Hypertensive urgency in a child with focal epilepsy: Is it sodium valproate induced?

Dear Editor,

A 2-year-old girl presented with a history of fever for the past 5 days. On day 5 of illness, she had persistent irritability and inconsolable cry. There was no history of cough, ear discharge, and crying during micturition. She had four episodes of focal unaware motor seizures in the past 3 months and was on oral sodium valproate therapy (40 mg/kg/day). She was born to a nonconsanguineous couple with a normal perinatal period. Her developmental milestones were age appropriate, and her family history was unremarkable for any neurological disorder. On examination, she was conscious but irritable, had hypertension (134/76 mmHg, >99th centiles), and had multiple ecchymotic patches all over the body. The rest of the neurological examination was normal.

Investigations showed thrombocytopenia (19 × 109/L), mild transaminitis (aspartate aminotransferase – 109 U/L and alanine aminotransferase – 67 U/L), and hyperammonemia (251 micromoles/L). Her hemolytic workup, coagulation profile, renal function, urine examination, C3, C4, antinuclear antibodies, and antistreptolysin O were normal. Her renal Doppler, 2D echocardiography, electroencephalogram, and magnetic resonance imaging of the brain were also normal and fundoscopy did not reveal any signs of hypertensive retinopathy. Her serum free valproate level was 54 mcg/ml (toxic levels >50 mcg/ml). The common underlying causes for hypertension such as renal parenchymal, renovascular, cardiac, and endocrine causes were ruled out. A possibility of valproate toxicity with hypertensive urgency was considered. Sodium valproate was stopped, and she was started on oral enalapril (0.3 mg/kg/day) and levetiracetam (20 mg/kg/day). After stopping valproate, her platelet counts, transaminitis, and irritability have improved. At 1-month follow-up, enalapril was gradually tapered and stopped and her remaining laboratory parameters were within normal limits.

Sodium valproate is one of the commonly used antiepileptic drugs in childhood epilepsy. The side effects such as weight gain, transient hair loss, drowsiness, nausea, headache and tremors to severe and life-threatening events like bone marrow suppression, hepatotoxicity, pancreatitis, coagulation diorders and encephalopathy, depending on the dose and duration of the drug exposure.[1] Valproate-induced hypertensive urgency among the other adverse effects has been rarely reported. Till date, there has only been one case report in the literature of an 8-year-old boy who was on multiple drugs for his underlying illness along with valproate and presented with hypertensive urgency.[1] They had attributed the events to the multiple drug interactions with valproate. Valproic acid increases glutamate decarboxylase-mediated y-aminobutyric acid (GABA) synthesis. GABA potentiates dopamine release in the presence of a low concentration of GABAergic compounds and reduces dopamine in the opposite condition. Therefore, GABA can modulate dopamine concentration in different brain regions and produce physiological and behavioral changes.[23] Dopamine is a precursor of norepinephrine, which produces an inotropic and chronotropic effect on the myocardium, resulting in an increase in heart rate, cardiac output, and blood pressure.[45] It is important for the clinicians to be aware of the possible adverse events and to have a high index of suspicion so that the offending drug can be withdrawn early for the blood pressure to stabilize and prevent untoward complications such as a hypertensive emergency.

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