Atypical neuroleptic malignant syndrome in a young male precipitated by oral sodium valproate

To the Editor

Neuroleptic malignant syndrome (NMS) is an uncommon but life-threatening adverse drug reaction. We report the case of a young adult male who developed atypical NMS within a few days of starting oral extended-release valproate.

A 25-year-old male with a diagnosis of bipolar affective disorder—current episode mania with psychotic symptoms was managed with 600 mg chlorpromazine, 10 mg lorazepam and eight sessions of electroconvulsive therapy (ECT). Medications administered prior to ECT included atropine, thiopentone and succinylcholine. After stopping ECT, extended-release preparation of sodium valproate was started at 500 mg and up-titrated to 1500 mg/day. Following 3 days after starting valproate, he presented to us with difficulty in swallowing, incontinence and muscular rigidity. On examination, he had mild fever (37.6°C), labile blood pressure (alternating between 100/70 and 140/90 mmHg) and was severely diaphoretic. Laboratory investigations revealed highly elevated creatine phosphokinase (CPK) (>5000 IU/L). A tentative diagnosis of NMS was made, following which we stopped all medications and started him on 2.5 mg oral bromocriptine two times a day. The patient exhibited a total recovery with fluctuation in autonomic signs and rigidity resolving within 5 days of treatment. The CPK levels had also normalized by then.

In this case, valproate was suspected to be the precipitating agent mainly due to the temporal association of symptom onset with its initiation. We posit that the absence of typically defined hyperthermia (>38°C), but presence of other features of NMS in the case could also point the needle of suspicion to valproate. To elaborate, the hyperthermia in NMS is thought to be due to blockade of hypothalamic dopamine sites (Adnet et al., 2000) which may not occur as robustly with valproate as with antipsychotics. Hence, we have called this an atypical NMS. Furthermore, the co-administration of chlorpromazine with valproate is known to increase serum valproate levels, but not vice versa, thus, again suggesting a stronger etiological role of valproate (Besag and Berry, 2006). To the best of our knowledge, there has only been one prior report of NMS precipitated by valproate and the reported case had all the typical manifestations of NMS (Verma et al., 2014). The take-home message for clinicians could be that NMS precipitated by valproate could present without hyperthermia. Awareness of this fact could save valuable time and initiate prompt action that could pre-empt potentially lethal complications of NMS including death.