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