What are the manifestations, pathophysiology, and management of Neuroleptic Malignancy Syndrome (NMS) in an elderly patient with a history of psychiatric disorders taking antipsychotic medications such as haloperidol (haloperidol) or risperidone (risperidone)?

Neuroleptic Malignant Syndrome: Manifestations, Pathophysiology, and Management

What Is NMS?

Neuroleptic Malignant Syndrome is a life-threatening emergency caused by antipsychotic medications (both typical drugs like haloperidol and atypical drugs like risperidone) that requires immediate recognition and discontinuation of the offending drug, with mortality dropping from 76% to less than 10-15% when caught early. 1, 2

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Clinical Manifestations: The Classic Tetrad

NMS presents with four cardinal features that typically develop within days of starting or increasing antipsychotic medication 2:

1. Mental Status Changes

• Delirium is the most common presentation, ranging from alert mutism to agitation to stupor to coma 2
• Confusion and altered consciousness are hallmark features 3

2. Muscle Rigidity

• Lead pipe rigidity is the most common neurologic finding 2
• Other muscle abnormalities include akinesia, dyskinesia, or waxy flexibility 2
• Rigidity is severe enough to cause rhabdomyolysis 3

3. Hyperthermia

• Fever progressing to hyperpyrexia (often >100.4°F) 2, 3
• Extreme hyperthermia >41.1°C represents a medical emergency requiring advanced interventions 1

4. Autonomic Instability

• Tachycardia and blood pressure fluctuations often precede other symptoms 2
• Diaphoresis (excessive sweating) is frequent 2
• Irregular pulse, cardiac dysrhythmias 3
• Sialorrhea and dysphagia may occur 2

Laboratory Findings

• Creatine kinase elevation (often ≥4 times upper limit of normal, sometimes massively elevated) 2, 3
• Leukocytosis (WBC 15,000-30,000 cells/mm³) 2
• Elevated liver enzymes 2
• Electrolyte abnormalities consistent with dehydration 2
• Myoglobinuria indicating rhabdomyolysis 3
• Metabolic acidosis 1

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Pathophysiology: The Dopamine Connection

NMS results from acute reduction in brain dopamine activity caused by dopamine receptor blockade from antipsychotic medications. 4

• Both typical antipsychotics (like haloperidol) and atypical antipsychotics (like risperidone, olanzapine) can trigger NMS 3, 5, 6
• The syndrome can also occur from abrupt withdrawal of dopaminergic agents 2
• The mechanism involves severe dopamine antagonism leading to muscle rigidity, hyperthermia from hypothalamic dysfunction, and autonomic instability 4

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Risk Factors to Watch For

Patient-Specific Risks

• Male gender (2:1 male predominance) 2
• History of previous NMS episodes 4
• Organic brain disease or mood disorders 4
• Dehydration, physical exhaustion 2, 4

Medication-Related Risks

• Use of high-potency typical antipsychotics (especially haloperidol) 6
• Long-acting depot antipsychotics 2
• Rapid dose escalation or high doses 4
• Coadministration of multiple psychotropic agents 2
• Concurrent lithium use (increases risk, especially in mood disorders) 3, 4

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Diagnostic Scoring Criteria

Use this point-based system where ≥76 points indicates probable NMS: 2

Criterion	Points
Dopamine antagonist exposure or dopamine agonist withdrawal within 3 days	20
Hyperthermia (>100.4°F oral on ≥2 occasions)	18
Rigidity	17
Mental status alteration	13
Creatine kinase elevation (≥4 times upper limit)	10
Sympathetic nervous system lability	10
Negative workup for other causes	7
Hypermetabolism	5

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Differential Diagnosis: What to Exclude

The diagnosis is clinical with no pathognomonic laboratory findings, so you must exclude 2, 3:

• Serotonin syndrome: Distinguished by hyperreflexia, clonus, myoclonus, and recent serotonergic drug exposure (not lead-pipe rigidity) 2
• Malignant hyperthermia: Triggered by anesthetics, not antipsychotics 2
• Anticholinergic toxicity 2, 3
• CNS infections (meningitis, encephalitis) 2
• Acute catatonia 2
• Heat stroke 3
• Drug fever 3

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Management Algorithm

Step 1: Immediate Actions (First Priority)

Discontinue all antipsychotic medications immediately—this is the single most critical intervention. 1, 2, 3

• Stop all dopamine-blocking agents 1
• If NMS was triggered by abrupt withdrawal of an anti-Parkinson drug, consider reintroducing it 2
• Avoid physical restraints as they worsen isometric muscle contractions, increasing hyperthermia and lactic acidosis 1

Step 2: Aggressive Supportive Care (Foundation of Treatment)

Intensive supportive measures form the cornerstone of NMS management: 1, 2

• Cooling measures: External cooling for hyperthermia 1, 2
• IV fluids: Aggressive hydration for dehydration and to prevent renal failure from rhabdomyolysis 1, 2
• Benzodiazepines: For agitation (avoid chemical restraints) 1, 2
• Normalize vital signs: Manage autonomic instability with IV fluids and other agents 1

Step 3: Pharmacologic Interventions for Severe Cases

Consider these agents after initiating supportive care in severe NMS: 1, 2

• Bromocriptine (dopamine agonist): Addresses dopamine deficiency 1, 7, 6
• Dantrolene sodium (muscle relaxant): Reduces muscle rigidity and hyperthermia 1, 7, 6
• Note: There is no general agreement about specific pharmacological regimens for uncomplicated NMS 3

Step 4: Advanced Interventions for Extreme Cases

For extreme hyperthermia (>41.1°C), escalate to: 1

• Emergency sedation
• Neuromuscular paralysis
• Intubation
• ICU admission (necessary for approximately 25% of patients) 1

Step 5: Second-Line Treatment

Electroconvulsive therapy (ECT) is a second-line treatment for severe and persistent NMS, particularly if the patient has a concurrent psychiatric condition that would benefit from ECT. 1, 7

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Monitoring for Life-Threatening Complications

Order comprehensive laboratory testing and monitor closely for: 1, 2

• Complete blood count, electrolytes, renal function, liver function 1
• Creatine kinase, arterial blood gases, coagulation studies 1
• Rhabdomyolysis with elevated CK 1, 2
• Metabolic acidosis 1, 2
• Renal failure (may require hemodialysis) 1, 2
• Seizures 1, 2
• Disseminated intravascular coagulation 1, 2
• Hepatotoxicity 2
• Pulmonary edema 2

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Critical Pitfalls to Avoid

During Acute Management

• Never use anticholinergics for routine prevention of extrapyramidal symptoms—they worsen autonomic instability 1
• Avoid pro re nata (p.r.n.) chemical restraints—they are prohibited 1
• Do not use physical restraints—they exacerbate muscle contractions and worsen outcomes 1

After Recovery

• Wait at least 2 weeks before considering antipsychotic rechallenge 8, 4
• Monitor carefully if reintroducing antipsychotics, as recurrences have been reported 3, 4
• Use the lowest effective dose of the least potent antipsychotic if rechallenge is necessary 4
• Obtain informed consent after explaining the risk-benefit analysis to patient and family 8

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Clinical Course and Prognosis

• NMS typically lasts 7-10 days in uncomplicated cases receiving oral antipsychotics 4
• The syndrome can present with variable severity, from relatively benign to potentially fatal 8
• Early recognition and prompt management have decreased mortality from 76% in the 1960s to less than 10-15% currently 1, 2
• Approximately 25% of patients require ICU admission 1
• The diagnosis can be delayed due to slow and insidious symptom presentation 5

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Special Considerations for Elderly Patients

Elderly patients with psychiatric disorders on antipsychotics like haloperidol or risperidone face additional risks:

• Higher baseline risk for dehydration and autonomic instability 2, 4
• Greater susceptibility to falls from somnolence and postural hypotension caused by antipsychotics 3
• Increased likelihood of complications from rhabdomyolysis and renal failure 1, 2
• May have concurrent organic brain disease, which increases NMS risk 2, 4