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TOXIC MYOPATHIES

Classification of Toxic Myopathies

• Mitochondrial
  • AZT & Other nucleoside analogs
  • Germanium
• Myosin Deficiency (Thick-filament loss) Myopathies: Associated with
  • Corticosteroids
  • Non-depolarizing blocking agents: Vecuronium; Atracuronium
• Rhabdomyolysis syndromes
  • Ethanol
  • Opiates: Heroin; Cocaine
  • Toluene
  • Snake Venoms
  • Cholesterol-lowering-agents (Statin; Fibrate)
  • Cyclosporine
• Hypokalemic myopathies
• Inflammatory
  • D-penicillamine
  • α-interferon
  • Intramuscular gene therapy
  • Checkpoint inhibitors: Immune myopathy
  • Fasciitis: Eosinophilia-myalgia; Toxic oil
  • Aromatase inhibitors
• Lysosomal
  • Colchicine
  • Chloroquine & Hydroxychloroquine
• Myofibrillar
  • Emetine
• Muscle overactivity syndromes
  • Neural
    • CNS overactivity: Phencyclidine; Amphetamine; Cicutoxin
    • Neuroleptic malignant syndrome: Lithium; Haloperidol; Phenothiazines
      • Combinations are especially likely to produce myopathy
      • Features: Altered mental state, Muscule rigidity, Autonomic Δ, Hyperpyrexia
      • Treatment: Dopamine agonist (Bromocriptine; Amantadine)
    • Agonist-induced myopathy: Organophosphates
    • Motor neuron hyperactivity: Tetanus; Strychnine
  • Myotonia
    • Inducing
    • Exacerbating
• Atrophy
  • Androgens: Low levels or Blockade
• Local toxicity: Due to injections of drugs
  • Focal fibrosing myopathies: Meperidine; Pentazocine

• Drug & Toxin induced ⁹
  • Agonist-induced myopathy: Organophosphates
  • Amphiphilic Drug Myopathies
    • Necrotizing
    • Vacuolar
  • Anti-microtubule drugs: Especially colchicine
  • Chlorphenoxy herbicides
  • Cyclosporine
  • Emetine
  • Focal fibrosing myopathies: Due to injections of drugs
  • Inflammatory myopathies
    • D-penicillamine
    • 1,1'-Ethylidinebis[tryptophan]: Eosinophilia-myalgia syndrome
    • Lupus ± myositis: Procainamide; Hydralazine
  • Interferons: α-2a; α-2b
    
  • Ipecac
  • Isotretinoin
  • Labetalol
  • Lipid myopathy (MADD syndromes): Sertraline
  • Methotrexate: Myalgias when given with pantoprazole ⁷
  • Neuroleptic
    • Malignant syndrome
    • High CK
      • Specific drugs: Clozapine; Loxapine; Haloperidol; Melperone; Risperidone ¹⁶; Olanzapine
      • General: Drugs with potent serotonin 5-HT2a effect more than dopamine D2 receptor antagonism
  • Selumetinib
    
  • Valproate
    • Mitochondrial disorders (MELAS): Induces myopathy & encephalopathy
    • CPT-2 deficiency: Precipitates myopathy & rhabdomyolysis
    • Paraspinous weakness
    • Also see: Possible treatment for SMA 5q
  • Vitamin E (Overdose)
• Myalgia syndromes
• Myasthenia gravis

• General features
  • Drugs with hydrophobic moiety and hydrophilic region containing amine group
  • Often produce multisystem disorders: Especially neuropathy & cardiomyopathy
• Myopathy type: Necrotizing
  • Drugs: Chlorphenteramine; Chlorcyclizine; Triparanol; Iprindol;
      20,25-Diazacholesterol, Local anesthetics
  • Drug features
    • Highest lipid solubility & high pH in solution
    • Hydrophobic region partitions into membranes
• Myopathy type: Vacuolar
  • Drugs
    • Chloroquine; Hydroxychloroquine; Doxorubicin; Perhexiline & Amiodarone
    • Dose related myopathy: Daily dosages of chloroquine of 500 mg given for 1 year or longer
  • Drug features
    • At extracellular pH drugs are poorly ionized & penetrate membranes
    • Acid pH in lysosome: Cationic region interacts with polar materials
    • Long half-lives: 3.5 to 12 days
  • Clinical: Weakness, Proximal > Distal
  • Pathology
    • Vacuoles with lipid & membranous material
    • Acid phosphatase staining in muscle fibers
    • Normal PAS staining for glycogen

• Peptide
  • Venom component of Hymenoptera (Bees & Wasps)
  • Blocks Ca⁺⁺ sensitive K⁺ channels, Small conductance (SK) type
• Epidemiology
  • Multiple stings from "Killer" or "African" bees
  • Central America & Mexico
• Clinical
  • Rhabdomyolysis
  • Renal failure
  • Mechanism: ? Syndrome related to toxin effect or anaphylaxis after bee stings

• Toxicology
  • Toxin: Soluble salts; Acetate, Carbonate, Chloride, Hydroxide, Nitrate, Sulfide
  • Doses (Oral): Toxic 200 mg; Lethal 1 to 15 g
  • Exposure
    • Oral: Suicide; Food contamination (Table salt, Flour, Potato meal substitution
    • Inhalation
    • Burns: Molten barium chloride
• Clinical
  • Acute toxicity
    • GI: Nausea; Vomiting; Diarrhea; Abdominal pain; Xerostomia
    • Perioral paresthesias (Occasional)
  • Weakness
    • Quadriparesis: Flaccid
    • Muscle twitching
    • No involvement of cranial nerves or respiration
    • Reflexes: Often absent; May be preserved
    • Rhabdomyolysis: Occasional
    • Mechanism or weakness: Shift of extracellular K⁺ into muscle
  • Autonomic: Diaphoresis; Salivation
  • Sensory & Mental status normal
  • Systemic features
    • Testicular tenderness
    • Headaches
    • Cardiac: Ventricular tachyarrhythmias
    • Renal: Reversible acute insufficiency
  • Fatalities: Related to respiratory failure or cardiac arrhythmias
• Laboratory
  • Hypokalemia: Often severe, K⁺ as low as 0.8 mEq/L
  • EKG: T wave change; Prominent U waves
• Treatment: K⁺ supplementation; Oral sulfates
• Barium variant disorder: Muscle fiber direct toxicity ¹⁵
  • Mechanism
    • Sarcolemma depolarization → Sarcoplamic Ca⁺⁺ overload → Ca⁺⁺dependent proteolysis
  • Utility
    • Muscle fiber injury model
    • Other muscle fiber injury models
      • Freeze
      • Cardiotoxin (Naja atra) snake ¹⁷
      • Notexin (Tiger snake)
      • Marcaine

• Specific medications
  • Colchicine
  • ? Vincristine
• Mechanisms of toxicity ¹⁰
  • Binds to tubulin; Prevents polymerization & formation of microtubules
  • Defective intracellular movement of vesicles & lysosomes
  • Degradation pathways
    • Inhibits: Lysosomal exocytosis
    • Blocks: Autophagic flux: Autophagosomal transport during maturation
  • Membrane ACh receptors
    • Increased endocytosis
    • Reduced degradation
• Colchicine uses
  • Gout treatment
  • Other treatment
    • Pulmonary fibrosis
    • Liver cirrhosis
    • Pericarditis
    • Psoriatic arthritis
    • Vasculitis
    • Scleroderma
    • Familial Mediterranean fever
    • Amyloidosis
    • Sweet’s syndrome
    • Behçet’s disease
• Risk factors
  • Organ failure
    • Renal insufficiency
      • Colchicine not recommended with GFR <10 mL/min
      • Dialysis removes only 0% to 5% of colchicine
    • Liver disease
    • Clearance of colchicine: Normally dependent on both renal & hepatic systems
  • Age > 50 years
  • Prolonged colchicine treatment
  • Concomitant therapy: Statins, Cyclosporine A, Grapefruit juice, ? Prednisone
• Clinical
  • Onset
    • Drug dose: High or Normal; 0.6 to 4 mg/d
    • Treatment duration: Prolonged, Ocasionally brief; 1 week to 1 year
    • Syndrome development: Subacute (2 weeks) to chronic (3 months)
    • Prodrome: Muscle pain & weakness
  • Myopathy
    • Weakness: Proximal; Mild to Severe
    • Myalgias
    • Myoedema
    • Recovery: Weeks to months after drug is discontinued
  • Neuropathy
    • Vincristine & Vinca alkaloids; ± Colchicine
    • Type: Axonal; Mild
  • Cardiac toxicity
  • Gastrointestinal intolerance (nausea, vomiting, abdominal pain)
    • Common: Dose related side effect
    • Myopathy may occur in the absence of this side effect
• Laboratory
  • Serum CK: Very high
  • EMG: Myopathy; Spontaneous activity; Myotonia
  • Renal failure: Some patients
• Muscle pathology ⁵
  • Muscle fiber size: Varied
  • Lysosomal accumulation
  • Inclusions
    • Central: Basophilic on H & E stain
    • Membranous, filamentous & vacuolar
    • AVSF
    • Acid phosphatase positive: Autophagic
    • Stain for αB-crystallin
    • More common in type I muscle fibers
  • MHC class I positive Muscle fibers
  • Membrane attack complex: Granular deposits on surface of myofibers
  • Myofibrillar disorganization
• Treatment: Discontinue colchicine

Cyclosporine

• Rhabdomyolysis: With lipid lowering agents
• Myopathy with anti-Microtubule drugs: Colchicine
• Myopathy (Rare)
  • Clinical
    • Onset: 1 to 5 months after onset of treatment
    • Discomfort: Myalgias; Cramps
    • Weakness: Proximal or Diffuse; Symmetric; ? Legs > Arms
    • Time course: Resolution in months after stopping Cyclosporine
  • Laboratory
    • Serum CK: Normal or High
    • Muscle biopsy: Type 2 muscle fiber atrophy; Mitochondrial changes (10%)

• Ataxia
• Erythromelalgia ¹⁸
  • Epidemiology: 3 patients
  • Drug doses: 150 to 300 mg/day
  • Clinical
    • Onset: 1 week to 1 year after starting drug
    • Hyperaesthesia:To pinprick & and warm stimuli
    • Allodynia to light touch: Distal; Legs
    • Erythromelalgia worse with
      • Standing
      • Feet in ice water
    • Erythema,
    • Edema
    • Increased temperature in feet
    • Skin ulcers
    • Vibration & Joint position sense: Normal
    • Course: Resolution within 3 months of stopping drug

• Molecule: Lipopeptide from Streptomyces roseosporus
• Uses: Antibiotic
• Effect on muscle fibers
  • Probably concentration dependent
  • Damage to sarcolemma
  • Necrosis
  • Dysferlin: Increased on sarcolemma of some fibers
• Clinical: Myopathy
  • Frequency: 0.2%
  • Muscle pain
  • Weakness
  • Improves with drug withdrawal
  • Serum CK: High

• Molecule type: Cholesterol analog, Reduces cholesterol synthesis
• Clinical
  • Myotonia
  • Cramps
  • Muscle weakness: Some patients
  • Palmoplantar keratoderma (20%)
  • Course
    • Onset: Months after beginning treatment
    • Resolution: ~2 Months after stopping drug
• Laboratory
• Serum cholesterol: Reduced
• EMG: Myotonia (96%)
• Muscle biopsy: Myopathic

• Toxin
  • 1,1'-Ethylidinebis[tryptophan]
  • Contaminant of tryptophan produced by Showa Denko KK in 1989
  • Tryptophan ingestion in 98% of patients
  • Other related contaminants
    • 3-(phenylamino) alanine (PAA)
    • (S)-2-amino-3-(2-((S,E)-7-methylnon-1-en-1-yl)-1H-indol-3-yl)propanoic acid
    • (S)-2-amino-3-(2-((E)-dec-1-en-1-yl)-1H-indol-3-yl)propanoic acid
• Epidemiology
  • ~1,500 US patients involved
    • Predominantly white: 97%
    • Female: 84%
    • Age: Most common 35-60 years; Range 17-81 years; Mean 49 years
  • Epidemic occurred in 1989 to 1991: Few new cases since
  • Similar disorder: Toxic oil syndrome
  • Non-L-tryptophan cases (2%)
    • Younger
    • More common neuropathy & skin disorders
• Clinical
  • Onset
    • Sudden
    • Skin changes (57%)
    • Myopathy (34%)
    • Neuropathy (34%)
  • Other early features
    • Edema
    • Fever
    • Alopecia
    • Arthralgias
  • Myalgias & Fatigue
    • Severe
    • At onset of syndrome
  • Myopathy
    • Proximal weakness
    • Myalgias
    • Cramps
    • Perimysial & perivascular inflammation (macrophage)
  • Polyneuropathy
    • Paresthesias
    • Sensory loss: Distal
    • Motor: Progressive to severe weakness in some
  • Skin (33%)
    • Scleroderma-like rash
    • Edema
    • Onset: 3 weeks after myalgias
  • Vascular: Thromboembolic events
  • Pulmonary
    • Pneumonia: Non-bacterial
    • Interstitial disease
    • Hypertension
  • CNS: Encephalopathy; Seizures; Spasticity
  • Prognosis
    • Slow resolution over years (60%): Myalgias; Skin changes
    • Occasional patients: Severe residual weakness or myalgia
    • Persistent features: Cognitive changes; ? Polyneuropathy
    • Death: 2% to 20% in 18 months; Especially in older patients
  • Treatment
    • Stop offending drug
    • Prednisone not effective
    • Pain control
• Lab
  • Eosinophilia (> 1,000 cells/mm³): Up to 10,000-30,000 cells/μL
  • Leukocytosis
  • Aldolase: High (60%)
  • CK: High (10%); Often normal
  • Pulmonary: Reduced diffusion capacity in 50%
  • Liver function tests: Abnormal in 40%
  • ANA: 40%; Low titer
• Pathology
  • Nerve
    • Axon loss ± Demyelination
    • Inflammation: Epineurium
  • Muscle
    • Perimysial inflammation (Fasciitis)
    • Inflammatory cell type: Macrophages
• Support group: Eosinophilia-Myalgia Association

Sources Thespesia populnea: Cotton plant flower Gossypium herbaceum: Seed & Root Predominant pigment Intoxication route: Ingestion of raw cottonseed oil Uses Male contraceptive Uterine hemorrhage (in China) Animal feed: Cotonseed Epidemiology Location: Common in cotton growing areas of China Seasonal: More common in Winter & Spring Clinical Prodrome: Nausea; Anorexia; Tingling in hands; Cramping; Weakness Progression: Over 1 to 2 weeks Polydipsia Polyuria GI: Anorexia; Nausea & vomiting Palpitations Weakness Proximal > Distal Other: Wrist weakness; Occasional respiratory Tone reduced Tendon reflexes: Reduced Normal cranial nerves & sensation Course: Resolution over weeks Laboratory Serum K+: Low Urine: High K+; Distal renal tubular acidosis EKG: Long QT; T wave change; PVC; AV block Mechanism of myopathy: Hypokalemia K+ wasting in urine Treatment Stop gossypol intake K+ supplementation: IV or oral Animal toxicity Source: Cottonseed feed Affected animals: Non-ruminants; Younger age Sudden death Cardiomyopathy

Gossypol

• Source: Cephaelis ipecacuanha
• Composition: 2 major alkaloids emetine & cephaeline
• Uses: Induction of vomiting
• Clinical features
  • Myopathy
    • Painless proximal weakness
    • Weakness reverses on stopping medication
    • Serum CK: High
    • Muscle pathology: "Floccular or Geographic" Inclusions
  • Other systems: Cardiac

• Source
  • Alkaloid from Cephaelis ipecacuanha
  • Major component of ipecac
• Herbal & Historical aspects
• Uses: Treatment of amebiasis
• Toxicity
  • Cumulative 2° slow urinary excretion
  • Dose related: Especially > 500 to 600 mg over 10 days
  • Mechanism: ? Inhibition of muscle protein synthesis
• Myopathy
  • Clinical
    • Discomfort: Pain; Tenderness; Stiffness
    • ± Rhabdomyolysis
    • Course: Improvement after discontinuation of drug
  • Pathology
    • Myofibrillar degeneration: Cytoplasmic bodies
    • Mitochondrial degeneration
    • Muscle fiber Necrosis & Regeneration
    • Motheaten muscle fibers
  • Laboratory
    • Serum CK: High
    • EMG: Irritable myopathy, or Normal
• Systemic disorders
  • Skin change
  • Associated cardiotoxicity

• Uses: Herbicides for control of broad-leaved weeds
• Common compounds
  • 2,4-dichlorophenoxyacetic acid (2,4-D): Component of Agent Orange
  • 2-methyl-4 chlorphenoxypropionic acid (MCPP)
• Toxic mechanisms
  • Cell membrane damage: Dose dependent
  • Oxidative phosphorylation: Uncoupling
  • Acetylcoenzyme A metabolism: Disrupted
  • Herbicide mechanism: Plant growth hormone
• Routes of exposure: Ingestion; Inhalation; Skin
• Clinical
  • Acute effects after ingestion
    • GI: Vomiting; Abdominal pain; Diarrhea
    • Hypotension: Occasional; Due to hypovolemia
  • Myopathy
    • Weakness: Limb; Proximal
    • Cramps
    • Myotonia
    • Occasional rhabdomyolysis
  • Other Motor
    • Hypertonia
    • Weakness
    • Fasciculation
    • Hypoventilation
  • Tendon reflexes: Increased
  • CNS
    • Dose dependent: ? Blood-brain barrier damage
    • Encephalopathy: Coma; Hallucinations; Seizures
    • Cerebellar: Ataxia; Nystagmus
  • Ocular: Miosis
  • Dermal exposure syndromes
    • GI irritation: After latent period
    • Polyneuropathy: Rare reports
      • Weakness: Legs
      • Fasciculations
      • Sensory loss: Light touch; Pain; Temperature
      • Pain & Paresthesias
      • Tendon reflexes: Reduced
  • Prognosis: Mortality 33%
• Laboratory
  • Serum cholesterol reduced: Analog of clofibrate
• Treatment
  • Supportive care
  • Alkaline diuresis
  • Hemodialysis

• Uses: Acne
• Clinical features
  • Myalgias
  • Rare rhabdomyolysis
  • May be Asymptomatic
• Laboratory
  • High CK (> 5,000), especially after exercise or IM injection
  • Serum carnitine: Reduced
  • Liver enzymes: High
  • Serum lipids: High
• Frequency: 1.6% to 15%
• Course: CK returns to normal within 2 weeks
• Treatment: ? Dietary supplement with L-carnitine

• Caused by injections of drugs
  • Meperidine
  • Pentazocine
  • Heroin
  • Antibiotics in infants
  • Penicillin
  • Diphenhydramine
  • Piritramid
  • Pethidine
  • Triamcinolone
• Clinical
  • Stiffness: Limited active & passive joint movement
  • No pain
  • Muscles: Fibrous; Hard & Indurated
  • Strength: Mildly reduced
• Laboratory
  • Serum CK: Normal
  • EMG: Silent
  • Ultrasound: Enlarged muscle structure; Thickened connective tissue
  • Muscle biopsy
    • Variable muscle fiber size
    • Inflammation
    • Endomysial connective tissue: Increased
• ? Treatment: Prednisone; Penicillamine; Physical therapy; Stop injections

• Functions
  • Roles
    • Immune system development
    • Immune response regulation
    • T-cell-mediated tissue injury
    • Antigen-presenting cell function
    • Regulating apoptosis of potentially autoreactive T cells
  • Cytokine: Pro-inflammatory & Immunoregulatory properties
  • Involved in normal inflammation immune responses
  • Growth factor: Prothymocytes & Thymocytesi
  • Influences generation of the T-cell repertoire
• Source: TNF-α secreted by macrophages
• Receptors
  • p55 (TNFRSF1A)
  • p75 (TNFRSF1B)
• Associated biologic responses: Expression of molecules responsible for
  • Leukocyte adhesion & migration: E-selectin, intercellular adhesion molecule-1 (ICAM-1), Vascular cell adhesion molecule (VCAM-1)
  • Chemoattraction: Interleukin-8 (IL-8); Monocyte chemotactic protein (MCP-1)
  • Tissue degradation: Matrix metalloproteinase (MMP) 1 & 3; Stromelysin
• Circulating TNF-α levels: High in systemic disorders
  • Chronic obstructive lung disease
  • Heart failure
  • Sepsis
  • Transplant rejection
  • Neuropathies, immune: GBS; CIDP; MMN
• Associations
  • Focal invasion of muscle fibers
  • Muscle pain: May be chemical stimulus
  • Muscle protein degradation
  • Paraneoplastic Sensory-Motor Neuromyopathy
  • POEMS
• Polymorphisms associated with susceptibility to
  • Malaria
  • Septic shock
  • Acute motor axonal neuropathy (AMAN)
  • Dermatomyositis
  • Systemic lupus erythematosus: TNF superfamily gene 4 (TNFSF4 )
• Other TNF-α related: Hereditary
  • Recurrent fever with localized myositis or fasciitis (TNFRSF1A)
• TNF-α antagonists ¹¹
  • Drugs
    • Infliximab: Monoclonal antibody vs TNF-α
    • Etanercept: p75 TNF-receptor fusion protein conjugated to Fc region of human IgG
    • Adalimumab: anti-TNF monoclonal antibody
  • Uses: Treatment of advanced inflammatory rheumatic & bowel disease
  • Associated disorders: Immune; Idiosyncratic
    • Epidemiology
      • Female: 80%
      • Mean age at diagnosis of associated vasculitis: 51 years
      • Length of anti-TNF treatment: Mean 9.5 months
      • Previous vasculitis: 9%
    • Acute immune neuropathies: Guillain-Barré; Miller Fisher
    • Chronic inflammatory demyelinating polyneuropathy
    • Multifocal motor neuropathy
    • Vasculitis
      • Neuropathy: Mononeuritis multiplex; Necrotizing vasculitis
      • Leukocytoclastic: Most common; Purpura; 25% with extracutaneous involvement
    • Sensory-Motor polyneuropathy: Axonal; Distal; Symmetric; Legs > Arms
    • Lupus: Cutaneous or systemic
    • Interstitial lung disease: Poor prognosis; Possible association with methotrexate
    • Leprosy type
    • Immune myopathy: IMPP pathology
  • Treatment
    • Discontinue use of TNF-α antagonist
    • Course after discontinuation
      • Improvement: Mean time to resolution 1 year
      • Re-exposure to drug: May be associated with relapse of immune syndrome
• TNF-α: Experimental systems
  • Reduces muscle contractile force
  • Normal muscle mass and ultrastructure

• Drug
  • Mechanisms: Selective non-ATP competitive small-molecule inhibitor of MEK1/2
  • Uses: Clinical trials for solid tumors
• Clinical
  • Weakness
    • Posterior neck: Head drop
    • Proximal arms: Some patients
  • Course: Improvement after drug stopped
• Laboratory
  • EMG: Myopathic
  • Serum CK: Mildly high
  • Muscle biopsy: Varied fiber size; Occasional regeneration
  • PET: Uptake in posterior neck muscles

• Drugs: Finasteride & Dutasteride
• Uses: Benign prostatic hyperplasia (BPH)
• Clinical
  • Reports of associated rhabdomyolysis: Not more than controls
  • Myopathy
    • Statistical association of increased frequency (Hazard ratio 1.6)
    • Specific myopathy type not defined

• Drug
  • Antidepressant (Zoloft)
  • Inhibits statin metabolism
• Clinical
  • MADD syndromes, Late onset
  • Weakness
  • Treatment
    • Riboflavin
    • Discontinue drug
  • Muscle pathology: Lipid myopathy
  • Lipid storage: type I > II
  • SDH stain: Pale
  • Fiber sizes: Varied; Hypertrophy