Sodium valproate induced increased frequency of micturition and enuresis.

Sodium valproate is a commonly used antiepileptic drug (AED) for control of a broad range of seizures. Adverse drug reactions (ADR) due to sodium valproate range from sedation to nausea, vomiting, weight gain, idiosyncratic adverse effects like hepatotoxicity and life threatening conditions like pancreatitis. We present a case of sodium valproate induced enuresis in child. This ADR of valproate is an underreported ADR and requires special attention of pediatricians as it can interfere with the further treatment of the disease.

Introduction

About 1% of the population worldwide suffers from epilepsy, and antiepileptic drugs (AEDs) are often used as a lifelong treatment. Prevalence rates of childhood epilepsy reported from different countries have shown a wide variation, with most clustering around 4-6 per 1,000 children.[1] AEDs are often associated with drug interactions, complicated pharmacokinetics, and adverse drug reactions (ADRs).[2] Sodium Valproate is a broad spectrum AED effective in the treatment of absence, partial and tonic-clonic seiziures.[3] Enuresis remains to be an underreported ADR of valproate. The search of literature revealed that not many reviews on Sodium valproate mentioned about this ADR. In pediatric patients it is difficult to distinguish between normal for age enuresis, one due to epilepsy and other due to drug itself. If it is implicated to be due to epilepsy it can lead to change in dosage of antiepileptic drugs, which itself leads to worsening of this effect.

Case Report

A five year old boy, known case of seizure disorder since one year presented for routine follow up in the pediatrics OPD. He was on syrup Sodium valproate 5ml BD (25mg/kg/day) since two month duration. Syrup was of Sanofi-Synthelabo (India) Ltd with manufacturing date September 2010, expiry dated August 2012 and batch no 210114. Patient was taking the medicine regularly.

Parents of the patient noticed increased frequency of micturition and bed wetting in night one month after starting the present dose of medication and reported this on his follow up visit. The child had approximately 20 episodes per day. Increased frequency was not associated with pain or burning sensation during micturition. There was no history of fever. Child had normal frequency and control of urination prior to AED treatment. No family history suggestive of enuresis was obtained. Child was not on any other medication.

At the start of therapy, child was prescribed syp Sodium Valproate in the dose of 2.5ml BD, @ 15 mg/kg/day. He was asymptomatic for 6 months. As the boy once again presented with convulsions, dose of Valproate was increased to 3ml BD. Three months later, child again presented with h/o convulsions inspite of taking regular medication. TDM was done and drug concentration was found to be 37 μgm /dl, which is below the therapeutic concentration (50-100 μgm /dl). Hence the dose was further increased to 5ml BD. Now the child was seizure free since last three months. One month after starting this dose (5ml Bd), child's parents complained of increased frequency of micturition along with bed wetting in night (Enuresis). Child had achieved bladder control at the age of three years and nocturnal enuresis was never a problem with this child. But this time the bed wetting started at this increased dose. Enuresis or bed wetting occurred twice or thrice in the night almost daily for last two months. The child was a bit disstressed due to this devolupment as this has occurred almost after two years of attaining physiological control over micturition.

On investigation, complete blood count showed Hb 9.4mg/ dl, WBC 17.3 /cmm, platelets 3lakh. Liver function tests were done and found to be within normal limits (AST- 31IU/L, ALT- 9IU/L). Urine microscopy was within normal limits. Therapeutic drug monitoring of valproate was not done at this increased dose. After the other causes of increased frequency of micturition were ruled out child was diagnosed of Valproate induced increased frequency of micturition and enuresis. The Naranjo's criteria is frequently used for determination of causality for suspected ADRs.[4] Causality assessment using the Naranjo's criteria revealed that the drug valproate was the probable cause of this ADR (overall score, 5).

Discussion

Valproic acid, an eight carbon fatty acid, was found while being used as a solvent for derivative of Khellin to have an anticonvulsant action.[5] Various side effects of Sodium Valproate are transient GI synptoms including anorexia, nausea and vomiting. CNS side effects include sedation, ataxia and tremors; these are dose related side effects. Chronic Sodium Valproate therapy causes rash, alopecia, stimulation of appetite and weight gain. Fulminant hapatitis is a rare complication which is fatal. Acute pancreatitis and hyperammonemia are also seen with Sodium Valproate therapy. Sodium Valproate also has teratogenic effects such as neural tube defects.[3]

Enuresis is defined as the voluntary or involuntary repeated discharge of urine into clothes or bed after developmental age when bladder control should be established . Most children with a mental age of five years obtain bladder control during the day and night.[6]

Egger and Brett reported seven out of 100 children on Sodium Valproate developed nocturnal enuresis.[7] C.P. Panayiotopoplos reported two cases of nocturnal enuresis attributed to Sodium Valproate; appeared 2-3 days of the start of treatment, during a seizure free period and disappeared on reduction or discontinuation of Sodium Valproate.[8] Other studies on use of Valproate in children.[79-12] have recoreded enuresis as side effect, the frequency being 1-7%. But surprisingly these studies are quite old and we could not find recent citations.

Two most likely explanations for Sodium Valproate induced enuresis are that the enuresis is secondary to a central effect on the thirst center, resulting in polydipsia, or secondly is a consequence of the increased depth of sleep commonly associated with Sodium Valproate.[9] Increased thirst has been demonstrated in several studies with Sodium Valproate.[10-13] Although this explanation suits well to the cause of incresesd frequency which this patient also has but in our opinion it can not explain enuresis in a patient who has already achieved bladder control two years ago.

Considering the fact that the disease itself can cause this symptom it becomes more difficult to establish a causal relationship but the absence of enuresis during period of regular epileptic attacks rules out disease induced enuresis. Dechallenge with valproate is not planned for now as the patient is currently seizure free although de-challenge can confirm the causality relationship of this ADR. But de-challenge or change in drug was not attempted as it could have resulted in worsening of epilepsy. When this option (of de-challenge or changeover) was discussed with the parents they agreed to accept this ADR against the possible events following the dechallege or changeover.

Enuresis is an under reported ADR of Sodium Valprote. It can cause stress to the child and parents. Although the exact cause of this ADR is not known, it can be attributed to increased thirst and/or increased depth of the sleep. In this patient this ADR seems to be dose related as it did not occur at the previous low doses given. An awareness of this ADR can help plan AED treatment in pediatric patients better.