Differential Diagnosis in Neurology

12.14. Endocrine Myopathy

• General features:
  • Glucocorticoids induce nuclear gene expression; the hormone receptor complex binds to glucocorticoid-response elements that regulate transcription of steroid responsive genes
  • Primary action on muscle is the mobilization of amino acids from skeletal muscle for both oxidation and gluconeogenesis. They decrease protein synthesis and increase the rate of proteolysis. Their effect is primarily expressed in type II muscle fibers
  • Glucocorticoids specifically activate ATP dependent protease pathways which are active during disuse, sepsis and cachexia
  • May have direct effect on cellular membranes
  • 50–80% of patients with Cushing's disease develop muscle weakness
  • 2.4–20% of patients with iatrogenic steroid use develop muscle weakness
  • Women develop myopathy more frequently than men at the same dose of glucocorticoid
  • All synthetic glucocorticoids cause atrophy; the incidence is higher in 9-alpha fluorinated compounds
  • Effects on muscle are less severe with an alternate day course; doses of 30 mg of Prednisone a day or equivalent of steroid are usually necessary to induce atrophy; 10 mg per day rarely cause significant disease
• Clinical presentation:
  • Onset is insidious
  • Quadriceps and iliopsoas are often the first muscles affected
  • Proximal greater than distal muscle weakness
  • Facial and neck muscles are spared
• Laboratory evaluation:
  • CK and aldolase are normal
• EMG:
  • Normal insertional activity
  • Low amplitude short duration, polyphasic (MUAP) potentials
• Pathology:
  • Type II muscle fiber atrophy
  • EM: mitochondrial aggregation, swelling and vacuolation

Steroid Myopathy vs Exacerbation of Inflammatory Myopathy

• Increased sed rate and CK (inflammation)
• EMG: fibrillation potentials (inflammation)
• Biopsy: Active inflammation; white cell invasion of muscle fibers
• May have normal enzymes with exacerbation of myopathy
• Type II atrophy on muscle biopsy with steroids

Myopathy from ACTH

• Clinical Presentation:
  • Proximal weakness
  • Wasting of muscle
  • Thoracic ("fish mouth") vertebrae with prolonged use
  • Hyperpigmentation
• EMG:
  • Sharp waves or fibrillation potentials
• Muscle biopsy
  • Subsarcolemmal lipid deposits

Myopathy of Addison's Disease

• General features:
  • Adrenal insufficiency in the USA is primarily an autoimmune disease. It may also be caused by tuberculosis, pituitary failure, hemorrhage or congenital enzyme defects
  • Muscle weakness is caused by:
    • Decreased muscle blood flow
    • Impaired carbohydrate metabolism
    • Electrolyte abnormalities
  • Enhanced sensitivity to insulin
  • Depletion of glycogen stores and inadequate stimulation by epinephrine of glycogen dephosphorylation in both muscle and liver
  • Adrenergic insensitivity is prominent
  • Addisonian patients suffer hyponatremia, hyperkalemia and hypovolemia
• Clinical presentation:
  • 25–50% of patients have generalized muscle weakness, cramping and severe fatigue
  • Isolated respiratory weakness occurs; may precipitate myasthenic crisis
  • Associated joint contraction (flexion posture)
  • Hyperkalemic paralysis occurs from:
    • Prolonged sarcolemmal depolarization that causes sodium channel inactivation
    • Intracellular potassium depletion
    • Loss of membrane excitability
    • Provoked by exercise and potassium load
  • Associated disorders:
    • X-linked congenital adrenal hypoplasia:
      • Adrenal cortex affected
      • AX-1 gene (encodes a nuclear hormone receptor)
      • Associated with Duchenne muscular dystrophy and glycerol kinase deficiency
      • Boys present with salt wasting and hyperpigmentation neonatally; aldosterone loss occurs before cortisol
    • Kearne-Sayre Syndrome:
      • Adrenal insufficiency occurs concomitantly with:
        • DM
        • Hypoparathyroidism
        • GH deficiency
• Laboratory evaluation:
  • High serum potassium with loss of serum sodium
  • Eosinophilia
  • Decreased plasma cortisol
  • ACTH stimulation test is positive
  • CK and aldolase are normal
• EMG:
  • Normal

Differential Diagnosis of Flaccid Quadriparesis of Adrenal Insufficiency

• Hyperkalemic periodic paralysis:
  • Cold and potassium induced
  • Usually short attacks 20–30 minutes
  • Family history
  • Myotonia is prominent and may be seen between attacks
• Adrenal insufficiency:
  • Attacks resolve with glucocorticoids
• Paramyotonia congenita:
  • Prominent cold induced weakness (rarely flaccid paralysis)
  • Paradoxical myotonia (exercise increases myotonia)

Myopathy of Thyroid Disease

• General Features:
  • Thyroid hormone regulates the transcription of muscle-specific genes that effect contractibility:
    • Sodium-potassium ATPase
    • Myosin heavy-chain isoform
    • Sarcoplasmic reticulum-calcium ATPase
  • Increase skeletal muscle heat production, mitochondrial oxygen consumption, pyruvate and malate consumption
  • Stimulates glycolytic activity
  • Causes insulin resistance and increased degradation of skeletal muscle protein
• Clinical Presentation:
  • Female predominance of 3:1 to 4:1; weakness occurs in 50% of patients
  • Mean age of onset is 50
  • Proximal weakness
  • Weakness out of proportion to wasting:
    • Rhomboids and shoulder girdle muscles may be severely affected
    • Distal weakness occurs
    • Sphincters and bulbar muscles are spared; affected with concomitant MG
    • Myalgia, fatigue and exercise intolerance is common
    • Controversial:
      • Bulbar involvement and respiratory insufficiency in the absence of MG
    • Rare inflammatory myopathy
    • Weakness develops:
      • Minimal hyperthyroidism of long duration
      • Rapidly with severe disease (storm):
        • Rhabdomyolysis
        • Myoglobinuria
        • Renal failure
    • Tendon reflexes are normal to increased
    • Myasthenia gravis:
      • 7.5% are hyperthyroid
      • 5.3% are hypothyroid; 2% have a non-toxic goitre
    • Thyrotoxic periodic paralysis (hypokalemic):
      • Usually south eastern Asian patients
      • Attacks usually develop over several days
      • Precipitated by carbohydrates, muscle cooling or rest after exercise; maybe "walked off" (aborted by exercise)
      • Generalized attacks affect proximal > distal > bulbar and respiratory musculature (rare)
      • Hypokalemia of 1–3.5 meq/dl; associated hypophosphatemia and hypomagnesemia
• Laboratory evaluation:
  • Decreased TSH with elevated T3, T4
  • CK, LDH, SGOT usually normal
  • Creatine may be elevated
• EMG:
  • Short duration MUAP; increased polyphasic potentials
  • Fibrillation and fasciculations are rare
  • Approximately 30% of patients with normal strength have an abnormal EMG
• Pathology (muscle biopsy):
  • Fatty infiltration between myofibrils
  • Isolated fiber necrosis with lymphocytic and macrophage infiltration
  • Atrophy of Type I/II fibers

Thyroid Ophthalmopathy

• General features:
  • Chronic inflammatory condition of orbital tissue
  • Associated with immune thyroid disease
  • Ophthalmopathy occurs in 5% of patients with Grave's disease; subclinical disease (ultrasound) occurs in 90%
  • Lymphocytes and macrophages that invade retroorbital tissue secrete cytokines that stimulate orbital fibroblasts which secrete glucosaminoglycans into the extracellular space
• Clinical presentation:
  • Ocular findings may be noted prior to or concomitant with hyperthyroidism or may appear during treatment
  • Conjunctival and lid swelling
  • Proptosis
  • Weakness and enlargement of extraocular muscles. Inferior and medial recti may be least involved. Fromerly thought that inferior rectus enlarges first. Impairment of elevation and abduction is most common functional deficit
  • Corneal ulceration occurs with severe proptosis
  • Optic nerve compression in the orbit occurs with concomitant scotoma
  • Exophthalmos:
    • Painful
    • Diplopia occurs
    • Associated with an increase of orbital contents and perimysial connective tissue
    • Most often bilateral; is the most common cause of unilateral proptosis
    • Compresses the vascular supply to the optic nerve
    • Poor correlation between thyroid function and ophthalmopathy

Hypothyroid Myopathy

• General Features:
  • Decreased mitochondrial oxygen capacity, glucose uptake and muscle oxidative enzyme activity
  • Fasting hypoglycemia; insulin resistance and glycogen accumulation occurs in muscle
  • Decreased adrenergic receptors on muscle cells which causes diminished glycogenolysis
• Clinical Presentation:
  • Proximal muscle weakness
  • Difficulty initiating movements
  • Muscle fatigue and stiffness
  • Myalgia and myoedema
  • Pseudohypertrophy of muscle
  • Delayed relaxation phase of reflexes:
    • Slowing of calcium sequestration by the sarcoplasmic reticulum
  • Painful cramps in adult thyroid myopathy
  • Myokymia (reduced sodium-potassium pump activity)
  • Hypothyroid myopathy without cramps (Kocher–Debre–Semelaigne syndrome)
  • Rarely hypothyroidism is associated with proximal weakness and atrophy
  • Rare rhabdomyolysis
• Laboratory Evaluation:
  • Elevated CK in symptomatic patients
  • Serum myoglobin elevated in proportion to severity of the hypothyroidism
  • Creatine excretion is not elevated
  • Increased TSH with low free and total T4
  • Macrocytic anemia of around 10 grams/dl
  • Elevated antithyroglobulin antibodies in autoimmune thyroiditis
  • Secondary hypothyroidism; TSH and T4 are both low
  • Creatine excretion is not elevated
• EMG:
  • Normal or low amplitude polyphasic motor unit potentials
  • Rarely increased insertional activity and positive sharp waves are noted
  • Concomitant findings of sensorimotor neuropathy and CTS
  • Myoedema:
    • Electrically silent muscle contraction
    • Non-propagating contraction
    • Initiated by a slight mechanical stimulus
• Pathology (muscle biopsy):
  • Atrophy, necrosis and hypertrophy of fibers
  • Increased ring fibers, glycogen accumulation and interstitial connective tissue
  • Inflammatory infiltrate and muscle fiber necrosis in patients with rhabdomyolysis

Acromegalic Myopathy

• General Features:
  • GH stimulates the formation of somatomedins which are insulin-like growth factors (IGF)
  • IGF–1 is the most important of these and is manufactured in the liver
  • GH accelerates fatty acid oxidation, decreases glucose utilization and induces insulin resistance
  • Muscle protein synthesis is increased and protein breakdown in muscle is decreased
  • Decreased force-generating ability in the face of increased fiber diameter
  • Associated cardiomyopathy, arthritis of large joints, spinal cord compression (hypertrophied ligaments) carpal and tarsal tunnel syndrome
• Clinical Presentation:
  • Initial increased bulk and strength
  • Insidious onset of proximal weakness, fatigue and exercise intolerance
  • Muscle weakness affects 50% of patients
  • Minimal muscle wasting
• Laboratory Evaluation:
  • GH and IGF-1 levels are increased
  • Paradoxic GH response to thyrotrophin releasing hormone occurs in 2/3 of patients
  • Lack of GH suppression during glucose tolerance test
  • Slight elevation of CK and aldolase
  • Creatine excretion is normal or slightly increased
• EMG:
  • 50% of patients have myopathic changes
  • Neuropathy in 50% of patients:
    • Generalized hypertrophic neuropathy
    • Entrapment neuropathy (CTS and TTs)
  • Neuropathy and myopathy occur independently and evolve separately
  • Pathology (muscle biopsy):
    • Isolated fiber necrosis (primarily type II)
    • Nuclear enlargement with prominently enlarged nucleoli
    • Increased muscle glycogen

Hypopituitarism

• General features:
  • Etiology:
    • Pituitary tumors (primarily chronophobe adenoma) craniopharyngioma (15% intrasellar origin); meningioma, and rarely pituitary cancer
    • Head trauma
    • X-RT
    • Thrombophlebitis
    • Granuloma (sarcoid)
    • Cysts
    • Meningitis
    • Lymphocytic adenohypophysitis
  • Muscle manifestations are due to:
    • Decrease of thyroid hormone
    • Growth hormone
    • Rarely cortisol
  • Prepubertal panhypopituitarism:
    • Secondary to craniopharyngioma; rarely idiopathic or GH receptor dysfunction
    • Muscle wasting
    • Dwarfism
    • Alabaster white skin; no melanocyte stimulating hormone
    • Lack of sexual development
• Clinical presentation:
  • Severe weakness
  • Fatigability (exercise intolerance)
  • Disproportionate preservation of muscle mass
  • Isolated decrease of GH secretion:
    • AR
    • Dwarfism
    • Poor muscle development
    • Gross reduction of muscle number
  • Familial dwarfism:
    • Resembles GH deficiency
    • Elevated GH level
    • Inability to produce somatomedins in response to GH insulin like growth factor (ILGF)

Primary Hyperparathyroidism

• General features:
  • Parathyroid hormone directly affects mineral and ion transport of bone and kidney
  • Action on vitamin D synthesis
  • Stimulates protein degradation of muscle:
    • Activation of sarcoplasmic reticulum calcium channels to increase intracellular calcium (cyclic AMP mediated)
    • Increases mitochondrial calcium permeability
    • Increased intracellular calcium activates intracellular proteases
  • Vitamin D deficiency:
    • Dysfunctional excitation contraction coupling
    • Inability to absorb calcium from the gut with decreased storage in mitochondria and the sarcoplasmic reticulum
    • Depressed myofibrillar ATPase
    • Decreased protein synthesis (wasting)
    • Uremic myopathy (secondary hyperparathyroidism):
      • Inability to convert 25-OH-D3 to 1,25 (OH)2 D3 the active from of Vitamin D
      • Degradation of troponin I by calcium activated proteases
• Clinical presentation:
  • Proximal muscle weakness (25% of patients)
  • Wasting and cramps
  • Fatigability and exercise intolerance
  • Painful stiffness without myotonia
  • Bulbar musculature and sphincters are spared
  • May have increased tendon reflexes
  • A few patients have been described with bulbar involvement and fasciculations
  • Waddling gait and difficulty walking
• Laboratory evaluation
  • Elevated serum alkaline phosphatase and calcium (>14 mg/dl); decreased serum phophate (<3.5 mg/dl)
  • Elevated PTH
  • Salt and pepper skull lesions; erosion of the radial side of the index finger and acromial head of the clavicle
  • Normal serum CK and aldolase
  • Increased urinary creatine excretion
• EMG:
  • Decreased MUAP amplitudes
  • Increased polyphasic potentials without spontaneous activity
• Pathology (muscle biopsy):
  • Type II fiber atrophy
  • Internal muscle nuclei
  • Focal areas of atrophy with polymorphonuclear cell infiltrate

Renal Failure (Secondary Hyperparathyroidism)

• Clinical presentation:
  • Resembles myopathy of primary hyperparathyroidism
  • Legs predominate, but over time it affects all extremities
  • Often associated with dialysis encephalopathy
• Laboratory evaluation:
  • Aldolase and CK are normal
• EMG:
  • Myopathic
  • Concomitant decreased motor nerve conduction velocities and has parameters of distal sensory neuropathy
• Pathology (muscle biopsy):
  • Type II fiber atrophy
  • Z-line degeneration and vacuolization
  • Increased lipofusion beneath the cell membrane
  • Calcium deposition in necrotic muscle

Ischemic Myopathy of Renal Failure

• Clinical Presentation:
  • Myoglobinuria
  • Proximal weakness
  • Exertional pain
  • Gangrenous skin lesions
• Laboratory evaluation:
  • Elevated CK
• EMG:
  • Myopathic
• Pathology (muscle biopsy):
  • Calcium deposits in necrotic muscle
  • Medial arterial wall calcification with fibrous intimal proliferation

Myopathy of Hypoparathyroidism

• General Features:
  • Differential diagnosis of hypoparathyroidism:
    • Surgical excision of parathyroid glands or damage to their blood supply during thyroidectomy
    • Isolated hypoparathyroidism in association with thymic agenesis
    • DiGeorge Syndrome (22q11; deletion of 10p)
    • Familial deficiency of adrenal, thyroid and gonadal hormones
    • Pseudohypoparathyroidism:
      • Signs of hypoparathyroidism with 4th/5th metacarpal abnormalities short stature and cognitive dysfunction
      • Normal PTH; defective cellular response to PTH (mutation of a guanyl nucleotide-binding protein gene)
      • Patients are hypomagnesemic concomitantly
    • Mitochondrial myopathy
• Clinical presentation:
  • Mild proximal weakness
  • Tetany (clinical features):
    • Perioral and distal numbness and paraesthesias
    • Carpopedal spasm
    • Diffuse muscle cramping
    • Latent tetany made manifest by hyperventilation
    • Mechanical sensitivity (Chvostek's sign over the VIIth nerve)
    • Carpopedal spasm induced by impeding venous return (Trousseau's sign)
    • Increased by metabolic and respiratory alkalosis
    • Severe tetany causes laryngeal stridor and spasm
    • Normocalcemic tetany (familial disorder)
    • Hypocalcemia following thyroidectomy
• Laboratory Evaluation:
  • Decreased serum calcium and phosphate levels
  • Low or non-detectable PTH
  • Minimal CK elevation
• EMG:
  • Couplet firing on EMG
  • Spontaneous or repetitive firing (decreased calcium and magnesium levels)
• Pathology (muscle biopsy):
  • Slight atrophy
  • Pseudohypoparathyroidism patients with increased CK and LDH without weakness
    • Decreased glycogen phosphorylase activation