A 28-year-old man on haloperidol 10 mg daily for schizophrenia develops severe muscle rigidity, fever (39.8°C), altered mental status, and a serum CK of 2400 U/L over 3 days. Which investigation is most useful for differentiating neuroleptic malignant syndrome (NMS) from serotonin syndrome in this case?

## Differentiating NMS from Serotonin Syndrome **Key Point:** While both NMS and serotonin syndrome present with fever, rigidity, and elevated CK, serum prolactin is the most useful single investigation to differentiate them. Elevated prolactin strongly suggests NMS (dopamine antagonism), while normal or low prolactin favors serotonin syndrome. ## Pathophysiology Comparison | Feature | NMS | Serotonin Syndrome | |---|---|---| | **Mechanism** | Dopamine antagonism (D2 blockade) | Excessive serotonergic activity | | **Prolactin level** | **Markedly elevated** (loss of dopamine inhibition) | Normal or low | | **Onset** | Days to weeks after neuroleptic exposure | Hours to days after serotonergic drug initiation/increase | | **Clonus** | Absent | Present (spontaneous or inducible) | | **Hyperreflexia** | Variable | Prominent | | **CK elevation** | Often > 1000 U/L | Variable | **High-Yield:** Serum prolactin > 200 ng/mL in the context of fever and rigidity is highly suggestive of NMS. This patient's exposure to haloperidol (dopamine antagonist) and the acute presentation support NMS, and prolactin would be markedly elevated. **Mnemonic:** **DOPAMINE-NMS** — NMS = Dopamine blockade → Prolactin elevated; Serotonin syndrome = Serotonin excess → Prolactin normal/low. ## Why Other Investigations Are Not Ideal | Investigation | Why Not Best | |---|---| | **CSF analysis** | Non-specific; cell count and protein are usually normal in both conditions. Used to exclude meningitis/encephalitis, not to differentiate NMS from serotonin syndrome. | | **TSH/Free T4** | Thyroid dysfunction can cause fever and rigidity (thyroid storm), but is not the primary differentiator. TSH would be suppressed in thyroid storm, not elevated. | | **Urine/serum myoglobin** | Marker of rhabdomyolysis; elevated in both NMS and serotonin syndrome. Non-specific for differentiation. | **Clinical Pearl:** In clinical practice, the drug exposure history is the first clue (dopamine antagonist → NMS; serotonergic agent → serotonin syndrome). Prolactin measurement confirms the mechanism.