NM + Endocrine Disorders

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NEUROMUSCULAR DISORDERS & ENDOCRINE DISEASE

Acromegaly
Adrenal
Carcinoid myopathy
Corticosteroid
Diabetes
Gonadal
Dysgenesis
Gynecomastia
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
  - Female > Male
  - Muscle pain, cramps & stiffness
  - Fatigue
  - Paresthesias
- Myopathy
  - Weakness
    - Mild (4/5)
    - Symmetric
    - Proximal
    - Occasional: Posterior neck
  - 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 ptosis⁷
  - 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
  - Carpal tunnel syndrome (25%)
  - Cranial nerves: Deafness; Hoarse voice (Local vocal cord lesion)
  - Polyneuropathy (19%): Sensory; Axonal
  - Tendon reflexes: Reduced Ankle reflex
- Lab
  - Low free thyroxine
  - TSH
    - Primary hypothyroidism: High
    - Pituitary-Hypothalamic disease: Low
  - CK¹⁰
    - 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
- Myasthenia gravis: Exacerbation of preexisting disease
- Entrapment neuropathies: Carpal Tunnel
- ? Myasthenic syndrome
- ? Sensory-Motor neuropathy
- Ataxia
- May increase risk of: Statin myopathy
External links
- eMedicine

Hyperthyroidism

From T Miller

Epidemiology
- Female > Male
- Onset: Average 5th decade
Myopathy (80%)
- Onset
  - Slowly progressive; More common with increasing age
  - Acute onset
    - Rare: Most often with thyroid storm
    - Rule out: Myasthenia gravis; Rhabdomyolysis
- Clinical
  - Weakness
    - Proximal ± Distal (20%)
    - Distal weakness may rarely be presenting sign
    - Painless: Occasional myalgias
    - Fatigue
  - Atrophy: Shoulder girdle; Scapular winging
  - Fasciculations
  - Rhabdomyolysis: With thyroid storm
  - Bulbar syndrome: Dysphagia
  - Tendon reflexes: Brisk
- 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 normalization of thyroid hormone
Other 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
  - Thyroid Disease associations
    - May occur before or during thyroid dysfunction, or after treatment: Usually ± 18 months
    - Graves' (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 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
  - 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
      - Muscles involved: Most commonly inferior & medial rectus
      - 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 probably associated with residual deficit after treatment
  - 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
  - Treatment
    - Protection of eye from keratitis
    - Drugs: Prednisone; Cyclosporine; Pentoxifylline
    - Treat thyroid disorder
    - Orbital radiation: for acute disease & active inflammation
    - Orbital decompression
      - Indications: Compressive optic neuropathy, Keratopathy, Cosmesis
      - Often with Prednisone
  - 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)
  - 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
Hyperthyroidism: Other associated disorders
- Periodic paralysis
- Myasthenia gravis: Exacerbation of preexisting disease
- Inflammatory myopathy
- β-blockade: Masks systemic thyroid signs but not weakness
- Stiffman syndrome
- Cramps & fasciculations
- Low K⁺ & Rhabdomyolysis
- CNS (Hashimoto's): Encephalopathy; Myelopathy¹
External link: Loyola

PARATHYROID DISEASE

Hypoparathyroidism

Nerve
- Sensory: Muscle pain; Paresthesias; Perioral & distal numbness
- Spasms: Carpal & Pedal; Tetany
  - Axonal hyperexcitability 2° to Reduced action potential threshold
- Carpal tunnel syndrome
- Hyporeflexia
Muscle⁹
- Weakness
  - Proximal
  - Symmetric
  - Mild
- Cramps & Fasciculations
- Laboratory
  - Serum CK: Often elevated
Systemic
- Cataracts
- Hair loss
- Dental abnormalities
- Cardiomyopathy: Rare
Nervous system
- Acroparesthesia
- Tetany & Smooth muscle spasm
- Ataxia
- Seizures
- Emotional lability
- Psychosis
- Cognitive: Slowing; Mental retardation; Dementia
- Basal ganglia calcification
Laboratory
- Hypocalcemia
- Phosphate: High
- Magnesium: Low
- Parathyroid hormone: Low

Hyperparathyroidism

Primary
- Muscle atrophy
- Myalgias
- Tendon reflexes: Increased
- Fasciculations
Secondary: Especially with osteomalacia
- Weakness
  - Proximal
  - Symmetric
- Other systemic
  - Pruritus
  - Bone pain
  - Calcinosis
- Lab
  - Serum alkaline phosphatase: High
  - Serum CK: Normal
  - EMG: Myopathy
  - Plasma iPTH levels: High
  - Radiology
    - Subperiosteal resorption
    - Bone cysts & Periosteal neostosis
    - Extraskeletal calcifications
  - Parathyroid glands: Enlarged by ultrasound
- Renal disease
  - Rule out drug-induced myopathy
  - Also see: Spondyloarthropathy
- Treatment: Parathyroidectomy, subtotal
Other

Vitamin D deficiency
Teriparatid treatment⁸
- Recombinant human 1�34 amino acid sequence of parathyroid hormone
- Osteoporosis treatment
- Clinical
  - Cramps
  - Muscle tenderness
  - Time course: Hours after treatment

Other features
- Osteomalacia
- Calciphylaxis

ADRENAL & CORTICOSTEROIDS

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

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

From Pincus Taft

Cushing's Syndrome

From Pincus Taft

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
- CK: Normal
- EMG: Normal or mild myopathy
- Muscle pathology: Type 2 fiber atrophy
Mechanisms
- Muscle protein catabolism: Increased
- ? Other
Treatment: Reduce steroid dose

Myosin loss myopathy

Nelson's syndrome: After total bilateral adrenalectomy

Clinical
- Weakness
- Fatigue
- Skin: Hyperpigmentation
Lab
- CK: Normal
- EMG: Irritable myopathy
- Muscle pathology: Increased lipid in muscle fibers
Cause: ? Related to high levels of ACTH produced by pituitary

Adrenal insufficiency

From Bramwell: Atlas of Clinical Medicine

Addison's Disease

Clinical
- Muscle
  - Fatigue
  - Weakness: Mild; Occasionally respiratory
  - Cramps
  - Myalgias
- Systemic
  - Weight loss
  - Anorexia
  - Depression
  - Skin: Hyperpigmentation
- 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
Causes
- Precipitants
  - Rapid steroid withdrawal
  - AIDS
  - Drugs: Mitotane; Ketoconazole; Phenytoin; Rifampin
- Hereditary forms:
  - Adrenomyeloneuropathy
  - AAA syndrome
Treatment
- Cortisone (20 to 37.5 mg/day)
- Fludrocortisone (0.05 to 0.1 mg),
- Na⁺ intake (3 to 4 g/d)

Fatigue syndrome with corticosteroid-binding globulin deficiency

l SERPINA6

; Chromosome 14q32.1; Dominant

Mutations: Missense or Termination
Protein
- Function: Binds serum cortisol (95%)
- Mutant protein: Lower cortisol affinity
Clinical
- Fatigue: Muscle; Especially after stress
- Blood pressure disorder
Laboratory
- Free cortisol levels in 24-hour urine: Elevated
- Saliva cortisol concentration: High in the morning
- EMG: Normal
- Serum CK: Normal
- Muscle biopsy: Normal

Corticosteroid withdrawal

Myalgias & arthralgias
Joint effusions
Rash
Subjective weakness

ACROMEGALY Cushing: The pituitary body & its disorders
Before disease	Disease onset
12 yrs of disease	17 yrs of disease
Square hand	Phalanges: Tufting; Exostoses

ACROMEGALY

Myopathy
- Clincal
  - Weakness
    - Proximal
    - Late in disease course
  - Fatigability
  - Muscle hypertrophy
- 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
  - Rule out: Hypothyroidism, Hypoadrenalism, Diabetes
- Physiology: Reduced force generation by muscle
- Prognosis: Improves when growth homone ® Normal
Neuropathy
- Carpal tunnel syndrome²
  - Frequency: Clinical 50% to 60%; NCV > 80%
  - Course: Improvement after levels of circulating growth hormone reduced
  - MRI
    - Enlarged median nerve (Edema) in carpal tunnel
    - Pathology in symptomatic patients resolves after treatment
- Cubital tunnel syndrome
  - Frequency: 21% to 50%
  - May occur early in disease course
  - Enlarged ulnar nerve proximal to elbow
- Polyneuropathy: Hypertrophic; Distal
  - Frequency: 1/3 Clinical; 2/3 Neurophysiological
  - Sensory: Pansensory loss; Paresthesias
  - Weakness: Small foot muscles
  - Enlarged nerves (45%)
  - Pathology
    - Axonal loss
    - Hypertrophy of endoneurium & subperineurium
Skeletal
- Gigantism
  - Coarse features
  - Hands: Large
  - Feet: Large
  - Height: Increased
- Trigger finger (25%): Transient locking of fingers in flexion
  - Thickening & constriction of proximal flexor tendon sheath at base of finger or thumb
  - 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
- Inability to suppress serum growth hormone to < 2 ng/ml by oral glucose challenge
Treatment
- Surgery
- Octreotide
Hereditary acromegaly:

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
  
  Skin lesions in calciphylaxis
  - High serum phosphate: Increased risk
  - High alkaline phosphatase: Increased risk
  - Low serum albumin: Increased risk
- Warfarin treatment: ? Increased Susceptibility
- Diabetes: ? Increased Susceptibility
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
- 2° Hyperparathyroidism
- Functional protein C deficiency
- Corticosteroid treatment
- Other disorders: Crohn�s disease; AIDS
  
  From Utah: K Flanigan & J Townsend
  
  Calcium in vessel wall
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
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

Hypoglycemic Neuropathy⁵

Common associated disorder: Insulinoma ⁴
Onset
- After prolonged & recurrent severe hypoglycemia: Usually with encephalopathy
- Burning & Tingling paresthesias
- Hands & Feet
Peripheral Neuropathy
- Clinical features
  - Symmetric
  - Distal
  - Limb distribution
    - Usually upper + lower
    - Selective: Upper limb predominant (26%); Lower limb predominant (6%)
  - Modalities involved
    - Usually Sensory-Motor
    - Selective involvement: Motor only (32%); Sensory only (9%)
  - Treatment response: Improvement in sensory, but not motor, symptoms after removal of pancreatic tumor
- Electrophysiology
  - CMAPs: Reduced amplitude
  - NCV: Normal velocity
  - SNAPs: Reduced or absent
- Pathology: Few reports
  - Nerve: Axonal loss; Wallerian degeneration
  - Muscle: Denervation
CNS: Sustained damage in 30%
Insulinoma
- Onset
  - Often: Neuropsychiatric symptoms; Weight gain from food ingestion; Lengthy history
  - Age: 5th to 7th decades
- Laboratory
  - Fasting hypoglycemia with elevated insulin levels
  - Exclude exogenous insulin administration: C-peptide levels normally parallel insulin levels
  - Tumor localization: CT (50%); Endoscopic ultrasonography; Angiography with venous sampling for insulin levels (80%)
  - Tumor types: Insulinoma (80%); Islet cell carcinoma (10%); MEN1 syndrome with multiple tumors