Are elevated Creatine Kinase (CK) levels and hyperthermia characteristics of Neuroleptic Malignant Syndrome (NMS)?

Elevated Creatine Kinase and Hyperthermia in Neuroleptic Malignant Syndrome

Yes, elevated creatine kinase (CK) levels and hyperthermia are characteristic features of Neuroleptic Malignant Syndrome (NMS), though CK elevation may occasionally be absent in some cases. NMS is a potentially life-threatening condition characterized by a tetrad of symptoms that develop in response to dopamine antagonism or dopamine withdrawal.

Core Clinical Features of NMS

• Hyperthermia is a hallmark feature of NMS, with temperatures that can reach up to 41°C or higher 1
• Elevated creatine kinase (CK) is considered a key diagnostic criterion, often included in formal diagnostic frameworks for NMS 1
• Muscle rigidity (typically "lead pipe" rigidity) is a cardinal feature that contributes to both hyperthermia and CK elevation through muscle breakdown 1
• Altered mental status, ranging from alert mutism to delirium to coma, is consistently present 1
• Autonomic instability manifests as tachycardia, blood pressure fluctuations, diaphoresis, and other dysautonomic features 1, 2

Pathophysiology Connecting CK and Hyperthermia

• Hyperthermia in NMS results from dopamine D2 receptor blockade in the hypothalamus, which increases the temperature set point and impairs heat-dissipating mechanisms 1
• The same dopaminergic blockade in nigrostriatal pathways produces muscle rigidity via extrapyramidal pathways 1
• Increased calcium release from the sarcoplasmic reticulum causes sustained muscle contractility, leading to both rigidity and heat production 1
• This sustained muscle contraction results in muscle cell breakdown (rhabdomyolysis), which releases CK into the bloodstream 1

Diagnostic Criteria and Laboratory Findings

• According to expert consensus, CK elevation (≥4 times upper limit of normal) is assigned 10 points in diagnostic scoring for NMS 1
• Leukocytosis (15,000-30,000 cells/mm³) commonly accompanies NMS 1
• Electrolyte abnormalities consistent with dehydration are frequently observed 1
• Elevated liver enzymes may also be present due to the systemic stress response 1

Atypical Presentations and Diagnostic Challenges

• While CK elevation is typical, cases of NMS without significant CK elevation have been reported 3, 4
• In one case report, a patient with confirmed NMS had normal CK levels throughout the course of illness but still died from respiratory failure 3
• Another case showed only mild CK elevation that rapidly normalized despite ongoing NMS symptoms 5
• The diagnosis of NMS remains primarily clinical, and the absence of CK elevation should not rule out NMS when other characteristic features are present 3

Differential Diagnosis

• Serotonin syndrome can present similarly but typically features hyperreflexia, myoclonus, and clonus rather than lead-pipe rigidity 6
• Malignant hyperthermia is more often identified in the operating room and is triggered by anesthetic agents 1
• Toxic metabolic encephalopathies may present with altered mental status but typically lack the severe rigidity and hyperthermia of NMS 7

Clinical Implications

• Early recognition of NMS is crucial as mortality has decreased from 76% in the 1960s to <10-15% with prompt management 1, 2
• Management involves primarily supportive care and immediate discontinuation of the triggering agent 1
• IV fluids are essential to manage dehydration and elevated CK with potential rhabdomyolysis 1
• External cooling measures should be implemented for hyperthermia 1
• Benzodiazepines are recommended as first-line agents for agitation 1

NMS should be considered in any patient with fever and altered mental status who is taking or has recently taken an antipsychotic medication, even if CK elevation is minimal or absent 2, 3.