What are the initial symptoms of Neuroleptic (antipsychotic) Malignant Syndrome (NMS)?

First Signs of Neuroleptic Malignant Syndrome (NMS)

The initial symptoms of Neuroleptic Malignant Syndrome typically manifest as autonomic dysfunction (which often precedes other symptoms), including tachycardia, blood pressure instability, diaphoresis, and fever, followed by mental status changes and muscle rigidity. 1

Early Manifestations of NMS

Autonomic Dysfunction (Often First to Appear)

• Tachycardia and blood pressure fluctuations (systolic or diastolic ≥25% of baseline) 1
• Diaphoresis (excessive sweating) 1
• Fever, which can progress to hyperthermia up to 41°C or higher 1
• Sialorrhea (excessive salivation) and dysphagia (difficulty swallowing) 1
• Pallor and cardiac dysrhythmias 1

Mental Status Changes (Often Among Initial Symptoms)

• Delirium is the most common presentation 1
• Can range from alert mutism to agitation to stupor to coma 1
• Changes in mental status are among the first signs in 82.3% of cases 2

Muscle Abnormalities

• Lead pipe rigidity is the most common neurologic finding 1
• May also present as akinesia, dyskinesia, or waxy flexibility 1
• Muscle rigidity is among the first signs in 82.3% of cases 2
• Tremors and involuntary movements may occur 1

Temporal Progression of Symptoms

Research indicates a typical progression sequence in NMS:

• Mental status changes and muscle rigidity typically appear first 2
• Followed by hyperthermia 2
• Then autonomic dysfunction 2

However, it's important to note that in many cases, autonomic symptoms may actually precede other manifestations 1, creating a potential diagnostic challenge.

Laboratory Findings in Early NMS

• Leukocytosis (15,000-30,000 cells/mm³) may be present 1
• Electrolyte abnormalities consistent with dehydration 1
• Elevated creatine kinase (≥4 times upper limit of normal) 1
• Elevated liver enzymes may be seen 1

Risk Factors to Consider

• History of antipsychotic use or withdrawal of dopaminergic agents 1
• Coadministration of multiple psychotropic agents 1
• Dehydration and physical exhaustion 1
• Preexisting organic brain disease 1
• Use of long-acting depot antipsychotics 1
• Male gender (2:1 male predominance) 1

Clinical Pearls and Pitfalls

• NMS can be difficult to recognize due to variable and attenuated presentations 1
• Early recognition is crucial as mortality has decreased from 76% in the 1960s to <10-15% with prompt management 1, 3
• NMS should be considered in the differential diagnosis for any patient presenting with fever and altered mental status who is taking antipsychotics 1
• The diagnosis is clinical, as there are no pathognomonic laboratory criteria 1
• Symptoms may develop within days (typically 1-7 days) after starting or increasing antipsychotic medication 1, 4

Diagnostic Challenges

• Symptoms can overlap with serotonin syndrome, malignant hyperthermia, and anticholinergic toxicity 1
• Atypical presentations with minimal muscle rigidity can occur, making diagnosis difficult 4
• Long-acting depot antipsychotics can complicate the clinical picture as symptoms may persist despite discontinuation 4

Early recognition of these initial signs is critical for prompt intervention, which includes immediate discontinuation of the offending agent and supportive care to reduce mortality 3, 5.