What is the diagnosis for a patient with worsening psychosis and paranoia, presenting with hyperthermia, tachycardia, hypertension, and rigidity, who is currently receiving risperidone, loperamide, benztropine, and hydroxyzine?

Neuroleptic Malignant Syndrome (NMS)

This patient has Neuroleptic Malignant Syndrome (NMS), a life-threatening complication of antipsychotic medication (risperidone) characterized by the classic tetrad of hyperthermia, muscle rigidity, altered mental status, and autonomic instability. 1

Clinical Reasoning

The diagnosis is based on the presence of all four cardinal features of NMS in a patient receiving risperidone (a dopamine D2 receptor antagonist):

• Hyperthermia: Temperature of 102.5°F (39.2°C) 1
• Muscle rigidity: Rigidity of upper and lower extremities (characteristic "lead pipe rigidity") 1
• Altered mental status: Worsening psychosis and paranoia 1
• Autonomic instability: Tachycardia (pulse 120), hypertension (BP 170/105) 1, 2

Pathophysiology

NMS results from dopamine D2 receptor blockade in the central nervous system caused by risperidone. 1 Blockade of D2 receptors in the hypothalamus produces an increased temperature set point and loss of heat-dissipating mechanisms, while antagonism in the nigrostriatal pathways produces muscle rigidity and tremor. 1 Peripherally, increased calcium release from the sarcoplasmic reticulum causes increased muscle contractility, leading to rigidity, heat production, and potential muscle breakdown. 1

Key Distinguishing Features from Serotonin Syndrome

While this patient is on multiple medications, NMS is the correct diagnosis rather than serotonin syndrome because:

• Lead pipe rigidity is characteristic of NMS, whereas serotonin syndrome presents with hyperreflexia and clonus 3, 2, 4
• The patient is on risperidone (a dopamine antagonist), which is the classic precipitant of NMS 1, 5
• Serotonin syndrome would require exposure to serotonergic agents; none of the listed medications (risperidone, loperamide, benztropine, hydroxyzine) are significant serotonin agonists 3, 4

Risk Factors Present

This patient has multiple risk factors for NMS:

• Coadministration of multiple psychotropic agents (risperidone, benztropine, hydroxyzine) - present in >50% of NMS cases 1
• Male gender (2:1 male predominance) 1, 2
• Worsening psychosis suggesting possible recent dose escalation 1

Expected Laboratory Findings

While not provided in the case, you should expect to find:

• Elevated creatine kinase (often markedly elevated, ≥4 times upper limit of normal) 2, 6, 4
• Leukocytosis (WBC 15,000-30,000 cells/mm³) 2, 4
• Elevated liver enzymes (AST, ALT) 6, 4
• Electrolyte abnormalities consistent with dehydration 2
• Low serum iron (distinguishes NMS from serotonin syndrome) 4

Immediate Management Algorithm

Step 1: Discontinue all antipsychotic medications immediately - this is the most critical intervention 1, 2, 5, 7, 8

Step 2: Provide aggressive supportive care:

• Benzodiazepines for agitation and muscle activity 2, 7
• External cooling measures for hyperthermia (not antipyretics, as fever results from muscular hyperactivity rather than hypothalamic thermoregulation) 3, 7
• IV fluids for dehydration and to prevent rhabdomyolysis 2, 7, 8
• Continuous cardiac monitoring 2

Step 3: Consider ICU admission given the severity of presentation with significant hyperthermia, tachycardia, and hypertension 2

Step 4: Monitor for complications:

• Rhabdomyolysis with myoglobinuria 5, 8
• Acute renal failure (may require hemodialysis) 2, 5
• Cardiac dysrhythmias 5

Prognosis and Follow-up

Mortality from NMS has decreased from 76% in the 1960s to <10-15% with prompt recognition and management. 1, 2 Symptoms typically resolve within days to weeks after discontinuation of the offending agent. 7, 8

Critical caveat: If antipsychotic treatment is required after recovery, wait at least 2 weeks following complete resolution of symptoms before attempting rechallenge, and carefully monitor for recurrence as patients with prior NMS are at increased risk. 7, 4 Consider using a lower-potency antipsychotic or an atypical agent at the lowest effective dose. 7

Common Pitfalls to Avoid

• Don't assume the fever is infectious - NMS should be considered in any patient on antipsychotics presenting with fever and altered mental status 1
• Don't continue benztropine thinking it will help - while anticholinergics are used for extrapyramidal symptoms, they do not treat NMS and the offending antipsychotic must be stopped 1
• Don't use antipyretics alone for hyperthermia - external cooling is required as the fever mechanism is different from typical infections 3, 7
• Don't overlook attenuated presentations - NMS can present with variable severity and incomplete symptom complexes 1