Acute Myopathies & Rhabdomyolysis

Acute myopathies encompass a heterogeneous group of disorders characterized by rapid-onset muscle injury, weakness, and often markedly elevated serum creatine kinase (CK). Rhabdomyolysis — the catastrophic breakdown of skeletal muscle with release of intracellular contents into the circulation — represents the most severe manifestation and carries significant morbidity from acute kidney injury (AKI), hyperkalemia, and disseminated intravascular coagulation. Understanding the diverse etiologies, from drug-induced and immune-mediated causes to infectious triggers, is essential for timely diagnosis and targeted management in the neuromuscular clinic and the emergency department alike.

Rhabdomyolysis

Definition & Pathophysiology

Rhabdomyolysis results from disruption of the sarcolemmal membrane of skeletal myocytes, releasing intracellular contents — CK, myoglobin, lactate dehydrogenase (LDH), potassium, phosphate, and urate — into the systemic circulation. The final common pathway involves uncontrolled elevation of intracellular calcium, activating proteases (calpains) and lipases that destroy the myocyte from within. Myoglobin, a heme-containing protein, is freely filtered by the glomerulus and precipitates in renal tubules under acidic conditions, causing direct tubular obstruction, oxidative injury via ferryl myoglobin radicals, and afferent arteriolar vasoconstriction.

Etiology

Clinical Features

The classic triad is myalgias, proximal muscle weakness, and dark (tea-colored or cola-colored) urine, though all three are present simultaneously in fewer than 10% of cases. Muscle swelling and tenderness, particularly of the thighs and calves, may be prominent. Myoglobinuria produces a positive urine dipstick for blood (heme) in the absence of red blood cells on microscopy. CK typically peaks 24–72 hours after the initial insult and may reach levels exceeding 100,000 U/L in severe cases.

Complications

Management

Beyond fluid resuscitation, management requires identification and treatment of the underlying cause. Offending drugs must be discontinued immediately. Metabolic myopathies warrant avoidance of triggers and dietary modifications. Recurrent episodes, particularly in young patients without clear precipitants, should prompt evaluation for underlying genetic or metabolic conditions including McArdle disease, CPT II deficiency, and RYR1-related disorders.

Immune-Mediated Necrotizing Myopathy (IMNM)

Overview

IMNM is a distinct subtype of autoimmune myopathy characterized by acute or subacute proximal weakness, very high CK levels (often >10,000 U/L), and muscle biopsy showing prominent myofiber necrosis and regeneration with minimal or absent inflammatory infiltrate. Two myositis-specific antibodies define the major subtypes: anti-signal recognition particle (anti-SRP) and anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR). Anti-HMGCR IMNM is strongly associated with prior statin exposure, though it can occur in statin-naive patients.

Anti-SRP Myopathy

• More severe phenotype with rapid onset of profound proximal weakness, often with dysphagia
• CK levels frequently exceed 10,000 U/L
• Extramuscular features include interstitial lung disease (uncommon) and cardiac involvement
• No association with statin use
• Muscle MRI shows diffuse edema on STIR sequences with fatty replacement in chronic cases
• Often refractory to treatment; requires combination immunosuppressive therapy

Anti-HMGCR (Statin-Triggered) Myopathy

• Approximately two-thirds of anti-HMGCR-positive patients have prior statin exposure
• Incidence in statin users: approximately 2–3 per 100,000 statin-user-years
• Weakness may persist or progress even after statin discontinuation, distinguishing it from self-limited statin toxic myopathy
• Anti-HMGCR antibody has high sensitivity (~94%) and specificity (~99%) for this condition
• Statin-naive patients tend to be younger and may have a more severe disease course

Treatment of IMNM

IMNM requires aggressive immunosuppressive therapy. All statins must be permanently discontinued in anti-HMGCR myopathy. First-line induction consists of high-dose corticosteroids (prednisone 1 mg/kg/day or IV methylprednisolone pulse). However, IMNM frequently requires escalation to combination therapy. Intravenous immunoglobulin (IVIg) 2 g/kg divided over 2–5 days is a critical component, particularly for anti-HMGCR disease. Steroid-sparing agents include methotrexate, azathioprine, and mycophenolate mofetil. Refractory cases may respond to rituximab. Treatment response is monitored by CK levels, manual muscle testing, and functional assessment. Many patients require prolonged immunotherapy, and anti-HMGCR myopathy is notable for its tendency toward relapse when immunosuppression is tapered.

Drug-Induced Acute Myopathy

Statin Myotoxicity Spectrum

Statin-related muscle injury spans a continuum from self-limited myalgias (5–10% of users) to clinically significant toxic myopathy and, rarely, autoimmune IMNM. Toxic statin myopathy is dose-dependent, resolves within weeks to months after discontinuation, and shows CK elevation typically <10× ULN. Risk factors include high statin dose, advanced age, renal or hepatic impairment, hypothyroidism, and concomitant use of CYP3A4 inhibitors or fibrates. In contrast, statin-triggered IMNM is an autoimmune process that persists and progresses despite statin withdrawal, requiring immunosuppression.

Other Drug-Induced Myopathies

Neuroleptic Malignant Syndrome (NMS)

NMS is a life-threatening reaction to dopamine receptor antagonists (typical and atypical antipsychotics, antiemetics such as metoclopramide) or rapid withdrawal of dopaminergic agents (levodopa, dopamine agonists). The tetrad of hyperthermia (>38°C, often >40°C), lead-pipe muscular rigidity, altered mental status, and autonomic instability (tachycardia, labile blood pressure, diaphoresis) develops over 24–72 hours. CK may exceed 100,000 U/L, and rhabdomyolysis-associated AKI is a major cause of mortality. Mortality is 5–10% with modern ICU management.

Malignant Hyperthermia (MH)

MH is a pharmacogenetic disorder of skeletal muscle triggered by volatile halogenated anesthetics (sevoflurane, desflurane, isoflurane) and succinylcholine. RYR1 mutations (autosomal dominant) account for the majority of cases, causing uncontrolled calcium release from the sarcoplasmic reticulum. The clinical syndrome includes rapidly rising temperature, muscle rigidity (masseter spasm as an early sign), metabolic acidosis, hyperkalemia, and rhabdomyolysis. Dantrolene (2.5 mg/kg IV bolus, repeated as needed up to 10 mg/kg) is the specific antidote and has reduced MH mortality from >70% to <5%. Susceptible individuals must avoid triggering agents and carry medical alert identification. Caffeine-halothane contracture testing remains the gold standard for diagnosis of MH susceptibility, though genetic testing for RYR1 and CACNA1S mutations is increasingly used.

Infectious Myositis

Viral Myositis

Viral myositis is most commonly associated with influenza A and B, presenting as acute myalgia and weakness during or shortly after the viral prodrome. CK is typically elevated 5–25× ULN and resolves spontaneously within 1–2 weeks. In children, benign acute childhood myositis (BACM) following influenza presents with sudden-onset calf pain and refusal to walk, with full recovery expected. COVID-19 (SARS-CoV-2) can cause myositis through direct viral invasion of skeletal muscle via ACE-2 receptors and through systemic inflammatory mechanisms, with reports of rhabdomyolysis in up to 2% of hospitalized patients. Other viral causes include enteroviruses (coxsackievirus), Epstein-Barr virus, cytomegalovirus, and HIV. Treatment is primarily supportive, with management of any associated rhabdomyolysis.

Pyomyositis

Pyomyositis is a bacterial infection of skeletal muscle that typically progresses to intramuscular abscess formation. Staphylococcus aureus is the causative organism in approximately 90% of cases. While historically called "tropical pyomyositis," cases are increasingly recognized in temperate climates, particularly in immunocompromised patients (HIV/AIDS, diabetes mellitus, transplant recipients, malignancy). The disease evolves through three stages: an invasive stage with localized cramping and low-grade fever, a suppurative stage with abscess formation and systemic toxicity, and a late septic stage with bacteremia and potential metastatic infection.

Evaluation of Recurrent Rhabdomyolysis

Patients who present with recurrent episodes of rhabdomyolysis, particularly those who are young, have exercise-triggered episodes, or lack a clear precipitant, require investigation for an underlying metabolic or genetic myopathy. McArdle disease (glycogen storage disease type V) classically presents with exercise intolerance and a "second wind" phenomenon. CPT II deficiency is the most common inherited cause of recurrent myoglobinuria in adults, triggered by prolonged exercise, fasting, cold exposure, or intercalating illness. Genetic testing panels for metabolic myopathies and RYR1-related disorders should be considered. A forearm exercise test (non-ischemic) can screen for glycolytic defects, while acylcarnitine profiles and tandem mass spectrometry can identify fatty acid oxidation defects.

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