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NEUROMUSCULAR DISORDERS & ENDOCRINE DISEASE

Acromegaly
Adrenal
Carcinoid myopathy
Corticosteroid
Diabetes
Gonadal
  Dysgenesis
  Gynecomastia
  Hypogonadism
Insulinoma
Parathyroid
  Hyperparathyroid
  Hypoparathyroid
Thyroid
  Hyperthyroid
  Hypothyroid

From Bramwell: Atlas of Clinical Medicine

Myxedema



THYROID DISEASE

Hyperthyroid
  Myopathy
  Ophthalmopathy
  Other associated disorders
Hypothyroid
  Adult
  Childhood
  Other associated disorders

External link: Testing

From Bramwell: Atlas of Clinical Medicine

Hypothyroidism

  • Adult
    • History
    • Myopathy
      • Weakness
      • Cramps (40%)
      • Muscle contraction: Slow; Delayed relaxation
      • Muscle enlargement: Occasional (Hoffman's syndrome)
      • Myoedema (33%): Local contracture after muscle tap or pinch
      • Myokymia
        • Associated with Na+ loss
        • May be associated with ptosis 7
      • Tendon reflexes: Reduced or Delayed
      • Rhabdomyolysis: In occasional patient; Muscle swellling & pain
      • Course
        • Progression of weakness: Slow over months
        • Resolution of weakness after treatment: Slow over months
    • Neuropathy
    • Lab
      • Low free thyroxine
      • TSH
        • Primary hypothyroidism: High
        • Pituitary-Hypothalamic disease: Low
      • CK 10
        • Very High: Some patients
        • More commonly high with overt (57%) than subclinical (10%) hypothyroidism
        • Lab correlations
          • TSH level: Positive
          • Free T3 level: Negative
        • No correlation with weakness
        • Usually become normal with effective treatment
      • Carnitine: Reduced
        • May be due to reduced γ-butyrobetaine hydroxylase activity
      • EMG: Normal or mildly myopathic
      • Muscle pathology
        • Usual: Non-specific
        • Pale central regions on NADH
        • Some patients: Accumulation of PAS staining material in muscle fibers
        • Reduced β adrenergic receptors & glycogenolysis
        • Slow contraction & relaxation
    • Treatment: Thyroid replacement
      • Strength recovers
  • Myopathy: Childhood (Debré-Kocher-Sémélaigne)
    • Weakness
    • Slow movements
    • Muscle hypertrophy
    • Growth retardation
  • Hypothyroid: Other associated neuromuscular disorders
  • External links

Oppenheim 1894

Dercum 1894

Hyperthyroidism

Epidemiology
Myopathy
Ophthalmopathy
Other
Associated disorders
  • Epidemiology
    • Female > Male
    • Onset: Average 5th decade
  • Hyperthyroid Myopathy (80%)
    • Onset
    • Clinical
    • Lab
      • High T3 or T4
      • CK: Normal or low
      • EMG: Myopathic; ± Fasciculations or fibrillations
      • Muscle pathology: Normal or type 2 atrophy
    • Prognosis
      • Weakness resolves 2 to 4 months after thyroid hormone normalization
  • Hyperthyroidism: Other associated features
    • Tremor (76%)
    • Hyperreflexia (38%)
    • Paresthesias & Numbness: With high free T4
  • Hyperthyroid Ophthalmopathy
    • β-adrenergic hyperactivity
      • Mild or asymptomatic
      • Lid lag; Upper lid retraction
      • Correlates with degree of hyperthyroidism
      • Reversed by β-adrenergic blocking agents
    • Dysthyroid ophthalmopathy (DO) 3
      • Disease associations
        • Thyroid
          • Onset: Variable
            • Before or during thyroid dysfunction,
            • After treatment: Usually ± 18 months
          • Graves'
            • Features
              • Autoimmune hyperthyroid
              • Ophthalmopathy
              • Pretibial dermopathy
            • 90% of DO associated with Graves' disease
            • Frequency of DO in Graves'
              • Clinical ophthalmopathy: 5% to 10% of Graves' disease
              • Female > Male
              • Ultrasound change in eye muscle: Up to 90%
          • Hashimoto's thyroiditis (Autoimmune hypothyroidism): 5%
          • No clinical thyroid dysfunction: 5%
        • Other risk factors for DO
          • Sex: Female
          • Smoking
          • Lithium treatment
          • Radioiodine therapy for hypothyroidism
        • Association with Myasthenia gravis
          • Frequency of MG when DO present
            • 1% clinical MG
            • 8% with anti-AChR antibodies
          • Especially when
            • Exotropia present
            • Non-restrictive ophthalmoplegia
            • New EOM paresis after period of stability
        • Differential diagnosis: Orbital myositis
      • Clinical features
        • Soft tissue swelling
          • Proptosis
          • Corneal ulceration due to exposure
          • Optic nerve compression & neuropathy (5%)
            • Especially with Severe ophthalmoplegia & Mild proptosis
            • Treatment: Orbital decompression
          • Orbital congestion
        • Restrictive ophthalmoplegia:
          • Due to: Extraocular muscle infiltration & enlargement
          • Distribution: Usually
            • Bilateral
            • Asymmetric
          • Painful
          • Rectus Muscles involved
            • Inferior > Medial > Superior > Lateral
          • Eye movement limitation: Restrictive
            • In direction opposite to action of involved muscle
          • Muscle stiffness: Causes limitation of eye elevation & abduction
          • Redness: Over insertions of horizontal rectus muscles
        • Eyelids: Retraction; Lag; Lagophthalmos
        • Course
          • Progressive over 6 to 18 months
          • Longer progression
            • Likely associated with residual deficit after treatment
        • Treatment
          • Protection of eye from keratitis
          • Drugs: Prednisone; Cyclosporine; Pentoxifylline
          • Treat thyroid disorder
          • Orbital radiation: for acute disease & active inflammation
          • Orbital decompression
            • Indications
              • Optic neuropathy, compressive
              • Keratopathy
              • Cosmesis
            • Often with Prednisone
      • Laboratory & Diagnosis
        • Imaging: Orbital MRI or CT
          • Enlarged EOM but not tendons
          • Differs from tendon expansion also found in orbital myositis
        • Orbital echography
        • Restrictive ophthalmopathy: Forced duction testing
        • EOM: Muscle pathology
      • Pathophysiology
        • ? Autoimmune
        • Target autoantigens
          • Cell target: Probably orbital fibroblast
          • Thyroid & Eye muscle autoantigen, 67-kD : Nonspecific
            • 73% of DO
            • 30% of Graves' without DO & Hashimoto's
            • 16% of Normals
          • Flavoprotein subunit of SDH (Complex II)
          • Sarcaluminin (55kD)
  • Hyperthyroidism: Other associated disorders
  • External link: Loyola

From T Miller

Hyperthyroid


Hyperthyroid after treatment

Booth 1894

PARATHYROID DISEASE

Hypoparathyroidism


Hyperparathyroidism


ADRENAL & CORTICOSTEROIDS

Adrenal insufficiency
Corticosteroid-binding globulin deficiency
Corticosteroid myopathy
Corticosteroid withdrawal
Myosin loss myopathy
Nelson

Cushing 1912
Cushing's Syndrome
("Pluriglandular Syndrome")
Corticosteroid Potencies
Drug Potency
Gluco- Mineralo-
SHORT-ACTING
Hydrocortisone 1 1
Cortisone 0.8 0.8
INTERMEDIATE-ACTING
Prednisone 4 0.25
Prednisolone 4 0.25
Methylprednisolone 5 <0.01
Deflazacort 5.2 ?
Triamcinolone 5 <0.01
LONG-ACTING
Paramethasone 10 <0.01
Betamethasone 25 <0.01
Dexamethasone 30–40 <0.01

Corticosteroid myopathy
  • Precipitants
    • Drug-induced
      • Especially with 9-α-fluorinated corticosteroids
      • Rare with Prednisone, especially < 30 mg qd
      • Also see: Myosin-loss myopathies
    • Endogenous
      • Cushing's syndrome 11
        • 50% to 80% of cases
        • General clinical features: Each may only occur in minority of patients
          • Fat distribution
            • Abnormal in supraclavicular & temporal fossae
            • Facial rounding ("moon faces")
            • Obesity
          • Muscle weakness: Proximal
          • Skin
            • Purple striae: Wide (> 1 cm)
            • Bruising
            • Hirsutism
            • Wound healing: Poor
          • Linear growth in children
            • Decreased with continued weight gain
          • Behavioral
            • Decreased libido: 91%-100%
            • Psychiatric: Lethargy, Depression
          • Other endocrine
            • Impaired glucose tolerance/diabetes
            • Menstrual changes
          • Atherosclerosis
        • Diagnosis
          • Cortisol
            • 24 hour urine free cortisol
            • Salivary cortisol
          • Dexamethasone suppression test
          • ACTH measurement
        • Rule out
          • Low K+
          • Low PO4
        • Treatment
          • Optimal: Surgical removal of tumor
          • Medical: Ketoconazole
      • Ectopic ACTH production
  • Clinical
    • Muscle
      • Weakness: Proximal; Symmetric; Legs > Arms
      • Wasting
      • Myalgias
    • Systemic
      • Weight gain (90%)
      • Hypertension (85%)
      • Skin: Hirsutism; Fragile; Plethora
      • Osteopenia
      • Neuropsychiatric
      • Metabolic: Glucose intolerance (75%); Diabetes (20%); Hyperlipidemia (70%)
      • Gonadal dysfunction: Menstrual change (70%); Impotence (85%)
  • Lab
  • Mechanisms
    • Muscle protein catabolism: Increased
    • ? Other
  • Treatment: Reduce steroid dose

From Pincus Taft
Cushing's Syndrome

From Pincus Taft

Myosin loss myopathy


Nelson's syndrome: After total bilateral adrenalectomy
Adrenal insufficiency
  • Causes
  • Clinical
    • Muscle
      • Fatigue
      • Weakness: Mild; Occasionally respiratory
      • Cramps
      • Myalgias
      • Rhabdomyolysis
    • Systemic
      • Weight loss
      • Anorexia
      • Depression
      • Skin: Hyperpigmentation
    • Treatment
      • Cortisone (20 to 37.5 mg/day)
      • Fludrocortisone (0.05 to 0.1 mg),
      • Na+ intake (3 to 4 g/d)
  • Laboratory
    • Electrolyte disturbances
      • Low Na+
      • High Ca++
    • Anemia
    • Serum CK: May be mildly increased
    • Diagnosis
      • Cosyntropin test
        • Screening: Plasma cortisol 30 to 60 min after 250 μg IM or IV
        • Confirming
          • Plasma ACTH or aldosterone
          • Increment 30 min after 250 μg IM or IV
      • Adrenal imaging

From Bramwell: Atlas of Clinical Medicine

Addison's Disease

Fatigue syndrome with Corticosteroid-binding globulin deficiency

  SERPINA6 ; Chromosome 14q32.1; Dominant
Corticosteroid withdrawal

ACROMEGALY

  • Myopathy
    • Clinical
      • Weakness
        • Proximal
        • Late in disease course
      • Fatigability
      • Muscle hypertrophy
      • Prognosis: Improves when growth homone levels → Normal
    • Laboratory
      • CK: Normal or mildly elevated
      • EMG: Myopathic (50% of acromegalic patients)
      • Muscle pathology: Usually insufficient to account for weakness
        • Nuclei: Enlarged; Prominent nucleoli
        • Lipofuscin & Glycogen: Increased
        • Muscle fiber size: Hypertrophy; Type II atrophy
        • Few necrotic fibers
        • Satellite cells: Proliferation & hypertrophy
        • May be normal
        • Physiology: Reduced force generation by muscle
      • Rule out: Hypothyroidism, Hypoadrenalism, Diabetes
  • Neuropathy 12
    • Carpal tunnel syndrome 2
      • Frequency
        • Clinical 50% to 60%
        • NCV > 80%
      • Course
        • Improvement after levels of circulating growth hormone ↓  
      • MRI & Ultrasound
        • Median nerve in carpal tunnel
          • Edema
          • Enlarged
          • Reduced size after
            • Disease treatment
            • Reduced GH & IGF-I levels
    • Cubital tunnel syndrome
      • Frequency: 21% to 50%
      • May occur early in disease course
      • Ultrasound imaging: Enlarged ulnar nerve proximal to elbow
      • Treatment: May improve with control of disease
    • Polyneuropathy: Hypertrophic; Distal
      • Frequency: 1/3 Clinical; 2/3 Neurophysiological
      • Clinical
        • Sensory
          • Loss: Pansensory
          • Paresthesias
          • Acromutilation
          • Especially with gigantism
        • Weakness: Small foot muscles
      • Laboratory
        • Ultrasound: Enlarged nerves (45%)
        • NCV: 30 to 37 m/s
        • Nerve Pathology
          • Axon loss: Small > Large myelinated axons
          • Hypertrophy: Endoneurium & Subperineurium
          • Teased axons: Segmental demyelination
          • Onion bulb-like structures 13
            • Early
            • Schwann cell processes surround axons & Collagen
            • Some patients
  • Skeletal
    • Gigantism
      • Coarse features
      • Hands: Large
      • Feet: Large
      • Height: Increased
    • Trigger finger (25%): Transient locking of fingers in flexion
      • Proximal flexor tendon sheath at base of finger or thumb
        • Thickening & Constriction
      • A1 pulley thickening
  • Metabolic
    • Glucose intolerance
    • Protein synthesis: Increased
  • Skin
    • Hyperhydrosis
    • Oiliness/acne
    • Hypertrichosis/hirsutism
    • Hyperpigmentation
    • Acanthosis nigricans
    • Skin tags/fibromas
  • Diagnosis
    • Clinical features
    • Serum IGF-1: Increased
    • Oral glucose challenge
      • Inability to suppress serum growth hormone to < 2 ng/ml
  • Treatment
  • Hereditary acromegaly:
ACROMEGALY
Cushing: The Pituitary Body & its Disorders

Before disease

Disease onset

12 yrs of disease

17 yrs of disease

Square hand


Phalanges:
Tufting; Exostoses


Putnam

CALCIPHYLAXIS 6

  • Nosology
    • Calcific uremic arteriolopathy
    • Vascular calcification—cutaneous necrosis
  • Epidemiology
    • Chronic renal failure
      • Renal dialysis
        • 94% of Calciphylaxis patients are on hemodialysis
        • Incidence: 1% of all dialysis patients
      • Onset: ~ 3 years after dialysis; Range = 1 month to 12 years
    • Age: Mean 54 years
    • Female > Male: > 3:1
    • Caucasian more frequent
    • Serum testing
      • High serum phosphate: Increased risk
      • High alkaline phosphatase: Increased risk
      • Low serum albumin: Increased risk
    • Warfarin treatment: ? Increased Susceptibility
    • Diabetes: ? Increased Susceptibility
  • Clinical
    • Skin: Most patients; Usual presenting feature
      • Livido reticularis
      • Thickening
      • Painful necrotic lesions
        • Well demarcated erythema; Bullae; Ecchymoses
        • Proximal > Distal (68%)
        • Lower > Upper
        • Ischemia of digits
        • Lesions may cause Sepsis
    • Panniculitis: May begin at site of trauma, or injection
    • Muscle: Some patients
      • Pain
      • Proximal weakness
      • ± Rhabdomyolysis
      • Serum CK: Increased with myopathy
    • Associated features
      • Chronic renal failure
      • Hyperparathyroidism
      • Functional protein C deficiency
      • Corticosteroid treatment
      • Other disorders: Crohn’s disease; AIDS
    • Treatment
      • Parathyroidectomy
      • Rapid reduction of Ca++ & PO4
      • Control of systemic disease & wound infections
    • Prognosis
      • Mortality
        • 40% to 70%
        • 8x higher than controls
        • Commonly associated with infection of skin lesions
      • Worse with proximal skin lesions
  • Lab
    • PO4: High; > 5 mg/dL (67%)
    • Parathyroid hormone: High; 80%
    • X-Ray: Fine double lines suggesting calcified vessels
  • Pathology
    • Diagnosis: Biopsy skin, muscle
    • Vessels: Calcification & Narrowing
      • Small-to-medium sized vessels
      • Subintimal, medial & perivascular
      • Intimal proliferation
    • Multifocal tissue ischemia
    • Muscle
      • Patchy muscle fiber necrosis
      • Fiber size variability
      • Type 2 muscle fiber atrophy

Skin lesions in calciphylaxis




From Utah: K Flanigan & J Townsend
Calcium in vessel wall

Hypoglycemic Neuropathy 5



Gynecomastia & Neuromuscular


Gonadal Disorders



Return to Neuromuscular Home Page

References
1. JNNP 2000;68:681-2
2. Ann Int Med 2000;133:197-201
3. Semin Neurol 2000;20:43-54
4. Muscle Nerve 2000;23:1891-1894
5. Acta Neuropathol 2001 (On-line)
6. Lancet 2001;358:1115-1116; Kidney Int 2001; 60:324-332
7. Eur J Neurol 2003;10:87-90
8. Ann Intern Med 2005;142:310
9. Arq Neuropsiquiatr 2004;62:154-157
10. Endocr Res 2005;31:171-175,
11. American Journal of Medicine 2005;118:1340-1346, NEJM 2017;376;1451-1459
12. Pituitary 2023 Jun 4
13. Q J Med 1985;57:833-842

6/6/2023