Atypical Neuroleptic Malignant Syndrome Without Rigidity During Clozapine Titration: A Diagnostic Challenge

Neuroleptic malignant syndrome (NMS) is a rare but potentially life-threatening complication of antipsychotic therapy, and it may mimic or overlap sepsis, leading to significant diagnostic uncertainty, particularly in the absence of rigidity. Our case was a 64-year-old man with schizoaffective disorder who presented with tachycardia, shortness of breath, and worsening of hand tremors approximately two weeks after the initiation of clozapine. Initial assessment revealed tachycardia and hand tremors with normal muscle tone. Clozapine was withheld due to concern for myocarditis by the psychiatrist. Initial investigations revealed mild elevations of inflammatory markers, and a CT pulmonary angiogram excluded pulmonary embolism. Within 24 hours, the patient deteriorated, developing high fever, confusion, and hypertension with normal tone and reflexes, prompting sepsis screening, and intravenous empirical antibiotics were commenced. Fever was refractory to antipyretics, and serial blood tests demonstrated a marked increase in creatine kinase (CK) over the subsequent 24-48 hours. Elevated C-reactive protein (CRP) was observed despite persistently normal lactate and negative microbiological cultures including blood, urine, and cerebrospinal fluid. CK elevation was transient, normalizing within five days, while CRP remained elevated for several days. Gradual clinical improvement was noted with supportive treatment. This case illustrated the rapid clinical deterioration occurring during clozapine titration with concurrent quetiapine therapy, alongside an atypical manifestation of NMS lacking the hallmark rigidity. This atypical presentation posed a diagnostic challenge because the symptoms overlapped with those of sepsis.