -100%

23. 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

24. 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.

25. 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

26. 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

27. 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.

28. Treatment • 4) suppression of recurrent chr. Sx– prophylaxis – • AEDs attenuate Sx activities; • not prevent formation of Sx focus - mainstay of Rx

29. 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)

30. 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 AED’s: • Efficacy; safety; • drug-drug interactions; • patients compliance, • cost effectiveness, • optimise quality of life.

31. Guidelines for treatment Rx policies • AEDs – mainstay of Rx • Isolated Sx 31 –71% recurrent risk • Accepted risk factors for treatment: • abnormal EEG • 2) abnormal neurologic o/e; normal intelligence • 3) Sx presenting as status epilepticus; • 4)postictal Todds palsy • 5)strong family hx of Sx. • 6) incomplete medical control of Sx for 1 to 5 yrs • 7) multiple Sx type either PS or G • 8) Sx + EEG changes. • 9) Sx + interval < 12 months. • 10) idiopathic Sx in a driver. • AEDs block the initiation or spread of Sx

32. Seizures not needing Rx • Benign Rolandic Epilepsy • Aura only seizures • Isolated Seizure – (ppt identified) • long interval b/t attacks;

33. Rational AED’s • 1857 – K+ bromide – std Rx in 1881 • 1912 – phenobarbitone – replaced Br- in 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)

34. Other AED’s • 1978 – Na valproate • 1993 – felbamate • 1993 – gabapentin • 1994 – lamotrigine • Clinical trials • Fosphenytoin • Vigabatrin • Tiagabine • Cinromide • Flunarizine • Oxcarbazepine • Progarbide • Topiramate • Zonisamide • Clobazam

35. Treatment summary • Sx type choice • Simple/complex partial/GTCS -CBZ Ph Absence;Myoclonic/prim. GTCS - Valpr • Absence only - Ethosuximide • Atonic -Poor resp. to conventional AED • Ethosuximide - inhibits the Ret. Inh. P; • others - inhibit Reticular excit. Pathwa

36. Adverse reactions of AED’s • idiosyncratic / dose-related • cerebellar toxicity – ataxia; nystagmus • folate deficiency – megaloblastic A • Phenytoin : hirsutism; gingival hyperplasia; gen lymphadenopathy • alopecia - valproate

37. 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

38. 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

39. 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.

40. No treatment • long interval b/t attacks • > 9 – 12 mths; • B. Rolandic epilepsy; • chn with only aura. • ? Simple Partial Sx

41. 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.

42. Refractory Treatment • 30% pts refractory = MDT (multi drug therapy) • optimal combination Rx • Rational polypharmacy • Goal: improve Sx control + minimal / no Adv effect. • achieved with drugs df mech. of action for synergism of anti-convulsant effect; few adv. effects and avoid D with similar adv. effect; limited/no interaction – significant enzyme induction/inhibition ; high Ric index; • Ric index = Effective dose/Toxic dose • Low : Phenobarb; Primidone; Benzodiazepines • Intermediate: Phy; CBZ;val.; ethosuximide • High: felbamat; Gabapent; lamotrigine; vigabatrin

43. Seizure control • Correct dose: smallest - Sx control without s/e • 2/3 adequate control -single - initial choice or alternative • 1/3 inadequate despite trials of several AED • ? inappropriate D selected; maximally tolerated dose not reached; doses were poorly timed; medications introduced too rapidly or Sx provoking events not identified - focal E related to structural lesions with multiple Sx type and developmental delay.

44. When to stop AED’s • 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.

45. 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

46. Refractory Seizures • Rx of refractory E: 30% ineffective AEDs • 20% in PGS and 35% in PS • Refractory (Medical intractability): Sx so frequent or severe that they limit pt ability to live life fully according to his or her wishes.; necessitate use of medications that, although effective, produce adverse effects. • Rx aims to < frequency and severity of Sx • 1st with 2 of 3 first line drug

47. Adverse reaction of AED’s • 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.

48. 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

49. 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

50. Status epilepticus • Hyperthermia; • cvs dysfn; • metabolic deraingement • irreversible neuronal injury after 2 hrs • Causes: • Stroke/tumor if not previously epileptic; • withdrawal or non compliance; • metabolic disturbance, • drug toxicity; • refractory epilepsy ; • CNS infection and head trauma