Creatine Kinase Elevation and Neuroleptic Malignant Syndrome

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Departments of Internal Medicine & Psychiatry, Yale University School of Medicine, New Haven, CT, USA

Creatine kinase (CK) is an enzyme released into serum in response to muscle injury. The prevalence and extent of CK elevation depends on the underlying cause.

Pathology

CK is present in many tissues. Skeletal muscle contains the majority of CK. CK has three different isoenzymes—MM, MB, BB. Ninety nine percent of skeletal muscle CK is CK-MM. Cardiac tissue has the highest concentration of CK-MB and brain tissue has high concentrations of CK-BB. Any damage to muscle causes release of CK and higher serum levels.

Etiology

CK elevation can be seen both with and without primary muscle disease. Major causes of CK elevation are listed in the table.

Causes of creatine kinase elevation

Primary neuromuscular disorders

Inflammatory myopathies (e.g., polymyositis, local myositis)

Muscular dystrophies (e.g., Duchennes)

Metabolic myopathies (e.g., inherited disorders of lipid, carbohydrate, and nucleic acid metabolism)

Motor neurone disease (e.g., amyotrophic lateral sclerosis—mild elevation)

Secondary or iatrogenic causes

Neuroleptic malignant syndrome (antipsychotics, antiemetics)

Malignant hyperthermia (inhalational anesthetics)

Medications (statins, fibrates, colchicine, antimalarials)

Recreational substances (cocaine, alcohol)

Acute muscle injury (trauma, seizures, surgery, intramuscular injections, infections, electrolyte imbalance)

Exercise (about threefold; peak at 24 h after exercise)

Untreated hypothyroidism (mild elevations)

Creatine kinase elevation can occur due to many causes besides complications of antipsychotic use.

Psychotropic Medications and CK Elevation

CK tends to be higher in younger people and in blacks. Values in these individuals may be a little higher than what is reported as the upper limit of normal and this should be considered when interpreting the lab value.

CK elevation is associated with antipsychotics as well as antiemetics that have dopamine-blocking properties. Neuroleptic malignant syndrome (NMS) is a rare but potentially life-threatening side effect of these medications. It is hypothesized to result from alteration of central neuroregulatory mechanisms and abnormal reaction of skeletal muscle to antipsychotics. NMS usually develops in days to weeks after exposure. See table for an overview of NMS.

Neuroleptic malignant syndrome

Neurologic syndrome with autonomic imbalance

Pathology: Unknown; possibly related to central dopamine blockade

Causes: antipsychotics, antiparkinsonian medication withdrawal, certain psychiatric conditions

Symptoms: altered mental status, muscle rigidity, hyperthermia, autonomic imbalance—usually develop in this order

Lab findings: elevated CK, elevated white cell count, multiple electrolyte abnormalities

Management: maintaining electrolyte and fluid balance, dantrolene or bromocriptine, stopping offending agent

CK is often, but not always, elevated in NMS. CK can be normal, especially in early stages. The CK is usually >1000 IU/L and sometimes as high as 100,000 IU/L. It is not a reliable marker for NMS as an isolated lab test. The incidence of NMS with antipsychotics is estimated at 0.2–3% and occurs both with typical and atypical agents [1]. While it is thought to occur more commonly with typical agents, several reports with atypical agents have been published [2].

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