A 48-year-old man with schizophrenia on haloperidol (15 mg daily) for 3 weeks develops fever (39.8°C), severe muscle rigidity, altered mental status, and tachycardia. You suspect neuroleptic malignant syndrome (NMS). Which investigation is most specific for confirming the diagnosis and assessing severity?

## Diagnostic Investigation of Neuroleptic Malignant Syndrome (NMS) **Key Point:** NMS, like serotonin syndrome, is a clinical diagnosis. However, CPK and myoglobin are the most specific and useful investigations because they directly reflect the severity of rhabdomyolysis and guide management of life-threatening complications. ### Why CPK and Myoglobin Are Most Useful **High-Yield:** NMS causes severe muscle rigidity leading to rhabdomyolysis. CPK and myoglobin: - Quantify muscle breakdown (CPK often >1000 U/L, may exceed 10,000 U/L in severe cases) - Myoglobin in urine indicates myoglobinuria → acute kidney injury risk - Guide aggressive fluid resuscitation and monitoring - Correlate with prognosis and mortality ### Diagnostic Criteria for NMS All four features required: 1. **Exposure** to antipsychotic (typical > atypical) 2. **Hyperthermia** (>38.5°C) 3. **Muscle rigidity** ("lead pipe" or "waxy") 4. **Altered mental status** (confusion, delirium, coma) Plus elevated CPK (usually >300 U/L, often much higher). ### Role of CPK and Myoglobin ```mermaid flowchart TD A[Suspected NMS]:::outcome --> B[Check CPK + Myoglobin + Urinalysis]:::action B --> C{CPK >1000 U/L?}:::decision C -->|Yes| D[Severe rhabdomyolysis]:::urgent C -->|No| E[Mild-moderate NMS]:::outcome D --> F[Aggressive IV hydration]:::action D --> G[Monitor urine myoglobin]:::action G --> H{Myoglobinuria?}:::decision H -->|Yes| I[High AKI risk - ICU monitoring]:::urgent H -->|No| J[Lower AKI risk]:::outcome ``` **Clinical Pearl:** Myoglobinuria (dark, cola-colored urine) is a red flag for acute kidney injury. Aggressive normal saline hydration (target urine output 200–300 mL/hr) and alkalinization of urine (sodium bicarbonate to maintain pH >6.5) reduce myoglobin precipitation in renal tubules. ### Comparison of Investigations in NMS | Investigation | Utility in NMS | |---|---| | **CPK + Myoglobin** | Confirms rhabdomyolysis; guides severity assessment and fluid management | | **Serum iron/ferritin** | No role; not related to NMS pathophysiology | | **TSH/Free T4** | Rules out thyroid storm (differential diagnosis), but not diagnostic for NMS | | **24-hr urine catecholamines** | Not indicated; NMS is not a catecholamine-excess disorder | **Warning:** Elevated CPK alone does not diagnose NMS—clinical criteria must be met. However, CPK elevation is nearly universal in NMS and correlates with severity.