Sodium Valproate in Epilepsy Vijay Sardana   MD,DM Professor & Head, Deptt. Of Neurology, Medical College, Kota
Sodium Valproate <ul><li>Broad Spectrum Anticonvulsant </li></ul>
Valproate : History 40 Years <ul><li>First Clinical trial – 1964 </li></ul><ul><li>Antiepileptic Drug – Introduced- France...
Valproate : Pharmacokinetics . <ul><li>rapidly & completely absorbed orally. </li></ul><ul><li>Peak valproate levels  – 1 ...
Valproate : Mechanism of action  Uncertain <ul><li>Enhance GABA – Mediated Inhibition by  </li></ul><ul><li>increasing GAB...
Valproate : Pharmacokinetics . <ul><li>Enzyme inducing drug (CBZ,Pb) Decrease  </li></ul><ul><li>valproate levels. </li></...
Valproate :  Adverse effects . <ul><li>Dose related –Tremors(40%), Sedation, Fatigue, Ataxia. </li></ul><ul><li>GI  -  Abd...
Valproate  :  Adverse   effects . <ul><li>Minor elevations of Liver Transaminases. </li></ul><ul><li>Fatal hepatotoxicity ...
Valproate : Risk factors for adverse effects . <ul><li>Children under 2 yrs. </li></ul><ul><li>Multiple AEDs. </li></ul><u...
Valproate : How to prevent Hepatotoxicit y. <ul><li>Avoid VPA < 3 yrs as part of Polytherapy. </li></ul><ul><li>Avoid in s...
Valproate :  Commonly accomplished side effects . <ul><li>Action tremors </li></ul><ul><li>Weight gain </li></ul><ul><li>A...
Valproate : Uses in Epilepsy . <ul><li>Absence </li></ul><ul><li>Myoclonic </li></ul><ul><li>Tonic </li></ul><ul><li>Atoni...
Valproate : Formulation <ul><li>Valproic acid/Sodium Salt – capsule ,tablet , Enteric  </li></ul><ul><li>Coated tablet , L...
Valproate : Dosage. <ul><li>starting Dose  -  250mg Adult & 125 mg children. </li></ul><ul><li>Increase 5-10 mg/kg every 3...
Valproate : Response rate . <ul><li>Generalized Seizures & GTC seizures  – 89%. </li></ul><ul><li>Absence,Myoclonic  > 90%...
 
Epilepsy Investigations   Types of EEG   <ul><li>Routine EEG </li></ul><ul><li>Provocative Procedures – </li></ul><ul><li>...
Seizures : Investigations <ul><li>EEG </li></ul><ul><li>Single 30 min EEG- picks up discharges in 50% </li></ul><ul><li>No...
ELECTROENCEPHALOGRAPHY Facts and Figures <ul><li>An abnormal EEG may not indicate epilepsy  </li></ul><ul><li>always which...
ELECTROENCEPHALOGRAPHY Uses of  EEG <ul><li>To confirm diagnosis of epilepsy </li></ul><ul><li>To find out type of epileps...
EEG – Idiopathic  generalised  epilepsy   <ul><li>Normal background  </li></ul><ul><li>Generalised epileptiform discharges...
EEG – Symptomatic epilepsy  <ul><li>EEG background is often abnormal. </li></ul><ul><li>Focal or multifocal epileptiform  ...
ELECTROENCEPHALOGRAPHY Abuses of EEG   <ul><li>Erroneous interpretations of EEG often  </li></ul><ul><li>leads to non-epil...
Epilepsy – When to start treatment <ul><li>Risk of recurrence </li></ul><ul><li>24% - idiopathic seizures and normal  EEG ...
AED after single Seizure <ul><li>Previous  h/o Myoclonic jerk,absence seizure </li></ul><ul><li>EEG shows unequivocal disc...
Scottish Intercollegiate Guideline Network Recommendations for first line AED <ul><li>Carbemazepine, Valproate, Lamotrigin...
EPILEPSY – what next when  initial monotherapy fails ? <ul><li>? To add a second drug  </li></ul><ul><li>?To substitute th...
AED Combination <ul><li>AEDs with different mechanism of action  </li></ul><ul><li>( CBZ + VPA) </li></ul><ul><li>Valproat...
EPILEPSY - Polytherapy <ul><li>Important questions </li></ul><ul><li>Did the benefit derived from improved seizure </li></...
AED : How to withdraw  <ul><li>2-5 Years </li></ul><ul><li>Factor associated with increadsed </li></ul><ul><li>risk of sei...
EPILEPSY – How to Withdraw Antiepileptic drugs  AED Adult dose mg Children  (decrement/   doses  4 week) (mg/kg) Carbamaze...
ANTIEPILEPTIC DRUGS IN SYSTEMIC ILLNESS <ul><li>Hepatic failure  :- Gabapentine, Levetericetam </li></ul><ul><li>  Phenoba...
Alcohol & Epilepsy Seizures in Alcoholics - * Alcohol withdrawal – 70% * Recent/past head injury – 20% * Pre existing epil...
Women and Seizures <ul><li>Seizure frequency may increase due to menstruation </li></ul><ul><li>Fertility levels of men & ...
Epilepsy – Planning Pregnancy <ul><li>Consider withdrawal of drug if seizure free for 2 yrs </li></ul><ul><li>Switch to mo...
Epilepsy : Prognosis <ul><li>75% achieve prolonged,often permanent remission </li></ul><ul><li>Poor prognosis </li></ul><u...
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Sodium Valproate & Epilepsy: Dr Vijay Sardana

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Sodium Valproate & Epilepsy: Dr Vijay Sardana

  1. 1. Sodium Valproate in Epilepsy Vijay Sardana MD,DM Professor & Head, Deptt. Of Neurology, Medical College, Kota
  2. 2. Sodium Valproate <ul><li>Broad Spectrum Anticonvulsant </li></ul>
  3. 3. Valproate : History 40 Years <ul><li>First Clinical trial – 1964 </li></ul><ul><li>Antiepileptic Drug – Introduced- France 1967 </li></ul><ul><li>USA – 1970 </li></ul><ul><li>Sprinkle Powder - 1990 </li></ul>
  4. 4. Valproate : Pharmacokinetics . <ul><li>rapidly & completely absorbed orally. </li></ul><ul><li>Peak valproate levels – 1 to 4 hrs. </li></ul><ul><li>Divalproex Sodium - 4 to 8 hrs. </li></ul><ul><li>90% Protein Binding. </li></ul><ul><li>Metabolized in Liver through Multiple Pathways. </li></ul><ul><li>Half Life- Monotherapy - 15 hrs. </li></ul><ul><li>With Add on drug- 8 to 9 hrs. </li></ul>
  5. 5. Valproate : Mechanism of action Uncertain <ul><li>Enhance GABA – Mediated Inhibition by </li></ul><ul><li>increasing GABA levels. </li></ul><ul><li>Block voltage activated Sodium channels. </li></ul><ul><li>Possibly calcium channel blockage. </li></ul>
  6. 6. Valproate : Pharmacokinetics . <ul><li>Enzyme inducing drug (CBZ,Pb) Decrease </li></ul><ul><li>valproate levels. </li></ul><ul><li>VPA - Inhibit metabolism of Pb & LTG. </li></ul><ul><li>VPA – Levels DPH levels, also displaces DPH from </li></ul><ul><li>Protein binding sites. May precipitate DPH toxicity. </li></ul><ul><li>Falbamate increases valproate levels. </li></ul>
  7. 7. Valproate : Adverse effects . <ul><li>Dose related –Tremors(40%), Sedation, Fatigue, Ataxia. </li></ul><ul><li>GI - Abdominal pain,Nausea,Constipation </li></ul><ul><li>Hematologic - mild thrombocytopenia(20-30%), </li></ul><ul><li>Platelet Dysfunction, </li></ul><ul><li>Macrocytosis, </li></ul><ul><li>Bone marrow suppression, </li></ul><ul><li>myelodysplastic change. </li></ul>
  8. 8. Valproate : Adverse effects . <ul><li>Minor elevations of Liver Transaminases. </li></ul><ul><li>Fatal hepatotoxicity risk- </li></ul><ul><li>< 2 yrs on multiple drugs – 1 in 500 </li></ul><ul><li>< 2 yrs on VPA monotherapy – 1 in 700 </li></ul><ul><li>> 2 yrs on VPA monotherapy - 1 in 45,000 </li></ul><ul><li>Hyperammonemia. </li></ul><ul><li>Women – Polycystic ovary disease, hyperandrogenism, Weight gain(20%), Teratogenic effects </li></ul><ul><li>Alopelia (4%), Weight gain(20%). </li></ul>
  9. 9. Valproate : Risk factors for adverse effects . <ul><li>Children under 2 yrs. </li></ul><ul><li>Multiple AEDs. </li></ul><ul><li>Underlying Metabolic drugs. </li></ul><ul><li>Developmental delay. </li></ul>
  10. 10. Valproate : How to prevent Hepatotoxicit y. <ul><li>Avoid VPA < 3 yrs as part of Polytherapy. </li></ul><ul><li>Avoid in strong Liver disease. </li></ul><ul><li>Avoid in F/L of Childhood hepatic disease. </li></ul><ul><li>Avoid VPA + Salicylate. </li></ul><ul><li>Clinical and transaminases monitoring . </li></ul>
  11. 11. Valproate : Commonly accomplished side effects . <ul><li>Action tremors </li></ul><ul><li>Weight gain </li></ul><ul><li>Alopecia </li></ul><ul><li>GI side effects </li></ul><ul><li>Increase in liver enzyme </li></ul><ul><li>Thrombocytopenia. </li></ul>
  12. 12. Valproate : Uses in Epilepsy . <ul><li>Absence </li></ul><ul><li>Myoclonic </li></ul><ul><li>Tonic </li></ul><ul><li>Atonic </li></ul><ul><li>GTC seizures </li></ul><ul><li>Partial onset seizures </li></ul>
  13. 13. Valproate : Formulation <ul><li>Valproic acid/Sodium Salt – capsule ,tablet , Enteric </li></ul><ul><li>Coated tablet , Liquid , Sprinkle , IV injections , </li></ul><ul><li>Suppositories , Control release formulations. </li></ul><ul><li>Different Forms – Divalproex Sodium , Magnesium or </li></ul><ul><li>Calcium Salt </li></ul>
  14. 14. Valproate : Dosage. <ul><li>starting Dose - 250mg Adult & 125 mg children. </li></ul><ul><li>Increase 5-10 mg/kg every 3-7 day as tolerated </li></ul><ul><li>Maintenance dose-20-60mg/day in two/three divided dosage. </li></ul><ul><li>Divalproex ER - Once a day dose. </li></ul>
  15. 15. Valproate : Response rate . <ul><li>Generalized Seizures & GTC seizures – 89%. </li></ul><ul><li>Absence,Myoclonic > 90%. </li></ul><ul><li>Partial Seizures with simple Symptoms - 100% </li></ul><ul><li>Partial Seizures with complex Symptoms- 37% </li></ul>
  16. 17. Epilepsy Investigations Types of EEG <ul><li>Routine EEG </li></ul><ul><li>Provocative Procedures – </li></ul><ul><li>Hyperventilation; Photic Stimulation; </li></ul><ul><li>Sleep </li></ul><ul><li>Brain Mapping </li></ul><ul><li>Ambulatory EEG </li></ul><ul><li>Video – EEG telemetry </li></ul><ul><li>Special Electrodes </li></ul><ul><li>Corticography – Acute; Chronic </li></ul>
  17. 18. Seizures : Investigations <ul><li>EEG </li></ul><ul><li>Single 30 min EEG- picks up discharges in 50% </li></ul><ul><li>Normal EEG doesn’t exclude epilepsy </li></ul><ul><li>Characteristic EEG patterns :- </li></ul><ul><ul><ul><li>Polyspikes – Myoclonic Epilepsy </li></ul></ul></ul><ul><ul><ul><li>3 Hz Spike &Wave – Petitmal Epilepsy </li></ul></ul></ul><ul><ul><ul><li>4-5 Hz Spike & Wave - Grandmal Epilepsy </li></ul></ul></ul>
  18. 19. ELECTROENCEPHALOGRAPHY Facts and Figures <ul><li>An abnormal EEG may not indicate epilepsy </li></ul><ul><li>always which is a clinical diagnosis </li></ul><ul><li>Normal people can have abnormal EEG </li></ul><ul><li>suggestive of epilepsy – indicate 2.4/1000 </li></ul><ul><li>population </li></ul>
  19. 20. ELECTROENCEPHALOGRAPHY Uses of EEG <ul><li>To confirm diagnosis of epilepsy </li></ul><ul><li>To find out type of epilepsy </li></ul><ul><li>To detect an epileptic focus </li></ul><ul><li>To detect underlying cerebral disease </li></ul><ul><li>To evaluate prognosis </li></ul>
  20. 21. EEG – Idiopathic generalised epilepsy <ul><li>Normal background </li></ul><ul><li>Generalised epileptiform discharges </li></ul><ul><li>often at 3 Hz, usually maximum in </li></ul><ul><li>anterior parasagittal regions </li></ul><ul><li>Presence of photosensitive response </li></ul>
  21. 22. EEG – Symptomatic epilepsy <ul><li>EEG background is often abnormal. </li></ul><ul><li>Focal or multifocal epileptiform </li></ul><ul><li>discharges </li></ul><ul><li>Rarely photosensitive </li></ul>
  22. 23. ELECTROENCEPHALOGRAPHY Abuses of EEG <ul><li>Erroneous interpretations of EEG often </li></ul><ul><li>leads to non-epileptic event being </li></ul><ul><li>wrongly diagnosed as seizures </li></ul><ul><li>Events which mimic epileptiform activity </li></ul><ul><li>EEG artifacts </li></ul><ul><li>Sleep rhythms </li></ul><ul><li>Normal EEG phenomenon </li></ul><ul><li>EEG contributes to practical management of </li></ul><ul><li>epilepsy in 15% cases only (Sawhney et al, 1996) </li></ul>
  23. 24. Epilepsy – When to start treatment <ul><li>Risk of recurrence </li></ul><ul><li>24% - idiopathic seizures and normal EEG </li></ul><ul><li>48% - symptomatic seizures or abnormal EEG </li></ul><ul><li>65% - symptomatic seizures and abn EEG </li></ul>
  24. 25. AED after single Seizure <ul><li>Previous h/o Myoclonic jerk,absence seizure </li></ul><ul><li>EEG shows unequivocal discharges </li></ul><ul><li>Congenital neurological deficit </li></ul><ul><li>Risk of seizure unacceptable </li></ul>
  25. 26. Scottish Intercollegiate Guideline Network Recommendations for first line AED <ul><li>Carbemazepine, Valproate, Lamotrigine & Oxcarbazepine </li></ul><ul><li>for Partial & Secondary Geanerlised seizures </li></ul><ul><li>Valproate & Lamotrigine – </li></ul><ul><ul><ul><ul><ul><li>Primary Generalised seizure </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>When doubt about seizure type/syndrome </li></ul></ul></ul></ul></ul>The adverse effect profile should direct the Choice of drug for the individual patient.
  26. 27. EPILEPSY – what next when initial monotherapy fails ? <ul><li>? To add a second drug </li></ul><ul><li>?To substitute the initial drug with </li></ul><ul><li>another </li></ul>
  27. 28. AED Combination <ul><li>AEDs with different mechanism of action </li></ul><ul><li>( CBZ + VPA) </li></ul><ul><li>Valproate + Lamotrigine </li></ul>
  28. 29. EPILEPSY - Polytherapy <ul><li>Important questions </li></ul><ul><li>Did the benefit derived from improved seizure </li></ul><ul><li>control outweigh the toxicity potential of the </li></ul><ul><li>added drug? </li></ul><ul><li>Did the improvement in seizure control have </li></ul><ul><li>any impact on overall quality of life? </li></ul><ul><li>Was any such impact sustained over a </li></ul><ul><li>prolonged period of time? </li></ul><ul><li>Could a similar (or better) clinical outcome be </li></ul><ul><li>achieved simply by adjusting the dosage of the </li></ul><ul><li>initially prescribed agent. </li></ul>
  29. 30. AED : How to withdraw <ul><li>2-5 Years </li></ul><ul><li>Factor associated with increadsed </li></ul><ul><li>risk of seizure relapse </li></ul><ul><ul><ul><ul><li>Type of seizure </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Age </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Age at onset </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Prolonged duration of epilepsy or </li></ul></ul></ul></ul><ul><ul><ul><ul><li>high number of seizures </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Known aetiology </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Abnormal electroencephalogram </li></ul></ul></ul></ul><ul><ul><ul><ul><li>History of afebrile and atypical febrile </li></ul></ul></ul></ul><ul><ul><ul><ul><li>seizures </li></ul></ul></ul></ul><ul><ul><ul><ul><li>History of status </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Short duration of seizure-free period </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Polytherapy at time of discontinuation </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Fast rate of drug withdrawal </li></ul></ul></ul></ul>
  30. 31. EPILEPSY – How to Withdraw Antiepileptic drugs AED Adult dose mg Children (decrement/ doses 4 week) (mg/kg) Carbamazepine 100 3 Ethosuximide 250 4 Phenobarbitone 25-30 1 Phanytoin 50 1.5 Valproic acid 200 6 (Sodium Valproate)
  31. 32. ANTIEPILEPTIC DRUGS IN SYSTEMIC ILLNESS <ul><li>Hepatic failure :- Gabapentine, Levetericetam </li></ul><ul><li> Phenobarbitone, Benzodizepine </li></ul><ul><li>Renal failure :- Valproate, Oxcarbazepine </li></ul><ul><ul><ul><ul><ul><li>Carbamazepine </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Avoid - Gabapentine, Levetericetam, Phenobarbitone </li></ul></ul></ul></ul></ul><ul><li>Renal Calculli –Topiramate </li></ul>
  32. 33. Alcohol & Epilepsy Seizures in Alcoholics - * Alcohol withdrawal – 70% * Recent/past head injury – 20% * Pre existing epilepsy – 4% Alcoholic Withdrawal Seizures * Within 72 hrs of stopping * Long h/o alcohol abuse * 2-3 seizures within a few hours Delirium Tremors Investigations * Focal seizures * > 3 Seizures * < 30 years > 60 years
  33. 34. Women and Seizures <ul><li>Seizure frequency may increase due to menstruation </li></ul><ul><li>Fertility levels of men & women with epilepsy 80-85% </li></ul><ul><li>Enzymes inducing Anticonvulsant :- Increased metabolism </li></ul><ul><li>of estrogen leads to contraceptive failure </li></ul><ul><li>No increased risk of abortion.Complications like toxemia, </li></ul><ul><li>PET not higher </li></ul><ul><li>Increase in perinatal mortality </li></ul><ul><li>Breast feeding not contraindicated. </li></ul>
  34. 35. Epilepsy – Planning Pregnancy <ul><li>Consider withdrawal of drug if seizure free for 2 yrs </li></ul><ul><li>Switch to monotherapy if possible </li></ul><ul><li>Folate supplementation even prior to conception </li></ul><ul><li>Use first line drug for seizure type/ syndrome </li></ul><ul><li>If seizures controlled, no need to increase dosage </li></ul><ul><li>in 2 nd and 3 rd trimesters </li></ul><ul><li>USG at 18 th -22 nd week </li></ul><ul><li>more than 90% pregnancies proceed without </li></ul><ul><li>problem </li></ul>
  35. 36. Epilepsy : Prognosis <ul><li>75% achieve prolonged,often permanent remission </li></ul><ul><li>Poor prognosis </li></ul><ul><ul><ul><li>multiple seizure types </li></ul></ul></ul><ul><ul><ul><li>Longer duration </li></ul></ul></ul><ul><ul><ul><li>FND and Mental Retardation </li></ul></ul></ul><ul><li>JME,Lennox Gastaut Syndrome – Life long treatment </li></ul>
  36. 37. Thanks

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