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Conventional Anti epileptic drugs

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Conventional Anti epileptic drugs

Conventional Anti epileptic drugs


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  • REFRACTORY EPILEPSY
  • Transcript

    • 1. DEBATE – EPILEPSYConventional Therapeutic Strategies Vs Modern Aggressive Management for Remission in Epileptic patients Prof. KS. Endowment Oration Black Thunder Resorts, Mettupalayam 27-28 October, 2012.
    • 2. CONVENTIONAL THERAPEUTIC MEASURES WITH CONVENTIONAL AED ARE ENOUGH Prof. Dr. B. PRAKASH. MD. DM. FAGE., PSG IMS & R, COIMBATORE. prakashneuro@yahoo.co.in, 9789481179
    • 3. REMISSION IN EPILEPSY• A Seizure free period of 5 years or more• 70-80 % acheive remission with medical treatment only• Prognosis of Epilepsy considered as poor - long ago – “Seizures beget seizures”• Prognosis depends on Etiology, Syndrome &Management• Mostly Conventional AED are enough and suitable• Aggressive Management is required only in a few
    • 4. 4 PERCENTAGE OF REMISSION• In 75 % of patients, AED can be withdrawn successfully after 2 to 5 years.• Even in pts with MR / CP, the remission can be achieved in 35 %• 10 percent of new patients fail to gain control of seizures despite optimal medical management
    • 5. 5
    • 6. AGE AND REMISSION• < 16 Years (Poor) – 50% - 5yr remission (9 yr follow up) • Onset < 1 yr: Poor prognosis • Childhood  Follow up 30 Yrs 80% Remission• 16 – 31 Yrs (Avg) – 70% - 5yr remission (9 yr follow up)• Middle Age (Good) – 80% - 5yr remission (9 yr follow up)• Elderly – Difficult to asses
    • 7. ETIOLOGY AND 5YR REMISSION (9YRS FOLLOW UP) • Acute Symptomatic Seizure : 80% • Idiopathic Seizures : 60% • Vascular Disease : 40% • Congenital Lesions : 30% • Cortical Dysgenesis : 24% • Post Traumatic : 20% • MTS : 10% • Dual pathology (MTS + ) : 03%
    • 8. OTHER FACTORS FOR REMISSION• Gender : No role• Early Treatment : No role• Always normal EEG : Good Prognosis• Gen paroxysmal EEG  Increase the risk of recurrence• Focal EEG abnormal  Less clear
    • 9. ROLE OF PHYSICIAN IN ACHIEVING REMISSION 1. Correct Diagnosis 7. Proper intake of drug 2. Proper Classification 8. Adding 2nd Drug 3. Appropriate Investig’n 9. Watch for S/E, D/I 4. Identifying Etiology 10. Use PK to fine tune 5. Selection of AED 11. Regular follow up 6. Correct Dose 12. DO NOT GIVE UP 10 Ref 9
    • 10. EPILEPTIC SYNDROMES WITH EXCELLENT PROGNOSIS• BECTS• Benign occipital Epilepsy
    • 11. REFRACTORY EPILEPSY
    • 12. REFRACTORY EPILEPSY• > 2 Seizures/month x 2 yrs & 2 mono + 1 Poly therapy failure – 36% of newly diagnosed  ↓ to 5% by giving suitable AED • Failure of 2 AED : Relative resistance • Failure of 6 AED : Absolute resistence – Partial seiz are usually refractory (CPS: 7.5 million-WW)• Decide within 2 years that epilepsy is refractory• Can we recommend surgery by the end of 2 yrs ?• More trials should be done as more drugs are available.• 1/5 has good hope even after sev yrs and trials of > 5 drugs
    • 13. RECURRENCE OF SEIZURESType : EEG abnormality:• Focal : Always • Nil: Rare• GTCS : 75% @ 3Yrs • Epileptiform : Twice the risk• Symptomatic Seiz : 40%@1 yrFrom 1st Seizure: Age:• Within 6 m :Mostly • Children : 52 – 83 %• Within 1 year:75% • Elderly : high• After 5 years: Rare 14
    • 14. RISKS FOR RECURRENCE• Family History • Head Injury  Epilepsy• Etiology (1 Yr recur’nce) – Mild: 2%, Mod: 5% – Congenital : 100% – Sev: 15%, Penetrg : 50% – Acquired : 75% • Seizure Type – Acute Pptg cause : 40% – Partial > Genelzd• Neu Abnormalities – Nocturnal> Day time• EEG Abnormalities • Initiating Tt – 12m: 26%, 24m: 50%,• Intra cranial infection – 36m: 57% 15
    • 15. 1 6 PREDICTORS OF RESISTANCE• Onset at Infancy• Organic brain damage• Seizure type• Multiple Seizures• Higher seizure Frequency• Long duration of uncontrolled seizures• Failure of past AED• Pathological EEG
    • 16. 17
    • 17. CONVENTIONAL AED
    • 18. CONVENTIONAL AEDFREQUENTLY USED RARELY USED• Phenytoin • Ethosuximide• Phenobarbitone • Primidone• Carbamazepine • Mg SO4• Valproate • Acetazolamide• Benzodiazepine • Bromide 19
    • 19. CONVENTIONAL AED• Emergency : handled by family Dr  BZD is his DOC• Emergency Situations in Hsptl : BZD / DPH / SVP• Rapid onset of Action : Most conventional AED• Forgets TDS dose : Most AED : OD /BD dose available• Special situations (MC/Abs/West) : SVP / ESX• Aura / SPS : Pocket BZD• Hepato toxicity : Use PB / Cardio toxicity : Use SVP• Skin Rash : Use BZD• Extremes of Age : SVP / BZD / PBAll above  Good Control  Rare recurrence  No newer AED / Aggressive Tt is needed.
    • 20. 21
    • 21. 1. PHENYTOIN 2. PHENOBARB• Developed in 1937 • Introduced 1912• Stood “TEST OF TIME” • Cheapest• For 75 yrs • Still the powerful AED• Only dependable AED • Childhood Seizures• Long T½ : Single dose • Sedation is overemphasized• Adv / Toxic effects are dose • 2nd in the SE Protocol dependent • In Hepatic Failure – Useful• Cost effective alternative• SE : SJS / ↓Ca / PNP • T ½ : 50-140 Hrs • Oral /IV/IM/Syrup 22
    • 22. 3. CARBAMAZEPINE 4. VALPROATE• Acts at VGSC • Na / Ca / GABA related• Plasma conc = CSF • IV formulations• CR preparations for BD • MC / Abs / West• SPS, CPS – Whole spectrum Cover• Least teratogenic • Hepatitis / Pancreatits – 1/45,000• Hemat / Cardiac SE 23
    • 23. 5. ETHOSUXIMIDE 6. MG SO4• Primary drug for Pure • Eclampsia Absence Seizures• ↓ Ca+ Currents at Thalamic Neurons• T ½ 30 Hrs• No renal / Hepato Toxicity• GI/Parks/Psy/Skin/ Hemat SE + 24
    • 24. CONVENTIONAL AED ARE BETTER !!• Newer AED (Emilio: Are Newer AED better than Older? Ref 13) – Less efficacy in GTCS / Narrow spectrum of activity / Costlier – Ad.E: Felb-toxicity, Vigab-Field, Seiz aggvn-GBT,Tiag,OXC – Seiz freedom – Cannot replace Older AED• SANAD: 6 yrs study – SVP is 1st line Tt for GTCS (Ref : 4)• KOMET: SVP/ CBZ are superior to LEV in Gen Seiz ( Ref :5)• ETX and SVP are the DOC in absences not responding to other (Ref: 6)• CBZ better than GBP/LTG/TPM/OXC for remission in 12 m (Ref: 10 )• CBZ / DPH (monotherpy) is DOC for adults GTCS / PS / both (vs PB/ PMD) (Ref: 7)• No good clinical evidence to support the use of newer monotherapy over older drugs (Ref: 11)
    • 25. SUCCESSIVE MONOTHERAPY TRIAL• Seiz continue with 1st AED• Add 2nd AED, mid ther dose Seiz Stops • Maintain 2 / ? WD 1st AED – Seizure Persists• Push to max tol dose Seiz Stops • Maintain 2 / WD 1st AED – Seizure Persists• Taper 1st – Wait for Seiz Stops • Maintain 3 / ? WD 2nd AED Clearance – Add 3rd , mid ther dose – Seizure Persists• Push to max tol dose Seiz Stops • Maintain 3 / WD 2nd AED – Seizure Persists• Addl AED  Surg  VNS 1: Phenytoin 2: Carbamaz 3: Valproate 26
    • 26. 27
    • 27. COMBINATION THERAPIES• 5 Conv & 11 New AED available• No single AED is superior in refractory epilepsy• No surgery gives FREEDOM from seiz in Ref Epi• Fine tuning of combination with PK principles• Total seizure freedom is usually achieved by combination AED• 16 AED  120 two drug combinations / Several 3 drug combinations• 265 drug addition in 155 pts (Shorvon) – Seizure Freedom: with One AED - 47%, with 2 or 3 AED - 11% Ref 9
    • 28. AGGRESSIVE ALTERNATIVES
    • 29. 3 0 SURGICAL TREATMENT• Highly invasive technique• Useful Only for refractory epilepsy – Small no: 1%• Even in most favorable MTS group – seizure freedom is achieved in only 90%• 2% will have significant neurological sequel
    • 30. SURGERY & AGGRESSIVE MEASURES• 1st AED  Fails  Escalate dose • Affordability• 2nd AED  Fails  Escalate dose • Willingness – Patient + Family• 2 AED  3 Drugs  Agg Rx • Single lesion • Resistant to trials of AEDNOT FIT FOR SURGERY: • No Significant Co-morbidities• Poor Cardiac fn – Elderly • Same Foci• Tumor – 1st Surgery done …? – Structural + Epileptogenic• Emergency situations – SE • No: of pts going to table : Less• Deep seated lesions / Multiple lesions • Well Experienced Surgeon • Any way  to continue medicationRef 8 31
    • 31. CONTRA INDICATIONS FOR SURGERY• ABSOLUTE – Primary Generalized Epilepsy – Minor seizures that do not impair QOL• RELATIVE – Progressive medical / Neurological disorders – Active Psychosis – Behavioral problems that impair rehabilitation – IQ < 70 – Poor memory function in hemisphere contra lateral to epileptic focus
    • 32. HIPPOCAMPAL STIMULATION• Reduced CPS frequency reported in uncontrolled studies• Median reduction in seizures of 15% – Effects seemed to carry over into the OFF period – Possible implantation effect. VAGAL NERVE STIMULATION (VNS)• A 50% reduction in seizure frequency has been reported in about one-third of patients.• However, seizure freedom is rare Tellez-Zenteno et al NEUROLOGY 2006;66:1490–1494
    • 33. RISKS OF BRAIN STIMULATION• VNS • TMS – Cough, Hoarseness when – Rare seizures at high (>10hz) stimulator on frequency – dyspnea, pain, paresthesia, an • Epilepsy therapy trials are at ≤ 1 hz d headaches – Mild headache, scalp discomfort – respond to alteration of stimulation settings • DBS – Very rare vocal cord – Bleeding paralysis, bradycardia – infarction during implant – intracranial infection – All less likely with surface RNS• The misdiagnosis of epilepsy and the management of refractory epilepsy in a specialist clinic - D. SMITH, - Q J Med 1999; 92:15–23• Surgical Treatment for Refractory Epilepsy: Review of Patient Evaluation and Surgical Options - KristenM. Kelly - Epilepsy Research and Treatment Volume 2011, Article ID 303624• The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol - Simon Shorvon - Brain 2011: Page 1 of 17• Refractory Epilepsy: One Size Does Not Fit All - Jacqueline A. French - Epilepsy Currents, Vol. 6, No. 6 (November/December) 2006 pp. 177–180 34
    • 34. COMPLICATIONS OF SURGERY• Rate of neurological complications reported : 5.4%• Vascular Injury / Spasm: Hemiplegia, Anopia, Lang’ge• Frontal lobe resection: Personality Changes• Dom Infr parietal lobe: Gerstmann Syndome• Hemispherotomy: Superficial hemosiderosis• Callosotomy: Mutism, Apraxia, Incontinence• Multiple sub-pial resections: Mild improvement only• VNS : Similar result to AED / 50% achieve 50% seiz reduction Walking pt with seizures  Bedbound, seizure free
    • 35. COMPLICATIONS OF SURGERY• Temporal Lobe Surgery • Frontal lobe Surgery: – Depression: 4-24 % – Some compln: 8.4% – Psychosis : 3% – Reduction in IQ : 10% • Hemispherectomy: – Perm’nt Complicn: 2% – Serious permn’t compln: 0.8% – Death : 0.24% • Mult. Subpial resections:• Corpus Callosotomy: – Aphasia : 5.9% – Paraly’s / Disconn / Lang : 3.6% Ref 14 36
    • 36. SURGICAL TREATMENT• Patient selection is complicated• After a prolonged pre-surgical evaluation many are not feasible to undergo surgery – Difficult to accept by the patient• Final recommendation is always a balance – Between probabilities of Risk Vs Benefit
    • 37. SUMMARY
    • 38. SUMMARY• Most of the Epilepsy needs only medications• Drugs alone or in combination brings remission in most of the cases• Surgery / aggressive measures are needed for very few, carry risks and are costlier• Conventional AED are powerful and superior and cover the whole spectrum of epilepsy.
    • 39. REFERENCES1. epilepsyfoundation.org/aboutepilepsy/whatisepilepsy/statistics.cfm2. Engel-3065G GRBT208-Engel-v4.cls July 2, 2007 19:333. Practical Guide to Epilepsy Mark Manford4. SANAD: Lancet. 2007 March 24; 369(9566): 1016–1026.5. KOMET: Epilepsia vol:50 pages:45-456. Arch Neurol. 1983;40(13):797-802.7. N Engl J Med 1985; 313:145–1518. uptodate.com/contents/evaluation-and-management-of-drug-resistant-epilepsy9. Neuropsychiatric Disease and Treatment 2010:610. Lancet. 2007;369:1000–101511. Health Technol Assess. 2005;9:1–157,iii–iv.12. Brain 2005;128:1188–1198.13. Ther Drug Monit, Vol. 24, No. 1, 200214. archive.ahrq.gov/downloads/pub/evidence/pdf/trepilep/trepilepsy15. Neurology 2008;70:54–65.