To the Editors, An acute episode of mania requires mood stabilizers and antipsychotics, with valproate being used as one of the most common mood stabilizers. The drug is mostly well-tolerated with mild side effects, but it can sometimes be associated with severe adverse effects. A rare but potentially lethal complication is valproate-induced delirium due to hyperammonemia, which can arise despite normal liver function tests, leading to diagnostic confusion, dosing errors, or sometimes even death. Our case will demonstrate acute-onset delirium secondary to valproate-induced hyperammonemia despite therapeutic dosing and normal liver function tests. Case Description A 51-year-old married male who is a known case of Bipolar affective disorder (BPAD) for 30 years presented to the emergency of a tertiary care hospital with manic symptoms of overtalkativeness, increased psychomotor activity, delusion of grandiosity, decreased need for sleep, and physical and verbal aggression. There was no history of any fever, head trauma, or ENT bleed before the onset of the episode. A general physical examination revealed stable vitals. Routine biochemical and hematological parameters were within normal limits. According to ICD-11, a diagnosis of Bipolar type 1 disorder, current episode manic, with psychotic symptoms was made. The Patient was then admitted for inpatient management and was started on the tablet divalproex sodium 1000 mg/day and olanzapine 20 mg/day. By the 5th day of admission, we increased divalproex to 1500 mg/day as his manic symptoms were still prominent. Two days later, we noticed a sudden change in his mental status. He became disoriented and started showing repetitive behaviors of picking bedding and clothing, impaired attention and concentration, increased psychomotor agitation, unsteadiness of gait, and hallucinatory behavior, which were significantly different from his baseline manic symptoms. His neurological examination was unremarkable with no meningeal, cerebellar, or extrapyramidal signs. The computed tomography scan brain was normal. Laboratory investigations showed a raised ammonia level of 173 μg/dL (range – 15–45 μg/dL) and a therapeutic serum valproate level of 82 μg/mL (range – 50–100 μg/mL). Creatine phosphokinase (CPK) was markedly elevated at 2900 IU/L (range – 10–120 IU/L), without any evidence for rhabdomyolysis or neuroleptic malignant syndrome. Liver functions were all within normal limits, thus indicating a hyperammonemia of nonhepatic origin. The patient was provisionally diagnosed with valproate-induced hyperammonemic delirium (VIHD). Both Valproate and olanzapine were discontinued immediately. Medical management was begun with vigilant monitoring of mental status and vital parameters. The patient started showing dramatic improvement with the disappearance of picking behaviors, confusion, and he became oriented to time, place, and person. Serum ammonia and CPK were normalized without the requirement for further pharmacologic intervention. For manic symptoms, the patient was started on tablet lithium 300 mg, which was optimized up to 900 mg with considerable improvement in manic symptoms, and the patient was then continued on the same. Discussion Valproic acid is an antiepileptic drug commonly used in various neuropsychiatric and neurological disorders. Valproate-induced hyperammonemia is usually a temporary and asymptomatic condition which can occasionally become chronic if left untreated. Lethargy, confusion, and reversible cognitive impairments could be its initial symptoms, which could later develop into severe sedation, a coma, or even death. Our case represents a notable clinical example of VIHD with several noteworthy aspects that differ from those in the existing literature. The rapid onset of delirium symptoms, occurring within 48 h of dose escalation to 1500 mg/day, differs from the typical presentation as described in previous case reports, where the onset of symptoms was mentioned after 13–15 days of treatment.1 Even in patients who have previously tolerated lower doses without experiencing any problems, this temporal relationship emphasizes the significance of increased vigilance during valproate dose adjustments. The clinical presentation of our case provides a clear qualitative distinction between the patient’s typical manic symptoms of overtalkativeness, grandiosity, and increased psychomotor activity, and new onset of delirium features of disorientation, repetitive picking behavior, and heightened agitation, which helped us distinguish VIHD from worsening of the underlying manic symptoms. Recognizing this difference is important, since misdiagnosis could lead to inappropriate management strategies such as increasing psychotropic medications instead of treating the underlying metabolic disturbance. The Naranjo score was applied, and the score was 9, indicating that the drug was the definite cause of the side effect.2 Another distinctive feature was the concurrent elevation of CPK along with hyperammonemia, accompanied by normal liver function tests, which has not been reported in previous cases, indicating other mechanisms of valproate toxicity or a more complex metabolic disruption.3 Beyond the well-established effects on ammonia processing, the elevation of several biochemical markers might suggest a more extensive influence on cellular metabolism. Our management strategy aligns with a recent systematic review, with valproate discontinuation serving as the primary intervention.4 Our patient’s clinical and laboratory profile was resolved with medication discontinuation and supportive care alone, unlike some cases that required lactulose or levocarnitine for recovery, suggesting that early recognition and timely intervention can prevent the development of a more severe encephalopathy.5 Conclusion Our case highlights the significance of recognizing VIHD in patients with unexplained mental status changes receiving valproate therapy, as early detection and prompt intervention can prevent serious complications and lead to complete resolution without specialized treatments. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
Gupta et al. (Sun,) studied this question.