Is an elevated Creatine Kinase (CK) level suggestive of Neuroleptic Malignant Syndrome (NMS) in a patient taking neuroleptic or antipsychotic medication?

Is CK 212 Suggestive of NMS?

A CK level of 212 U/L is mildly elevated but falls well below the diagnostic threshold typically seen in NMS, where CK is usually ≥4 times the upper limit of normal (typically >1000 U/L) and often dramatically higher (median ~2650 U/L). 1 However, NMS remains a clinical diagnosis that cannot be ruled out by CK alone, as rare cases with normal or minimally elevated CK have been documented. 2, 3

Interpreting CK 212 in the Context of NMS

Standard CK Elevations in NMS

• The diagnostic point-based system assigns 10 points for CK elevation ≥4 times the upper limit of normal, which typically means >800-1000 U/L depending on laboratory reference ranges, with ≥76 total points indicating probable NMS 1

• In documented NMS cases, the median CK is 2650 IU/L with a range from 335 to 20,270 IU/L, indicating that most cases present with substantially higher elevations than 212 U/L 4

• CK peaks around day 2 after fever onset and typically returns to normal by day 12, so timing of measurement relative to symptom onset matters 5

The Critical Caveat: NMS Can Occur Without Significant CK Elevation

• Over 90% of NMS cases show elevated CK, but rare cases with normal CK levels have been reported and can still be fatal 2, 3

• A documented fatal case presented with persistent hyperthermia, autonomic dysfunction, altered mental status, and severe muscle rigidity despite CK levels of only 669-710 U/L (only slightly higher than your value of 212) 2

• Another fatal NMS case had completely normal CK levels measured three times during the syndrome's course, emphasizing that clinical symptoms must drive diagnosis, not laboratory values alone 3

Clinical Decision-Making Algorithm

If CK is 212 U/L, evaluate for the complete NMS tetrad:

1. Mental status changes (delirium, alert mutism, agitation, stupor, or coma) 1
2. Muscle rigidity (lead-pipe rigidity is most common, though may be mild early in course) 1
3. Autonomic dysfunction (tachycardia, blood pressure fluctuations, diaphoresis, sialorrhea) 1
4. Fever/hyperthermia (>100.4°F oral on ≥2 occasions) 1

Additional supporting features to assess:

• Recent antipsychotic exposure or dopaminergic agent withdrawal within 3 days 1
• Leukocytosis (15,000-30,000 cells/mm³) 1, 6
• Electrolyte abnormalities consistent with dehydration 1
• Elevated liver enzymes 1, 6

If clinical suspicion for NMS exists despite CK of only 212:

• Immediately discontinue all antipsychotic medications as the first critical step 7, 6
• Initiate aggressive supportive care: benzodiazepines for agitation, external cooling for hyperthermia, IV fluids for dehydration and potential rhabdomyolysis 7, 6
• Monitor CK serially, as it may rise over the next 24-48 hours if measured early in the syndrome's course 5
• Rule out alternative diagnoses: serotonin syndrome (hyperreflexia, clonus), malignant hyperthermia (anesthetic exposure), anticholinergic toxicity, CNS infections 1

Key Clinical Pitfalls

• Do not wait for dramatically elevated CK to treat suspected NMS - early recognition and prompt discontinuation of causative agents has reduced mortality from 76% to <10-15% 7, 6

• Mild muscle rigidity may precede fever onset in 71% of cases, so the full syndrome may not yet be apparent when CK is first measured 5

• Physical restraints must be avoided as they exacerbate isometric muscle contractions, worsening hyperthermia and lactic acidosis 7

• The diagnosis of NMS is clinical, not laboratory-based - there are no pathognomonic laboratory criteria 1

In summary: CK 212 U/L alone does not suggest NMS, but if other clinical features of the NMS tetrad are present in a patient on antipsychotics, do not let the relatively normal CK falsely reassure you. Treat based on clinical presentation, discontinue the offending agent immediately, and provide aggressive supportive care. 7, 1, 3