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