Differential Diagnosis in Neurology

12.12. Myopathy Caused by Nutritional Deficiency

Vitamin E

• General features:
  • Difficult to achieve pure vitamin E deficiency nutritionally
  • α-tocopherol transporter deficiency
• Clinical features:
  • Cerebellar degeneration
  • Posterior column sensory loss
  • Peripheral large fiber neuropathy
  • Proximal myopathy
  • Rare extraocular muscle involvement
  • May be seen in cholestatic syndrome (if acquired)

Vitamin D Deficiency

• Clinical features:
  • Proximal muscle weakness of the extremities
  • Legs greater than arms; waddling gait
  • Wasting, pain, and tenderness of muscle
  • Weak neck muscles
  • Bulbar and ocular muscles are normal
• Laboratory evaluation:
  • Increased alkaline phosphatase
  • Normal CK
• Pathology (muscle biopsy):
  • Normal muscle biopsy

Osteomalacic Myopathy

• General Features:
  • Approximately 1/3 of patients with osteomalacic have weakness or myalgia
  • Myopathy occurs in:
    • Dietary deficiency or malabsorption of vitamin D
    • Dilantin
    • Renal tubular acidosis
    • Boys with X-linked Type I hypophosphatemic rickets:
      • No weakness
      • Vitamin D metabolism is normal
      • No renal response to vitamin D with phosphate wasting
• Clinical presentation:
  • Insidious onset
  • Proximal weakness
  • Myalgia
  • Myopathy may precede bony changes
• Laboratory evaluation:
  • Parathyroid levels are normal or increased
  • Normal CK
  • Decreased bone density
  • Increased urinary creatine excretion
  • Increased serum calcium, phosphate and alkaline phosphatase (not invariable)
• EMG:
  • Myopathic in 80% of patients
  • Slightly slowed NCVs in some patients
• Pathology (muscle biopsy):
  • Type II fiber atrophy
  • Fatty infiltration
  • Variation of fiber size
  • Interstitial fibrosis
  • Proliferation of nuclei

Primary Hypophosphatemic Osteomalacia

• Sporadic presentation in adult life
• No dwarfism or previous rickets
• Persistent hypophosphatemia
• Normal plasma and urinary calcium

Hypermagnesemia

• General features:
  • Usual clinical settings:
    • Treatment of eclampsia
    • Antacid and cathartic abuse
  • Magnesium inhibits calcium at the nerve terminal thus blocking the release of Ach
• Clinical presentation:
  • Serum concentration of 3–5 mEq/dl:
    • Smooth muscle paralysis
    • Dysautonomia
    • Dry mouth
    • Cutaneous flushing
    • Hypotension
    • Nausea and vomiting
  • Serum concentration of 5–6 mEq/dl:
    • Depressed tendon reflexes
    • Muscle weakness (7–8 mEq/dl)
    • Heart block (7–8 mEq/dl); cardiac arrest
    • Serum levels of 8–10 mEq/dl: confusion to coma
    • Magnesium may exacerbate MG
• EMG:
  • Low motor amplitudes on NCV studies
  • Incremental response with repetitives stimulation (facilitates Ach release)
• Pathology (muscle biopsy):
  • Mitochondrial myopathic features have been reported in two patients

Amphiphilic Drug Myopathy

• General features:
  • Cationic amphiphiles (as exemplified by chloroquine and congers):
    • Contain a hydrophilic region and a primary or substituted amino group
  • Hydrophobic region partitions in muscle membrane that then allows the drug to react with anionic groups of phospholipids that causes:
    • Conformational and surface change of the plasma membrane
    • Consequent abnormalities of permeability, transport, fusion and receptor properties
    • Necrotizing myopathic change induced:
      • Repeated cycles of segmental necrosis
      • Myoblast regeneration and abnormal myotube fusion
      • Chlorphentermine, chlorcyclizine, Triparanol and iprindole are representative drugs for this phenomena
  • Lysosomal vacuolization:
    • Produced by the non-porotomized forms of amphophile compounds
    • Complexes are formed with polar lipids in lysosomes; change of pH in the lysosome leads to dysfunction of lysosomal enzymes that induce the formation of vacuoles that contain lipids and membranous material (vacuolization of non-necrotic myofibers)
    • EM reveals autophagic vacuoles
    • Vacuoles, myeloid bodies and necrosis is characteristic of amphophil myopathy

Chloroquine Hydroxychloroquine

• Clinical presentation:
  • Doses of 200–500 mg taken daily for months are required for toxicity
  • A slowly progressive weakness
  • Legs affected prior to arms
  • Proximal greater than distal muscles
  • Face may be affected
  • Reduced or absent deep tendon reflexes
  • Associations:
    • Macular retinopathy
    • Cardiomyopathy
    • Axonal neuropathy
• EMG:
  • Myopathic changes
  • Increased insertional activity and fibrillation potentials
• Laboratory Evaluation:
  • CK moderately elevated
• Pathology (muscle biopsy):
  • Type I > II fibers affected
  • Vacuolar myopathy
  • Curvilinear and mitochondrial bodies noted by EM

Amiodarone

• Clinical presentation:
  • Peripheral neuropathy is the predominant neurological manifestations
  • Acute necrotizing vacuolar myopathy
  • Myopathy may be secondary to hypothyroidism
• Pathology:
  • Peripheral nerve, muscle, heart, skin and multi organ involvement
  • Phospholipids-contain myeloid inclusions; may persist for months after discontinuation of the drug

Differential Diagnosis (Amphiphilic Myopathy)

• Chloroquine toxicity versus exacerbation of inflammatory myopathy of the primary autoimmune disease:
  • Muscle biopsy is the only method to differentiate the two
• Perhexiline (associated neuropathy)
• Amiodarone (associated neuropathy
• Chlorpromazine (associated psychiatric problem)
• Imipramine (associated neuropathy)
• Quinacrine (yellow sclerae)
• Doxorubicin (DRG; ganglioneuritis; large fiber sensory loss)

Colchicine Myopathy

• Clinical Presentation:
  • Primarily men over 50 with secondary gout
  • Usual dose 0.5–0.6 mg twice per day
  • Subacute onset of proximal muscle weakness over 1–6 months
  • May involve weakness and atrophy of all muscle groups of the lower extremities
  • Normal deep tendon reflexes
  • Rare clinical myotonia
  • Chronic renal insufficiency is a risk factor
• EMG:
  • Abnormal spontaneous activity in 60% of proximal muscles
  • Myotonic discharges
  • Sensory motor axonopathy present
• Pathology (muscle biopsy):
  • Large spindle shaped vacuoles
  • Subsarcolemma or central location of vacuoles
  • Acid phosphatase and lipid positive material (lysosomal in origin)
  • EM: Sphero membranous bodies in the lysosomes; perinuclear aggregates of densely packed filaments
• Differential diagnosis:
  • Polymyositis
  • Subacute myopathies with axonal neuropathy:
    • Amiodarone
    • Vincristine
    • Alcohol
    • Chloroquine
    • Uremia (no CK elevation)

Lipid-Lowering Drug Myopathy

Fibric Acid Derivatives

• General Features:
  • Fibric acid derivatives
  • Clofibrate, bezafibrate and fenofibrate are primary examples
  • They are branched chain fatty acids
  • Mechanisms of action:
    • Inhibit hepatic release of very low density lipoproteins
    • Possibly cause alterations in the sarcolemmal membrane (myotonic discharges)
  • Gemfibrozil:
    • Fibric acid derivative
    • Risk of myopathy (0.4%)
• Clinical Presentation:
  • Causes myopathy in conjunction with HMG Co A-reductase inhibitors

Clofibrate

• General features:
  • More prevalent myopathy with concurrent renal insufficiency; low albumin (nephrotic syndrome)
• Clinical presentation:
  • Generalized cramps, weakness and muscle tenderness
  • Occurs within 2–3 months of initially of drug
  • Discontinuation of the drug leads to rapid improvement and decreased CK levels

3-Hydroxy-3-Methyl-Glutaryl Coenzyme A-Reductase Inhibitors (HMG-CoA)

• General features:
  • Microsomal enzyme HMG-CoA-reductase catalyzes the conversion of HMG CoA to mevalonic acid
  • Statins: fluvastatin, lovastatin, atorvastatin, pravastatin, simvastatin; all decrease the synthesis of mevalonic acid
  • Mevalonic acid is a precursor for:
    • Cholesterol
    • Ubiquinone
    • Dolichol
• Clinical presentation:
  • Transient myalgia (usual)
  • Mildly elevated CK (usual)
  • Necrotizing myopathy (severe):
    • Acute or subacute muscle pain
    • Proximal weakness
    • Deep muscle hyperalgesia
    • Rare myoglobinuria
    • Concurrent drugs that may cause necrotizing myopathy with statins are:
      • Macrobid antibiotics
      • Mibefradil (calcium channel blocker)
      • Nefazodone
      • Nicotinic acid
      • Itraconazole (fungal agent)
    • Mechanisms of drug interaction toxicity:
      • Increased HMG-CoA levels due to dysfunction of the enterohepatic circulation or decreased biliary excretion
      • Renal or liver failure
• Pathology:
  • Disruption of the sarcoplasmic membrane
  • Toxicity more severe with lipophilic rather than hydrophilic agents

Differential Diagnosis of Drug Induced Necrotizing Myopathy

• Ethanol
• Zidovudine
• Fibric acid derivatives
• Procainamide
• Etretinate

Zidovudine Myopathy (AZT)

• General Features:
  • 3′azido-2′,3′-dideoxythymide
  • Inhibits HIV replication
  • Dose dependent toxicity
  • A mitochondrial myopathy; causes dysfunction of DNA polymerase gamma
  • Decreased plasma and muscle carnitine
• Clinical Presentation:
  • Spectrum of myalgia and slight CK elevation to myopathy with weakness
  • Dose that induces myopathy:
    • 250 gm
    • Treatment period of greater than nine months
  • Insidious onset of muscle pain and proximal weakness
  • Minimal wasting of pelvic and shoulder girdles (exacerbated with HIV-wasting syndrome)
• EMG:
  • Myopathic; short duration, small amplitude polyphasic potentials; fibrillation potentials
  • Normal NCVs
• Pathology:
  • Atrophic degenerating fibers
  • Pseudoragged red fibers (outpouching from mitochondrial proliferation)
  • COX negative fibers
  • Interstitial lymphocytes
  • Intermyofibrillar lipid droplets
• Differential diagnosis:
  • HIV related inflammatory myopathy (similar to polymyositis)
  • HIV related muscle wasting syndrome
  • Proximal root presentation of CIDP in HIV

Unusual Toxic Myopathies

• Emetine hydrochloride:
  • Ipecac (abused in bulimic patients)
  • Painless proximal myopathy
  • Associated cardiac abnormalities
  • Elevated CK
  • Muscle biopsy:
    • Areas of absent myofibular ATPase staining
    • Type II greater than Type I fiber damage
• Epsilon-amino caproic acid:
  • Causes necrotizing myopathy
  • Rare myoglobinuria and renal failure
  • Severe proximal weakness
  • Usual toxic dose is 24 g/day for greater than four weeks; described with 10 gm/day for two weeks
• Organophosphates and anticholinesterase compounds:
  • Insecticide exposure
  • Causes necrotizing myopathy

Toxin Associated Inflammatory Myopathy

• Penicillamine
• Procainamide
• Tryptophane associated eosinophilia myalgia syndrome
• Toxic oil ingestion (Grape seed oil):
  • Clinical features:
    • Initial symptoms of a respiratory illness
    • Myalgia and numbness of the extremities
    • During the third and fourth week patients experienced muscle weakness and atrophy
    • Unusual features:
      • Sclerodermal skin features
      • Hypertension
      • Respiratory failure
  • Pathology:
    • Inflammatory infiltrate of the perimysium and sheaths of intramuscular nerves
• Snake venoms:
  • Cause of amputation of limbs in children
  • Severe compartment syndromes
  • Venom contains:
    • Single-chain peptides
    • A2 phospholipases
    • Pathology:
      • Vacuolization, lysis and necrosis of skeletal muscle