Clinical Reasoning: Rhabdomyolysis after combined treatment with simvastatin and fluconazole
O. Findling, MD,
N. Meier, MD,
J. Sellner, MD,
K. Nedeltchev, MD and
M. Arnold, MD
From the Department of Neurology (O.F., N.M., K.N., M.A.), Inselspital, Bern University Hospital, and University of Bern, Switzerland; and the Department of Neurology (J.S.), Klinikum rechts der Isar, Technische Universität München, Germany.
Address correspondence and reprint requests to Dr. Marcel Arnold, Department of Neurology, University Hospital, Inselspital, CH-3010 Bern, Switzerland marcel.arnold{at}insel.ch
A 65-year-old woman with obesity, hypertension, coronary arterydisease, ventricular tachycardia, and hypercholesterolemia presentedwith 2 weeks of progressive, proximal muscle tenderness andweakness. She was unable to walk. Neurologic examination revealeda severe proximal tetraparesis predominantly of the legs. Sensationwas normal. The patellar reflex was slightly reduced on theright side. The remainder of the examination was normal. Hermedical history revealed that she had been treated 3 weeks earlierwith fluconazole 800 mg daily for 3 weeks, for a Candida albicansinfection of her internal defibrillator. Simultaneously shehad been taking simvastatin 40 mg daily for 5 years.
Questions for consideration:
What is the differential diagnosis for symmetric proximal weakness?
In patients with progressive tetraparesis, myelopathy of thecervical spine must be excluded promptly. This considerationis important even in patients without additional signs of myelopathy,such as sensory loss or bladder dysfunction. In this patient,MRI scan of the cervical spine was normal.
An important differential diagnosis is acute motor polyradiculoneuropathy,which is characterized by progressive motor weakness and hyporeflexia.Although neuropathic pain can occur, muscular tenderness, asin our patient, is not typical. Furthermore, our patient’stendon reflexes were normal except for a slightly reduced rightpatellar reflex, making radiculopathy or neuropathy less likely.Motor neuron disease, such as amyotrophic lateral sclerosis,is another differential diagnosis, but symptoms develop overmonths or years, and not so rapidly as in our patient. A disorderof the neuromuscular junction, such as myasthenia gravis, ispossible, although there was no characteristic history of fatigue,fluctuating symptoms, or ocular symptoms. Furthermore, a disorderof the neuromuscular junction would not explain the proximalpain.
Myopathy (polymyositis or rhabdomyolysis) is one of the mostlikely diagnoses in our patient. Laboratory evaluation showeda creatine kinase (CK) up to 32,000 U/L (normal <167 U/L).Sedimentation rate was 51 mm/hour (normal <20) and C-reactiveprotein was 22 mg/L (normal <5). Blood chemistry showed increasedtransaminases (aspartate transaminase 1,461 U/L [normal 10–37],alanine transaminase 671 U/L [normal 5–41]) and lactatedehydrogenase 3,139 U/L (normal <480). Serum electrophoresiswas normal; urine electrophoresis showed myoglobinuria.
Electromyography of the right vastus medialis and iliopsoas,erector spinae, and left deltoid and tibialis anterior musclesshowed no signs of denervation, but a myopathic interferencepattern analysis. An MRI scan of the proximal leg muscles revealededematous swelling and contrast agent enhancement, especiallyin the adductors (figure).
Figure MRI of thigh showing muscular atrophy on native T1 imaging with fat suppression (A) and diffuse contrast agent enhancement (B) especially in the adductor muscles
Different types of myopathies such as toxic, metabolic, infectious,autoimmune-mediated, and hereditary myopathies are to be considered.Blood examination showed no evidence of parasitic, bacterial,or viral infection as a reason for infectious disease. Furthermore,there were no signs of autoimmune-mediated myopathy (negativeantinuclear antibody and antineutrophil cytoplasmic antibody,negative antibodies to double stranded-DNA, histones, nucleosome,cardiolipin-, and ribonucleoprotein). In addition, biopsy ofthe left vastus medialis muscle revealed no signs of metabolicor hereditary myopathy. The onset of hereditary myopathies isoften in childhood and symptoms develop over months to years.
Question for consideration:
What is the diagnosis and what treatment would you recommend?
The history of exposure to both simvastatin and fluconazole,in combination with the electrodiagnostic, laboratory, and MRIfindings, led to a diagnosis of statin-induced rhabdomyolysis.
Simvastatin was stopped, therapy with methylprednisolone 1,000mg IV daily was begun (for 3 days, until normal muscle biopsyresults returned), and bicarbonate infusions were performed.
Muscle strength slowly increased after 1 week, and muscle painremitted after 2 weeks. All laboratory values normalized within4 weeks. After 9 weeks of an inpatient rehabilitation program,she was able to walk 500 meters without assistance.
Rhabdomyolysis is characterized by widespread muscle pain, tenderness,weakness, and dark urine. Laboratory findings include elevatedtransaminases, myoglobinuria, elevated CK, rapidly rising serumcreatinine, and metabolic acidosis. MRI shows muscle edema andcontrast enhancement. Electromyographic findings often shownonspecific signs of myopathy. Biopsy findings such as multiplenecrotic fibers invaded by macrophages can support the diagnosis.However, there is limited sensitivity, and a negative biopsycannot exclude the diagnosis.1,2
Risk factors for statin-induced rhabdomyolysis include olderage, female sex, obesity, renal or liver dysfunction, diabetes,infections, major surgery or trauma, alcoholism, drug interactions,excessive exercise, and exorbitant consumption of grapefruitor cranberry juice.3
Simvastatin, which our patient had taken for 5 years, is metabolizedby the cytochrome P 450 system, especially by the CYP 3A4 isoenzyme.Inhibitors of P450 include fluconazole, as well as erythromycin,troleandomycin, nefazodone, ritonavir, and grapefruit juice.4,5For lovastatin, simvastatin, and atorvastatin, which are metabolizedby CYP 3A4, an incidence of 0.73 cases/million prescriptionshas been reported. For pravastatin (excreted to a significantextent unchanged in the urine, CYP3A4 plays only a minor role)and fluvastatin (oxidized by CYP 2A9), which are not oxidizedby the cytochrome P 450 system, the rate is 0.15/million prescriptions.4
The pathogenesis of statin-induced myopathies is not completelyunderstood. Possibly, a disturbance of the plasma membrane ofmuscle cells and influx of calcium ions leads to overcontractionand breakdown of the contractile apparatus. Ensuing disturbanceof protein synthesis and mitochondrial metabolism may causecell death.3,6,7
Management consists of discontinuing the triggering agent. Additionalmeasures are bicarbonate infusion to prevent dissociation ofnephrotoxic myoglobin, fluid replacement, and promotion of diuresis.8The prognosis after stopping the trigger is good, but in severecases muscle paresis can persist.
Drugs that are well-tolerated when used separately may induceserious side effects when used in combination. If simvastatinhad been temporarily discontinued during the treatment withfluconazole this side effect may have been avoided.
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