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Sodium Valproate in Epilepsy Vijay Sardana MD,DM Professor & Head, Deptt. Of Neurology, Medical College, Kota

Sodium Valproate & Epilepsy: Dr Vijay Sardana

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Page 1: Sodium Valproate & Epilepsy: Dr Vijay Sardana

Sodium Valproate in Epilepsy

Vijay Sardana MD,DM

Professor & Head,Deptt. Of Neurology,

Medical College, Kota

Page 2: Sodium Valproate & Epilepsy: Dr Vijay Sardana

Sodium Valproate

Broad Spectrum Anticonvulsant

Page 3: Sodium Valproate & Epilepsy: Dr Vijay Sardana

Valproate : History 40 Years

First Clinical trial – 1964 Antiepileptic Drug – Introduced- France 1967 USA – 1970 Sprinkle Powder - 1990

Page 4: Sodium Valproate & Epilepsy: Dr Vijay Sardana

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.

Page 5: Sodium Valproate & Epilepsy: Dr Vijay Sardana

Valproate : Mechanism of action Uncertain

Enhance GABA – Mediated Inhibition by increasing GABA levels.

Block voltage activated Sodium channels.

Possibly calcium channel blockage.

Page 6: Sodium Valproate & Epilepsy: Dr Vijay Sardana

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.

Page 7: Sodium Valproate & Epilepsy: Dr Vijay Sardana

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.

Page 8: Sodium Valproate & Epilepsy: Dr Vijay Sardana

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%).

Page 9: Sodium Valproate & Epilepsy: Dr Vijay Sardana

Valproate : Risk factors for adverse effects.

• Children under 2 yrs.•Multiple AEDs.• Underlying Metabolic drugs.• Developmental delay.

Page 10: Sodium Valproate & Epilepsy: Dr Vijay Sardana

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.

Page 11: Sodium Valproate & Epilepsy: Dr Vijay Sardana

Valproate : Commonly accomplished side effects.

Action tremors Weight gain Alopecia GI side effects Increase in liver enzyme Thrombocytopenia.

Page 12: Sodium Valproate & Epilepsy: Dr Vijay Sardana

Valproate : Uses in Epilepsy.

Absence Myoclonic Tonic Atonic GTC seizures Partial onset seizures

Page 13: Sodium Valproate & Epilepsy: Dr Vijay Sardana

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

Page 14: Sodium Valproate & Epilepsy: Dr Vijay Sardana

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.

Page 15: Sodium Valproate & Epilepsy: Dr Vijay Sardana

Valproate : Response rate.

Generalized Seizures & GTC seizures – 89%.

Absence,Myoclonic > 90%.

Partial Seizures with simple Symptoms - 100%

Partial Seizures with complex Symptoms- 37%

Page 16: Sodium Valproate & Epilepsy: Dr Vijay Sardana
Page 17: Sodium Valproate & Epilepsy: Dr Vijay Sardana

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

Page 18: Sodium Valproate & Epilepsy: Dr Vijay Sardana

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

Page 19: Sodium Valproate & Epilepsy: Dr Vijay Sardana

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

Page 20: Sodium Valproate & Epilepsy: Dr Vijay Sardana

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

Page 21: Sodium Valproate & Epilepsy: Dr Vijay Sardana

EEG – Idiopathic generalised epilepsy

• Normal background • Generalised epileptiform discharges often at 3 Hz, usually maximum in anterior parasagittal regions• Presence of photosensitive response

Page 22: Sodium Valproate & Epilepsy: Dr Vijay Sardana

EEG – Symptomatic epilepsy

• EEG background is often abnormal.

• Focal or multifocal epileptiform discharges

• Rarely photosensitive

Page 23: Sodium Valproate & Epilepsy: Dr Vijay Sardana

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)

Page 24: Sodium Valproate & Epilepsy: Dr Vijay Sardana

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

Page 25: Sodium Valproate & Epilepsy: Dr Vijay Sardana

AED after single Seizure

• Previous h/o Myoclonic jerk,absence seizure

• EEG shows unequivocal discharges

• Congenital neurological deficit

• Risk of seizure unacceptable

Page 26: Sodium Valproate & Epilepsy: Dr Vijay Sardana

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.

Page 27: Sodium Valproate & Epilepsy: Dr Vijay Sardana

EPILEPSY – what next when initial monotherapy fails ?

• ? To add a second drug

• ?To substitute the initial drug with another

Page 28: Sodium Valproate & Epilepsy: Dr Vijay Sardana

AED Combination

AEDs with different mechanism of action ( CBZ + VPA)

Valproate + Lamotrigine

Page 29: Sodium Valproate & Epilepsy: Dr Vijay Sardana

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.

Page 30: Sodium Valproate & Epilepsy: Dr Vijay Sardana

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

Page 31: Sodium Valproate & Epilepsy: Dr Vijay Sardana

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)

Page 32: Sodium Valproate & Epilepsy: Dr Vijay Sardana

ANTIEPILEPTIC DRUGS IN SYSTEMIC ILLNESS

• Hepatic failure :- Gabapentine, Levetericetam Phenobarbitone, Benzodizepine

• Renal failure :- Valproate, Oxcarbazepine Carbamazepine

Avoid - Gabapentine, Levetericetam, PhenobarbitoneRenal Calculli –Topiramate

Page 33: Sodium Valproate & Epilepsy: Dr Vijay Sardana

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

Page 34: Sodium Valproate & Epilepsy: Dr Vijay Sardana

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.

Page 35: Sodium Valproate & Epilepsy: Dr Vijay Sardana

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

Page 36: Sodium Valproate & Epilepsy: Dr Vijay Sardana

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

Page 37: Sodium Valproate & Epilepsy: Dr Vijay Sardana

Thanks