A 26-year-old man is brought to the hospital by his wife who complains that her husband has been behaving oddly for the past few hours. The patient’s wife says that she has known him for only 4 months. The wife is unable to give any past medical history. The patient’s speech is difficult to follow, and he seems very distracted. After 15 minutes, he becomes agitated and starts to bang his head on a nearby pillar. He is admitted to the psychiatric ward and is given an emergency medication, after which he calms down. In the next 2 days, he continues to become agitated at times and required 2 more doses of the same drug. On the 4th day of admission, he appears very weak, confused, and does not respond to questions appropriately. His vital signs include: temperature 40.0°C (104.0°F), blood pressure 160/95 mm Hg, and pulse 114/min. On physical examination, he is profusely diaphoretic. He is unable to stand upright or even get up from his bed. Which of the following is the mechanism of action of the drug which most likely caused this patient’s current condition?

Agonistic effect on dopamine receptors

A 22-year-old man presents to the emergency department with a 2-day history of fever and altered mentation. He reports fever without chills and rigors and denies sore throat, abdominal pain, headache, loose stool, burning micturition, or seizures. He has a history of tics and is currently on a low dose of haloperidol. At the hospital, his temperature is 39.6°C (103.2°F); the blood pressure is 126/66 mm Hg, and the pulse is 116/min. He is profusely sweating and generalized rigidity is present. He is confused and disoriented. He is able to move all his limbs. Normal deep tendon reflexes are present with bilateral downgoing plantar responses. A brain MRI is unremarkable. Urine toxicology is negative. The white blood cell count is 14,700/mm3. Creatine kinase is 5600 U/L. Lumbar puncture is performed and cerebrospinal fluid (CSF) studies show: CSF opening pressure 22 cm H20 CSF white blood cells 4 cells/mm3 CSF red blood cells 0 cells/mm3 CSF glucose 64 mg/dL CSF protein 48 mg/dL Serum glucose 96 mg/dL What is the most likely diagnosis?

Cerebral venous sinus thrombosis

Acute disseminated encephalomyelitis

A 19-year-old woman, accompanied by her parents, presents after a one-week history of abnormal behavior, delusions, and unusual aggression. She denies fever, seizures or illicit drug use. Family history is negative for psychiatric illnesses. She was started on risperidone and sent home with her parents. Three days later, she is brought to the emergency department with fever and confusion. She is not verbally responsive. At the hospital, her temperature is 39.8°C (103.6°F), the blood pressure is 100/60 mm Hg, the pulse rate is 102/min, and the respiratory rate is 16/min. She is extremely diaphoretic and appears stiff. She has spontaneous eye-opening but she is not verbally responsive and she is not following commands. Laboratory studies show: Sodium 142 mmol/L Potassium 5.0 mmol/L Creatinine 1.8 mg/dl Calcium 10.4 mg/dl Creatine kinase 9800 U/L White blood cells 14,500/mm3 Hemoglobin 12.9 g/dl Platelets 175,000/mm3 Urinalysis shows protein 1+, hemoglobin 3+ with occasional leukocytes and no red blood casts. What is the best first step in the management of this condition?

Switch risperidone to clozapine

A 67-year-old man presents to his primary care physician for fatigue. This has persisted for the past several months and has been steadily worsening. The patient has a past medical history of hypertension and diabetes; however, he is not currently taking any medications and does not frequently visit his physician. The patient has lost 20 pounds since his last visit. His laboratory values are shown below: Hemoglobin: 9 g/dL Hematocrit: 29% Mean corpuscular volume: 90 µm^3 Serum: Na+: 139 mEq/L Cl-: 100 mEq/L K+: 4.3 mEq/L Ca2+: 11.8 mg/dL Which of the following is the most likely diagnosis?

Vitamin B12 and folate deficiency

Neuroleptic malignant syndrome — USMLE Lesson

Pathophysiology & Etiology - The Dopamine Drop

Core Mechanism: Sudden, drastic ↓ in central dopamine (DA) activity, primarily from D2 receptor blockade.
Primary Triggers:
- Antipsychotics (Neuroleptics): High-potency typicals (e.g., Haloperidol) pose the highest risk.
- Antiemetics: Metoclopramide, prochlorperazine.
- Abrupt Withdrawal: Sudden cessation of DA agonists (e.g., Levodopa in Parkinson's disease).

⭐ NMS is an idiosyncratic reaction, not a true dose-dependent toxicity. It can occur at any point during therapy.

Clinical Presentation - The FEVER Pitch

Onset is typically gradual, over 1-3 days after altering dopamine antagonist therapy.
📌 FEVER mnemonic outlines the core features:
- Fever: Hallmark sign. Typically high, often >40°C (104°F).
- Encephalopathy: Universal feature of altered mental status, from delirium to coma.
- Vitals Instability: Autonomic dysfunction is common.
  - Tachycardia, labile BP, diaphoresis, tachypnea.
- Enzymes Elevated: Reflects muscle breakdown.
  - ↑ Creatine Kinase (CK), often >1,000 IU/L.
  - Myoglobinuria, leukocytosis, elevated AST/ALT.
- Rigidity: Severe, generalized "lead-pipe" muscle rigidity.

⭐ High-Yield: The rigidity in NMS is classically "lead-pipe" (diffuse, constant resistance), distinguishing it from the clonus and hyperreflexia more typical of Serotonin Syndrome.

Diagnosis & Differentials - NMS vs. The Impostors

Diagnosis is clinical, based on history (exposure to dopamine antagonists) and characteristic symptoms. Key labs show marked elevation in Creatine Kinase (CK >1000 IU/L), leukocytosis, and metabolic acidosis.
📌 FEVER Mnemonic for NMS: Fever, Encephalopathy, Vitals unstable, Elevated enzymes (CK), Rigidity of muscles.

Feature	NMS	Serotonin Syndrome	Malignant Hyperthermia
Key Feature	"Lead-pipe" rigidity	Clonus & Hyperreflexia	Masseter spasm, rapid temp ↑
Causative Agent	Dopamine Antagonists	Serotonergic Agents	Inhaled Anesthetics, Succinylcholine
Reflexes	Hyporeflexia	Hyperreflexia	Hyporeflexia
Pupils	Normal	Mydriasis (dilated)	Normal
Treatment	Dantrolene, Bromocriptine	Cyproheptadine, Benzodiazepines	Dantrolene

Management - Cooling & Counteracting

Immediate Cooling: Aggressive external and internal methods.
- Ice packs (axilla, groin), cooling blankets, misting.
- Consider chilled IV fluids or gastric lavage.
Pharmacologic Counteraction:
- Dantrolene: Direct muscle relaxant; inhibits Ca²⁺ release from sarcoplasmic reticulum.
- Bromocriptine: Dopamine (D₂) agonist to reverse central hypo-dopaminergic state.
- Benzodiazepines (e.g., lorazepam) for agitation.

⭐ Dantrolene is crucial for treating rigidity and hyperthermia in NMS, but bromocriptine is specifically added to address the underlying central dopamine receptor blockade that precipitates the syndrome.

High‑Yield Points - ⚡ Biggest Takeaways

A life-threatening reaction to neuroleptic agents, especially high-potency typical antipsychotics.

Classic tetrad: hyperthermia, autonomic instability, "lead-pipe" muscle rigidity, and altered mental status.

The underlying cause is central D2 receptor blockade.

Look for a markedly elevated creatine kinase (CK) from rhabdomyolysis.

Treatment requires immediate cessation of the drug, supportive care, and dantrolene or bromocriptine.

Key differentiator from serotonin syndrome is bradykinesia and extreme rigidity.

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Neuroleptic malignant syndrome