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

First Symptoms of Neuroleptic Malignant Syndrome (NMS)

The earliest manifestations of Neuroleptic Malignant Syndrome (NMS) typically include mental status changes and muscle rigidity, which appear before hyperthermia and autonomic dysfunction in most cases. 1, 2

Clinical Presentation and Progression

NMS typically follows a sequential pattern of symptom development:

1. Initial Symptoms (First to appear):

   • Mental status alterations: Confusion, agitation, delirium, or catatonia
   • Muscle rigidity: Stiffness, "lead-pipe" rigidity

2. Secondary Symptoms (Develop later):

   • Hyperthermia: Elevated body temperature
   • Autonomic instability: Tachycardia, blood pressure fluctuations, diaphoresis

This progression occurs in approximately 70% of NMS cases, with mental status changes or rigidity being the initial manifestation in over 82% of cases 2.

Detailed Symptom Presentation

Mental Status Changes

• Confusion
• Agitation
• Altered consciousness
• Catatonic signs
• Delirium

Muscle Rigidity

• "Lead-pipe" rigidity
• Tremors
• Involuntary movements
• Positive Babinski sign
• Trismus (jaw clenching)
• Opisthotonos (severe hyperextension)

Autonomic Instability

• Tachycardia
• Blood pressure fluctuations
• Diaphoresis (excessive sweating)
• Pallor
• Cardiac dysrhythmias
• Sialorrhea (excessive salivation)
• Dysphagia (difficulty swallowing) 1

Laboratory Findings

• Elevated Creatine Kinase (CK) levels
• Leukocytosis
• Electrolyte disturbances
• Elevated liver enzymes
• Metabolic acidosis
• Myoglobinuria 1

Important Clinical Considerations

Risk Factors

• Young adults
• Male gender (2:1 male-to-female ratio)
• Concomitant use of multiple psychotropic agents
• Use of long-acting depot antipsychotics
• Abrupt discontinuation of dopaminergic agents
• Rapid dose escalation of antipsychotics
• Dehydration
• Physical exhaustion
• Preexisting organic brain disease 1

Atypical Presentations

• NMS can present with normal or only mildly elevated CK levels in some cases 3
• Symptoms may develop gradually over days to weeks rather than acutely 4
• With long-acting depot antipsychotics, symptoms may persist longer due to extended medication release 4

Differential Diagnosis

NMS must be distinguished from conditions with similar presentations:

• Serotonin syndrome
• Malignant hyperthermia
• Lethal catatonia
• CNS infections
• Heat stroke
• Anticholinergic toxicity 1

Clinical Pitfalls to Avoid

1. Delayed recognition: Early symptoms may be subtle or attributed to the underlying psychiatric condition
2. Overlooking NMS with atypical antipsychotics: NMS can occur with both typical and atypical antipsychotics 5
3. Waiting for all classic symptoms: Not all symptoms may be present initially or simultaneously
4. Failure to monitor high-risk patients: Those on multiple psychotropics or with rapid dose escalation require closer monitoring
5. Missing NMS with normal CK levels: Some cases present with normal or only mildly elevated CK 3

Early recognition of the initial symptoms of NMS is crucial, as prompt discontinuation of the offending agent and supportive care can significantly reduce the mortality rate, which has decreased from 76% in the 1960s to less than 15% currently 1.