Differential Diagnosis in Neurology

Topic 12. Muscle Disease

12.11. Rhabdomyolysis and Myoglobinuria

Overview

Rhabdomyolysis is the lysis of skeletal muscle whose major clinical features are myalgias of the affected muscle, pigmenturia and elevated serum creatine kinase. Acute renal failure, cardiac arrest, and nerve damage from compartment syndromes are the major systemic complications. In general, muscle enzymes are elevated to five times normal and serum and urinary myoglobin is present.

The balance of extracellular and intracellular calcium across the muscle membrane is maintained by:

  • Sodium-potassium pumps regulated by sodium/potassium-activated adenosine triphosphatase
  • Calcium channels
  • Specific calcium-ATPase
  • Sodium-calcium exchangers

Disruption of the muscle and sarcoplasmic reticular membrane occurs (possible osmotic mechanism due to failure of Na pump mechanisms) and calcium homeostasis is lost that causes a dramatic rise in intracellular calcium. This calcium overload activates phospholipase-A2 and neutral proteases which further destroy muscle membranes. The elevated cytoplasmic calcium induces myofibrillar hyper contractures from enhanced action of myosin filament interaction.

Rhabdomyolysis causes myoglobinemia and myoglobinuria. Myoglobinuria at levels above 300 μg/liter causes renal failure (at levels of 1000 μg/liter greater than 82% of patients). The clearance of myoglobin through the kidneys is rapid as well as its conversion to bilirubin so serum values return to normal after an attack between 1–4 hours. Myoglobin levels in serum precede a CK increase. Myoglobin is detected by a positive toluidine blue test, pigmented casts in the urine, absence of RBC and a normal haptoglobin.

The most sensitive test for rhabdomyolysis is a five time normal elevation of serum CK. Approximately 200 grams of muscle is involved to effect a rise in serum CK. The CK isoenzyme CK mm is most prominent although CK-MB (cardiac greater than skeletal muscle) is also elevated. CK-BB is found in brain tissue. Serum CK rises 2–12 hours after the onset of rhabdomyolysis, peaks in 1–3 days and decreases 3–5 days after the muscle damage.

Immunologic measurement of carbonic amylase II is a very specific marker of skeletal muscle injury and is not present in cardiac tissue.

Rhabdomyolysis is associated with hyperkalemia, hypocalcemia and hyperphosphatemia. Approximately 150 grams of muscle destruction release 15 millimols of potassium which may elevate plasma levels acutely and contribute to or cause cardiac arrhythmia. Hypocalcemia seen in early rhabdomyolysis has been attributed to deposition of calcium in affected muscle. Hypocalcemia may also be secondary to a decrease of 1,25-dihydroxycholecalciferol due to hyperphosphatemia. In later stages of rhabdomyolysis, hypercalcemia may be seen as calcium is mobilized from necrotic tissue.

Rhabdomyolysis is also associated with elevated aldolase, lactate dehydrogenase, amino transferases, creatine and uric acid.

Muscle signs and symptoms are generally similar for all causes of rhabdomyolysis. Patients suffer muscle pain and edema; they have thin shiny skin, weakness, stiffness and later contractures. Patients may present without significant muscle weakness. The most commonly affected muscles are the quadrates lumborum (paraspinal muscles), the quadriceps and major muscles of the upper extremity. Rarely, muscles of the chest, abdomen, throat and masseter muscles are affected. All striated muscles may be affected focally or diffusely depending on specific etiology.

Myoglobinuria

  • Clinical features:
    • Associated with rhabdomyolysis
    • Swelling of affected muscles
    • Pigmenturia with myalgia
    • Weakness of the involved muscle group
    • Pain free episodes may be associated with:
      • Pigmenturia
      • Leakage of muscle enzymes
  • Myoglobinuria may develop with:
    • Severe and excessive stress upon fuel reserves of working muscle
  • During moderate exercise muscles utilize:
    • High energy phosphate to generate ATP
    • Muscle glycogen for the first 5–10 minutes
    • 15–90 minutes of exercise:
      • Blood glucose is derived from liver glycogen
      • Requires insulin for uptake
    • Greater than 90 minutes of exercise the metabolites utilized are:
      • Glucose
      • Free fatty acids
  • Myoglobin: facilitates rapid diffusion of 02 from capillaries to mitochondria in exercising muscles
  • Myoglobinuria with serum levels greater than 300 ug/liter may cause renal failure:
    • Levels greater than 100 ug/liter renal failure is common
    • Cleared rapidly through the kidneys:
      • May return to normal 1–6 hours after muscle injury
      • Concomitantly metabolized to bilirubin
    • Myoglobin detection:
      • Positive toluidine blue test
      • Colorless serum
      • Normal haptoglobin
      • RIA
      • ELISA assays

Hereditary Causes of Rhabdomyolysis and Myoglobinuria

  • General features:
    • Defects of glycolysis
    • Dysfunction of lipid metabolism
    • Genetic causes:
      • Idiopathic rhabdomyolysis
      • AD myoglobinuria
      • Malignant hyperthermia
      • Myoadenylate deaminase deficiency
      • Mono carboxylate transporter defect
      • Neuroleptic malignant syndrome
      • Dystrophinopathies

Genetic Metabolic Defects of Muscle with Myoglobinuria and Rhabdomyolysis

Glycolytic Defects

  • Myophosphorylase (McArdle's Disease)
  • Phosphofructokinase
  • Phosphoglycerate mutase
  • Phosphoglycerate kinase
  • Lactic dehydrogenase
  • Phosphorylase kinase

Clinical Features of Glycolytic Defects

  • Onset in childhood
  • Intense exercise causes:
    • Pain
    • Weakness
    • Cramps
    • Myoglobinuria
  • "Second wind" phenomena
  • Serum CK persistently increased (5–10 times normal values)
  • Pain may develop asymmetrically in any working muscle
  • Acute tubular necrosis described only in patients with gross pigmenturia

Myophosphorylase Deficiency (McArdle Disease)

  • Exercise intolerance most severe the first few minutes
  • Approximately 60% of patients:
    • Clear myoglobinuria
    • Elevated CK
    • At least 2 attacks
    • Exercise intolerance may occur without myoglobinuria

Phosphofructokinase Deficiency (Tarui's Disease)

  • Lifetime intolerance to severe exercise
  • Rhabdomyolysis with myoglobinuria relatively rare
  • Pain and stiffness of exercised muscle
  • Older onset of proximal myopathy in a subset of patients

Phosphoglycerate mutase (PGAM) and Lactate Dehydrogenase Deficiency (LDH)

  • Defect of terminal glycolysis:
    • Exercise intolerance, cramps, recurrent rhabdomyolysis
    • No permanent weakness

Phosphoglycerate Kinase (PGK); X-linked recessive

  • Enzyme defect occurs in:
    • Erythrocytes
    • Fibroblasts
    • Muscle
  • Associated features:
    • Hemolytic anemia
    • Seizures
    • Mental retardation

Lipid Metabolic Defects with Myoglobinuria and Rhabdomyolysis

  • Carnitine – palmityl transferase deficiency Type I and II:
    • Most common hereditary disorder of recurrent rhabdomyolysis and myoglobinuria
      • Transport of long chain fatty acids across mitochondrial membrane
    • Attacks associated with:
      • Prolonged exercise without food
      • Stress
      • Attacks can be blocked if carbohydrate intake is maintained during exercise
    • Much greater incidence of rhabdomyolysis with CPT than occurs than is seen in systemic carnitine deficiency, acid maltase or mitochondrial myopathies
    • Carnitine deficiency associated with lipid storage in muscle

Long-Chain 3-Hydroxyacyl-Coenzyme A Dehydrogenase (LCHAD) Deficiency

  • Defect in mitochondrial fatty acid beta-oxidation
  • Clinical features:
    • May be manifest in infancy
    • Hypoglycemic coma
    • Hepatic steatosis
    • Hypocarnitinemia
    • cardiomyopathy
  • Unusual features:
    • Peripheral neuropathy
    • Chorioretinopathy
    • Female carriers of LCHAD deficiency:
      • Pre-eclampsia
  • Diagnosis:
    • 3-hydroxylated acylcarnitine derivatives in the blood

L-3-Hydroxyacyl-Coenzyme A Dehydrogenase Deficiency

  • Clinical features:
    • Juvenile onset
    • Recurrent myoglobinuria
    • Hypoketotic hypoglycemic encephalopathy
    • Hypertrophic or dilated cardiomyopathy

Autosomal Dominant Myoglobinuria

  • Clinical features:
    • Swiss family
    • Both genders affected
    • Precipitated by febrile illness
    • Acute renal failure
  • Posited mechanism:
    • Nuclear encoded genetic defect of the respiratory chain

Myoadenylate Deaminase (MAD) Deficiency

  • Clinical features:
    • Cramping and fatigue with strenuous exercise
    • Few patients have exertional rhabdomyolysis
  • Catalyzes the deamination of adenosine monophosphate to inosine hypophosphate with ammonia formation

Mono Carboxylate Transporter 1 Mutation

  • Clinical features:
    • Muscle breakdown with heat and exercise
  • Muscle lactate transporter deficient; also expressed in RBC

Neuroleptic Malignant Syndrome

  • Clinical features:
    • Moderate hyperthermia of gradual onset
    • Triggered by:
      • Neuroleptic medications
      • Synthetic narcotics
      • Tricyclic anti-depressants
    • Autonomic signs and symptoms
    • Muscle rigidity and myoglobinuria
    • Elevated CK
    • Probably CNS disorder rather than the sarcolemmal ryanodine receptor and pyridine interaction of MH

Toxic Myopathy

  • General Features:
    • Muscles may be damaged by direct toxic effects or secondarily from immune mechanisms, electrolyte imbalance, ischemia or sustained contraction
    • Major categories of toxic compounds:
      • Alcohol
      • Corticosteroids
      • Amphiphilic agents
      • Anti HIV compounds
      • Anti microtubular drugs:
        • Vincristine and colchicine are the two primary agents of this class
        • Disruption of the microtubule cytoskeletal network in muscle is major pathology:
          • Possible dysfunctional movement or localization of lysosomes
      • Anesthetics
  • Clinical Presentation:
    • Pain and myoglobinuria
    • Generalized or focal weakness
    • Associated neurologic features specific to the toxin
    • Wasting of affected muscles
    • Cramps
  • Categories:
    • Acute alcoholic myonecrosis or rhabdomyolysis
    • Hypokalemia with alcoholic myopathy
    • Chronic alcoholic myopathy
    • Asymptomatic or subclinical myopathy
    • Alcoholic cardiomyopathy

Rhabdomyolysis from Drug Use

  • Opioids
    • General Presentation:
      • IV injection of heroin:
        • Generalized severe muscle tenderness
        • Edema and weakness
        • Clinical symptoms may occur hours after injection of heroin and adulterants
        • Lower limbs affected to a greater degree than upper limbs
        • Proximal greater than distal muscle involvement
        • Associated transverse myelitis (occasionally)
        • Pulmonary edema
        • Local rhabdomyolysis from IM or SC injection
    • Laboratory evaluation:
      • Elevated CK
      • Myoglobinuria
    • Pathology (muscle biopsy):
      • Necrosis of muscle fibers
      • Edema and focal hemorrhage of rare fibers
  • Barbiturates
    • Clinical Presentation:
      • Rarely cause myonecrosis and myoglobinuria following one large oral dose
      • SC injection may cause focal swelling and muscle necrosis
      • In barbiturate coma:
        • Associated bullous skin lesions
  • Amphetamines
    • Thin patients
    • Agitated; attention and concentration problems
  • Meprobamate
    • Dilated pupils
    • Depressed patients
  • Diazepam
  • Phencyclidine
    • Severe nystagmus
    • Self-mutilating behavior
    • Acute dystonic reaction
  • Antibiotics
  • Beta-Blockers
  • Clofibrate
    • Generalized cramps, weakness and muscle tenderness
    • Increased CK
    • Increased risk in chronic renal failure
  • B-HMG-CoA Reductase Inhibitors (Statins)
  • Phenformin/Fenfluramine
    • Acute rhabdomyolysis
    • Rapidly progressive weakness of all muscles
    • Elevated CK and LDH
    • Right heart valve lesions
    • Pulmonary hypertension
  • Hypokalemic-Induced Myonecrosis and Myoglobinuria
    • Occurs most frequently in patients utilizing purgatives and diuretics
    • Acute potassium loss from:
      • Amphotericin B
      • Licorice and carbenoxalone
    • Azathioprine
  • Chloroquine
    • Clinical aspects of toxic reaction:
      • Doses of 250–500 mg daily for months
      • Slow progressive muscle weakness
      • Legs affected prior to arms
      • Proximal greater than distal muscle weakness
      • Face may be affected
      • Reduced or absent deep tendon reflexes
      • Heart may be affected
    • Pathology:
      • Type I greater than Type II fibers affected
      • Vacuolar myopathy
      • EM demonstrates curvilinear mitochondrial bodies in muscles
  • Emetine hydrochloride
    • Clinical features:
      • Generalized muscle weakness, pain and tenderness
      • Stiffness
    • Pathology:
      • Generalized atrophy
      • Type II greater than I fiber involvement
  • Vincristine
    • Clinical features:
      • Minimal muscle involvement
      • Proximal muscles demonstrate slight fascicular necrosis
  • Colchicine
    • Rare muscle involvement
    • Weakness and atrophy of all muscle groups of the lower extremities
  • Neuroleptics
    • Possibly compounded by heat related effects
  • Succinylcholine
    • Associated malignant hyperthermia
  • Strychnine
    • Severe muscle contractions; patients are conscious in extreme extensor postures
  • B-HMG-CoA Reductase Inhibitors
    • Primarily associated with muscle pain and cramps
  • Zidovudine
    • Associated with proximal myopathy
  • Antihistamines
  • Theophylline
  • Cocaine
  • Plasmoid (Quinoline Derivative)
  • Epsilon Amino Caproic Acid
  • 5-Azacytidine

Drugs that Cause Rhabdomyolysis and Myoglobinuria

  • Amphetamines
  • Meprobamate
  • Diazepam
  • Phencyclidine:
    • Secondary to acute dystonic reaction
  • Phenformin and Fenfluramine:
    • Causes acute rhabdomyolysis
    • Rapidly progressive weakness of all muscles
    • Elevated CK and LDH

Drugs Causing Myalgia, Muscle Cramps, Myokymia and Weakness

  • Isoetharine
  • Albuterol
  • Cimetidine
  • Danazol
  • Metolazone
  • Bumetanide
  • 5-azacytidine
  • Ipecac

Most Often Implicated Drugs in Focal Myopathy

  • Pentazocine
  • Meperidine
  • Penicillin
  • Streptomycin
  • Chloromycetin
  • Paraldehyde
  • Colistimethate

Chronic Alcoholic Myopathy

  • General features:
    • Controversy as to whether the clinical picture is secondary to neuropathy or myopathy
  • Clinical presentation:
    • Chronic proximal muscle weakness and wasting
    • Apparently dose-dependent
  • Pathology (muscle biopsy):
    • Fiber size variability
    • Myopathic type grouping
    • Occasional vacuoles

Alcoholic Cardiomyopathy

  • General features:
    • Dilated cardiomyopathy secondary to ethanol
    • Cobalt poisoning (beer drinkers)
    • Beriberi:
      • Deficiency of thiamine
  • Clinical presentation:
    • Peripheral vasodilatation from alcohol
    • CHF of the high output type
    • Chronic alcoholic cardiomyopathy:
      • Dilated cardiomyopathy
      • EKG changes of left ventricular hypertrophy
      • Conduction defects

Toxic Myopathy with Myoglobinuria and Rhabdomyolysis

  • Grape seed oil ingestion (toxic oil syndrome):
    • Clinical features:
      • Initial symptoms of respiratory illness
      • Myalgia and numbness of the extremities
      • Muscle weakness and atrophy (3rd–4th week)
    • Severely affected patients:
      • Sclerodermal features
      • Hypertension
      • Respiratory failure
      • Carpal tunnel syndrome
    • Pathology
      • Monocellular inflammatory infiltrate of the perimysium and sheaths of intramuscular nerves
  • Penicillamine
    • Autoimmune induced myositis
  • Acute alcoholic myopathy (myonecrosis or rhabdomyolysis)
    • Incidence varies: approximately 5–10% of severely intoxicated alcoholics
    • Clinical features:
      • Alcoholics of long duration
      • Previous clinical attacks of pain and swelling of muscles
    • Acute attacks occurs during:
      • Bouts of heavy drinking
      • Withdrawal phenomenon
      • Sustained heavy drinking
  • Abrupt onset
  • Severe muscle cramps, pain and swelling
  • Rarely progressive
  • Pain and tenderness may occur without cramps:
    • Usual cramps last 20–30 seconds; some may last for hours
  • Process may affect single muscle groups (gluteus, quadriceps, scalenus and gastrocnemius); rarely trunk muscles (rectus abdominus)
  • Occasionally one or most of one extremity is involved
  • Course:
    • Usually benign
    • Cramps cease within 48 hours
    • Pain tenderness and swelling last 1–2 weeks
    • Weakness lasts 10–14 days
  • Myoglobinuria and rhabdomyolysis cause acute renal failure in severe cases
  • One attack increases susceptibility to future attacks
  • Laboratory Evaluation:
    • Elevated CK, SGOT, SGPT, LDH; may be a lag of CK elevation
    • Muscle biopsy:
      • Necrosis of individual muscle fibers
      • Segmental (rarely the entire fiber is involved)

Asymptomatic Alcoholic Myopathy

  • Only increase of CK is seen
  • May have serum and urinary myoglobin

Acute Hypokalemia in Alcoholics Patients

  • General Features:
    • Occurs during chronic alcoholism
  • Clinical Presentation:
    • Long history of severe alcoholism
    • Evolves over two to several days
    • Painless, weakness of proximal muscle
    • Serum potassium is 1.4–2.3 meq/l
    • Elevated CK and aldolase
    • Repletion of K+ with recovery in two weeks
  • Muscle biopsy during the acute phase of the illness:
    • Necrosis of individual fibers
    • Vacuolar myopathy both Type I or II fibers
    • Dilatation of the sarcoplasmic reticulum and T cells

Severe Hypokalemia with Myoglobinuria

  • Occurs at a Level of .6-2.3 mEq/l with:
    • Renal tubular acidosis
    • Amphotericin B therapy
    • Primary aldosteronism
    • Regional enteritis
    • Nasogastric suction and hyperalimentation
    • Laxative abuse
    • Hypernatremia
    • Water intoxication

Rare Toxins Causing Myoglobinuria and Rhabdomyolysis

  • Licorice ingestion:
    • Glycorrheic acid is the active precursor of carboxylase
    • Clinical features:
      • Licorice abuse (fad eating)
      • Muscle pain
      • Neck weakness
      • Quadriplegia
      • Depressed, but maintained reflexes
  • Cicuta (water hemlock):
    • Seizures
    • Myoglobinuria
    • Renal failure
  • Toluene (leukoencephalopathy, dorsal column disease)
  • Clozapine (basal ganglion)
  • Gasoline vapors (leukoencephalopathy)
  • Carbon monoxide (cortex, BG, cerebellar)

Direct Effect on Muscle Membranes with Myoglobinuria and Rhabdomyolysis (Envenomations)

  • Direct toxicity of sarcolemmal membranes:
    • Sea snake (Enhydrina schistosa)
    • Australian tiger snake (Pseudechis)
    • North and South American rattlesnakes (crotalus virilis viridis)
      • Myotoxin
        • Phospholipases A
  • Hornet sting
    • Alteration of the sarcoplasmic reticulum
  • Spider
    • Damage to the endoplasmic reticulum
  • Scorpion
    • Damage to the endoplasmic reticulum

Heat and Exercise

  • Leakage of myoglobin and CK
    • Type I and Type II A fibers when stressed produce excess lactate and lose sarcolemmal integrity
  • Exertional myoglobinuria:
    • Specific exercise (squat jump)
    • Military recruits
    • Long distance runners
    • Determining factors:
      • State of fitness of the individual
      • Ability to terminate the exercise if severe cramps or pain develop
      • Core temperature
      • Ambient temperature
      • Ischemia of specific muscles in particular positions
    • Normal serum myoglobin:
      • 10 ng/ml
      • Greater than 200 ng/ml may induce renal complications
  • Myoglobinuria during violent muscle contractions:
    • Status epilepticus
    • Electroshock therapy
    • Delirium tremors
    • Prolonged myoclonus
    • Tetanus
    • Prolonged dystonic spasms
    • Status asthmaticus
    • Sit ups
    • Cross country skiers
    • Anterior tibial syndrome
    • Wrestling
  • High body temperature and excessive muscle work:
    • Exercise in hot humid climate
    • Malignant hyperthermia
    • Neuroleptic malignant syndrome
    • Strychnine poisoning
    • Amphetamine intoxication
  • Heat stroke with myoglobinuria
  • Typhoid vaccination fever and myoglobinuria
  • Toxic shock syndrome with myoglobinuria (staphylococcus toxin)

Myoglobinuria and Rhabdomyolysis after Surgery

  • Contributing factors:
    • Renal dialysis
    • Opioids
    • Anesthetics
    • Compression of specific muscle groups
    • Prolonged exposure to cold

Ingestion Causing Myoglobinuria

  • Hoff's disease:
    • East Prussia, Sweden, Russia
    • Ingestion of fish
    • Myalgia
    • Stiffness of muscles
  • Hellebore (veratrum alkaloid)
    • Ingestion of quail
  • Heat stroke with Myoglobinuria and Rhabdomyolysis:
    • Association conditions:
      • Following several days of severe heat
      • Elderly individuals
      • Sickle cell trait
      • Amphetamine abuse
    • Concomitant medical conditions:
      • Encephalopathy
      • DIC (platelets are activated)
      • Hyperthermia frequently greater than 106–109 degrees Fahrenheit
      • Renal failure (cortex degenerate)
      • Heart failure

Crush Injury and Ischemia

  • Extensive muscle necrosis from crush injury:
    • Myoglobinuria
    • Acute tubular necrosis
    • Skin and nerve ischemia
    • Bullae on the skin (often with barbiturate overdose)
  • Comatose patients:
    • Narcotized greater than 12 hours; immobilized
    • Compression of limbs or torso
    • Impaired muscle metabolism from:
      • Sedatives
      • Hypnotics
      • Tranquilizers
      • Carbon monoxide
      • Alcohol
      • Hypotension
      • Acidosis
  • Crush injury with myxedema coma
  • Specific common compartment syndromes:
    • Anterior tibial
    • Posterior tibial
    • Forearm flexor
  • Myoglobinuria following muscle infarction:
    • Embolic arterial occlusion
    • Thrombin of vessels from trauma
    • Venous thrombosis
    • Secondary features:
      • Hyperkalemia
      • Hypocalcemia
      • Hyperphosphatemia
      • Myoglobinuria may occur only when the circulation is restored

Enzyme Deficiencies Associated with Myoglobinuria

  • Myophosphorylase
  • Phosphofructokinase
  • Phosphoglycerate kinase (PGK)
  • Phosphoglycerate mutase (PGM)
  • Adenylate deaminase (AMPD)
  • Lactate dehydrogenase
  • Carnitine palmityl transferase I/II (CPT)
  • Very long chain acylcoenzyme A dehydrogenase
  • Medium chain acylcoenzyme A dehydrogenase
  • Succinic dehydrogenase aconitase
  • Trifunctional enzyme deficiency (mitochondrial)
  • Coenzymes Q10
  • COX (cytochrome oxidase, subunit defects)
  • mtDNA (multiple deletions)
  • tRNA (phenylalanine) mtDNA defect

Muscle Disease with Prominent Myoglobinuria

  • Acute polymyositis
  • Acute dermatomyositis
  • Duchenne muscular dystrophy (rapid deterioration)

Infections with Myoglobinuria

  • Mechanisms:
    • Excessive endogenous heat (high fever)
    • Effect of bacterial toxins
    • Viral destruction of muscle
  • Bacterial infections with septicemia and myoglobinuria:
    • Shigella
    • Salmonella
    • Escherichia coli
    • Legionnaire's disease
    • Leptospirosis
    • Clostridium perfringens
  • Virus infections:
    • Influenza
    • Herpes Simplex
    • Herpes Zoster
    • Epstein Barr
    • Coxsackie virus
    • Adenoviruses
    • Enteroviruses (ECHO 9, 21, 24)
  • Cysticercosis

Focal Myopathy Secondary to Intramuscular Injection

  • Local effects:
    • Connective and fatty tissue replaced by granulation tissue
    • Fibroblastic reaction separates adjacent muscle from the inflammatory site
  • Clinical features:
    • Pain, swelling and hemorrhage at the injection site
  • Drugs most likely to cause a local reaction:
    • Tetracycline
    • Paraldehyde
    • Colistimethate
    • Ceftriaxone
    • Talwin (pentazocine)

Chronic Infection Focal Myopathy

  • Clinical features:
    • Frequent IM injections
    • Localized induration
    • Fibrosis of overlying connective tissue and skin
  • Most often implicated drugs:
    • Penicillin
    • Streptomycin
    • Chloromycetin
    • Meperidine
    • Pethidine
    • Pentazocine
  • Clinical features:
    • Quadriceps and deltoids most often affected
    • Segments of muscle replaced by hard indurated bands
    • Fixed contracture of the affected extremities
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