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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

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 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 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 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 Myasthenia gravis: Exacerbation of preexisting disease Cystinosis Entrapment neuropathies: Carpal Tunnel ? Myasthenic syndrome ? Sensory-Motor neuropathy SPG 22 Ataxia May increase risk of: Statin myopathy External links eMedicine

Oppenheim 1894 Dercum 1894

Hyperthyroidism

Epidemiology Female > Male Onset: Average 5th decade Hyperthyroid 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 Rarely: 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 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 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; Myelopathy 1 External link: Loyola

From T Miller Hyperthyroid Hyperthyroid after treatment Booth 1894

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
• Muscle ⁹
  • 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
• Associated disorder: APECED

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 treatment ⁸
  • 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

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

From Pincus Taft Cushing's Syndrome From Pincus Taft

• 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

Causes Precipitants Rapid steroid withdrawal AIDS Drugs: Mitotane; Ketoconazole; Phenytoin; Rifampin Hereditary forms: Adrenomyeloneuropathy AAA syndrome 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

• 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

• Myalgias & arthralgias
• Joint effusions
• Rash
• Subjective weakness

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 Surgery Octreotide 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 2° 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

• Common associated disorder: Insulinoma ⁴
• Peripheral Neuropathy
  • Clinical features
    • Onset
      • After prolonged & recurrent severe hypoglycemia: Usually with encephalopathy
      • Burning & Tingling paresthesias
      • Hands & Feet
    • 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
    • CNS: Sustained damage in 30%
  • Electrophysiology
    • CMAPs: Reduced amplitude
    • NCV: Normal velocity
    • SNAPs: Reduced or absent
  • Pathology: Few reports
    • Nerve: Axonal loss; Wallerian degeneration
    • Muscle: Denervation
• 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

Gynecomastia & Neuromuscular

• Bulbospinal muscular atrophy
• Adrenomyeloneuropathy
• Recovery from severe malnutrition & weight loss
• Pectoral muscle hypertrophy

Gonadal Disorders

• Dysgenesis
  • Ataxia & Pyramidal syndrome: COX10
  • HMSN + Minifascicles
  • HSN + Minifascicles & Mental retardation
• Hypogonadism
  • Hereditary
    • Ataxias
    • ANE: RBM28; 7q32
    • APECED: AIRE; 21q22
    • Cabezas: CUL4B; Xq24
    • Diaphyseal Dysplasia: TGFB1; 19q13
    • EOM disorders
      • CFEOM3: TUBB3; 16q24
      • Möbius syndrome, Type I
    • FGF8: HH6
    • FGFR1
    • Leukoencephalopathy/Leukodystrophy
      • Dystonia & Motor neuropathy: SCP2; 1p32
      • Ovarioleukodystrophy : EIF2B3; 1p34
    • Hemochromatosis
    • 4H syndromes: POLR1C; POLR3A; POLR3B; POLR3K
    • Malouf syndrome (Cardiomyopathy): Lamin A/C; 1q22
    • MDP syndrome: POLD1; 19q13
    • Myopathy +
      • Camera-Marugo-Cohen
      • Multicore myopathy
      • Myotonic Dystrophy 1: DMPK; 19q13
    • SPG46: GBA2; 9p13
  • Acquired
    • HIV wasting
    • POEMS
• Ovarian failure
  • Perrault syndromes (Ovarian dysgenesis & Sensorineural hearing loss)
    • Mitochondrial
      • Perrault 2 : HARS2
      • Perrault 3 : CLPP
      • Perrault 4 : LARS2
      • Perrault 5 (+ Neurological disorders) : Twinkle
      • Perrault 6 : ERAL1
      • COXPD54: PRORP
    • Peroxisomal
      • Perrault 1 + Neurological disorder: HSD17B4
  • Ataxia telangectasia
  • Leukoencephalopathy, progressive, with ovarian failure (LKENP): AARS2
  • MELAS
  • Myopathy + Hearing loss & Ovarian failure: GGPS1
  • Skeletal dysplasia, Weakness, Intellectual Disability, Ovarian Dysfunction: SOX8
• Neoplasms
  • NMDAR encephalitis: Ovary teratoma
  • GFAP meningoencephalitis: Ovary teratoma
  • Yo cerebellar syndrome: Ovary adenoCa; Lymphoepithelial
  • Ri cerebellar syndrome: Breast