How should I work up a patient with isolated elevated Creatine Kinase-MB (CKMB) without elevation in Creatine Kinase (CK), troponin, or C-Reactive Protein (CRP), who was recently started on a new medication and is currently taking multiple antipsychotics?

Workup of Isolated Elevated CK-MB in a Patient on Multiple Antipsychotics

An isolated elevated CK-MB without elevation in troponin, total CK, or CRP is not indicative of myocardial injury and should prompt evaluation for non-cardiac causes, particularly antipsychotic-induced asymptomatic CK elevation, rather than cardiac workup. 1, 2

Understanding the Clinical Context

Troponin is the gold standard for detecting myocardial injury, not CK-MB. 1, 2 When troponin is normal despite elevated CK-MB, this virtually excludes acute myocardial infarction. 1 The ACC/AHA guidelines explicitly state that measurement of total CK is not recommended for diagnosis of MI due to lack of specificity, and CK-MB has significantly lower sensitivity and specificity compared to troponin. 1

CK-MB can be elevated from non-cardiac sources, including skeletal muscle. 1 The European Heart Journal specifically notes that troponins will clarify cardiac involvement when CK-MB is falsely elevated from conditions like skeletal muscle trauma. 1, 2

Antipsychotic-Associated CK Elevation

Multiple antipsychotics are well-documented to cause massive asymptomatic CK elevation (MACKE) without signs of neuroleptic malignant syndrome or rhabdomyolysis. 3, 4, 5 This phenomenon has been reported with:

• Olanzapine 3, 5
• Clozapine 5
• Risperidone 5
• Haloperidol 5
• Loxapine 5

Key characteristics of antipsychotic-induced CK elevation include: 4, 5

• Onset from 5 days to 2 years after initiating treatment 5
• Duration of 4-28 days (median 8 days) 5
• Often asymptomatic or with only mild flu-like symptoms 4, 5
• Self-limiting in many cases despite continuing treatment 5
• Can recur with rechallenge 5
• CK elevations ranging from 1,206 to 177,363 IU/L 5

Recommended Diagnostic Approach

Initial Assessment

Confirm the isolated nature of the CK-MB elevation by verifying: 6

• Normal troponin (already done - excludes myocardial injury) 1, 2
• Normal total CK (already done - unusual pattern) 6
• Normal CRP (already done - excludes inflammatory myopathy) 1, 6

Perform focused clinical evaluation looking for: 1, 4

• Signs of neuroleptic malignant syndrome: fever, altered consciousness, muscle rigidity, autonomic instability 4
• Signs of rhabdomyolysis: dark urine, severe weakness, flu-like syndrome 1, 4
• Muscle pain, tenderness, or weakness 1, 6
• Recent trauma, intramuscular injections, restraints, or intense physical activity 4

Additional Laboratory Testing

If the patient is asymptomatic and NMS/rhabdomyolysis are excluded, obtain: 1, 6

• Repeat CK-MB and total CK in 2-4 weeks to assess trend 6
• Consider checking myoglobin if concerned about muscle damage 5
• Liver enzymes (AST, ALT, LDH, aldolase) to evaluate for muscle inflammation 1

Do not pursue cardiac workup (ECG, echocardiogram, stress testing) when troponin is normal. 1, 2 The ACC/AHA guidelines state that in the clinical setting of acute ischemia, MI is diagnosed when both troponin AND CK-MB are increased together—not CK-MB alone. 2

Management Strategy

If Patient is Asymptomatic

No immediate intervention is required. 6 The finding likely represents antipsychotic-induced MACKE, which is self-limiting and does not require discontinuation of effective psychiatric medication. 4, 5

Monitor with repeat CK-MB and total CK in 2-4 weeks. 6 If levels normalize or remain stable without symptoms, continue current antipsychotic regimen. 4, 5

If Signs of NMS or Rhabdomyolysis Develop

Immediately discontinue the antipsychotic if the patient develops: 4

• Fever, altered consciousness, or muscle rigidity
• Dark urine (myoglobinuria)
• Severe weakness or very high and persisting CK levels

Urgent referral to internal medicine or neurology is indicated. 1

Regarding Medication Changes

Switching to another antipsychotic is not necessarily safer. 4 Empirical evidence indicates there is no "safe" antipsychotic medication regarding CK elevation, and rechallenge with different agents can reproduce the elevation. 3, 4, 5

If the current antipsychotic regimen is therapeutically effective and the patient is asymptomatic, continuation is reasonable. 4, 5 The spontaneously remitting or intermittent course of MACKE suggests it should be kept distinct from both rhabdomyolysis and NMS. 4

Common Pitfalls to Avoid

Do not diagnose myocardial infarction based on isolated CK-MB elevation when troponin is normal. 1, 2, 7 Studies show that isolated CK-MB elevation without troponin elevation has limited prognostic value and does not identify patients at increased cardiac risk. 7

Do not unnecessarily discontinue an effective antipsychotic for asymptomatic CK elevation. 4, 5 Raising awareness of MACKE may reduce unnecessary diagnoses of NMS or rhabdomyolysis, which can lead to discontinuation of effective therapeutic agents. 4

Do not assume the isolated CK-MB elevation is cardiac in origin. 8 CK-MB can be elevated in patients with myopathy, neuropathy, skeletal muscle injury, or renal failure in the absence of myocardial injury. 8

Routine monitoring of CK is not necessary during antipsychotic treatment. 5 Weekly monitoring is only indicated when there are reasons to believe elevated CK is toxic or harmful, such as signs of NMS or rhabdomyolysis. 4