Muscle Pathology Surgical Pathology Unknown Conference November, 2008 Philip Boyer, M.D., Ph.D. Abnormal Neoplastic Non-Neoplastic Normal Vascular - Ischemic Toxic - Metabolic Degenerative Traumatic Developmental Symptoms / Signs / Imaging / Biopsy / CSF Analysis Other Primary Metastatic / Hematogenous Spread / Direct extension Infectious - Inflammatory (neoplastic divide) Reactive / Hyperplastic Etiologic Approach to Differential Diagnosis Case 1 A 75-year-old man presented with a rapid onset and progression of generalized skeletal muscle aches and weakness over a 4-5 day period prior to hospital admission. Difficulty raising his arms above the level of the shoulders Difficulty getting out of chairs and off the commode Laboratory evaluation identified a CPK level of greater than 13,390 U/L (not titrated, normal range, adult male U/L) Past history was significant for: Atherosclerotic coronary and peripheral vascular disease treated with three-vessel coronary vessel bypass grafting Hypercholesterolemia treated with the statin medication Zocor for over a year. He recently had been diagnosed with diabetes and was begun on Glucotrol (glipizide), a sulfonylurea class oral hypoglycemic agent, 2 weeks prior to hospitalization. History Acid Phosphatase Histochemistry: Lysosomal Protein Case 2 56 year-old woman 15 year history of seronegative rheumatoid arthritis Finger stiffness and swelling (PIPs and MCPs) Treatment: Plaquenil Methotrexate Recent 6 12 months: Progressive proximal weakness of arms and legs Dysphagia to pills and water History H&E Stain Acid Phosphatase Histochemistry Acid Phosphatase Histochemistry Case 3 - 6-year old male - History of difficulty walking, particularly in negotiating stairs - Neurologic Examination: - Weakness, proximal greater than distal - Gower sign on arising from floor - Calf muscle hypertrophy - Laboratory Evaluation: - Creatine Kinase = high: >10,000 History H&E Trichrome DystrophinSpectrin Case 4 History - l year old girl (A.O.) - History of congenital weakness - Neurologic Examination: - Weakness, proximal greater than distal - Laboratory Evaluation: - CK elevated (>1,000) - MRI: - White matter abnormality - No evidence of malformation Dystrophin Laminin Alpha-2 (Merosin) Case 5 H&E Low Power H&E Electron Micrograph Electron Microscopy Case 6 Histologic Findings H&E Histologic Findings H&E Histologic Findings Trichrome Electron Microscopy Case 7 History 21-year-old G2P2 woman with a past medical history significant only for obesity A year prior to the current admission, during the third trimester of her second pregnancy, developed symptoms which continued after delivery of healthy 40-week gestation infant Weight loss pounds Night sweats which continued after term delivery of a healthy infant; total weight loss was Four months prior to admission Arthralgias of the hips and knees Non-pruritic hyperpigmented macular rash involving her arms and torso but sparing her face Working diagnosis: "lupus-like syndrome Course of prednisone which resulted in resolution of the rash and cessation of weight loss Tapering of the prednisone, weight loss continued Two weeks prior to admission Burning sensation involving the soles of both feet with extension to the ankles in a stocking distribution Admitted for evaluation. Thin habitus Liver palpable to 4 cm below the right costal margin Extreme sensitivity to light touch of the feet to the level of the ankles bilaterally Strength and reflexes were normal Labs: CPK 34 U/L (normal adult female U/L), C-reactive protein 6.0 mg/dL (normal < or= 0.8 mg/dL), sedimentation rate 67 (normal female 0-29 mm in 1 hour), and angiotensin converting enzyme 59 U/L (normal U/L ) Chest X-ray: normal Histology - Muscle Histology - Nerve Histology - Liver Case 8 28-year-old woman Past Medical History: History of antibody negative myasthenia gravis Medications: None Presentation: Ptosis and swallowing difficulty Neurologic Examination: Ptosis Laboratory Evaluation: CPK 100 Myasthenia panel: negative History H&E Trichrome Succinate Dehydrogenase Histochemistry Electron Microscopy Case 9 -14-year old boy -History of difficulty keeping up with peers during physical activity - Not running, jumping, playing like others due to pain after exercise (exercise intolerance) - CPK 8,600 - EMG: myopathic motor units -Biopsy at age 4 identified focal inflammation, diagnosed with inflammatory myopathy -Treated with corticosteroids with some symptomatic improvement -Attempts to reduce corticosteroids resulted in increased CPK levels (500 10,000) but without associated symptoms -Needed wheel-chair by age After strength testing: severe pain and stiffness for several hours but not persistent - Re-evaluated now -Weakness, proximal greater than distal -Laboratory Evaluation: - Creatine Kinase = ~normal - Re-biopsied History H&E Trichrome Electron Microscopy Myophosphorylase PatientMyophosphorylase Control 2005 Biopsy Case 10 37-year-old man History since childhood of proximal weakness, lower extremities greater than upper extremities. Family history is significant for "muscular dystrophy" in aunts and uncles Biopsy of one uncle was non-diagnostic with a "whorling pattern" on oxidative preparations The differential diagnosis included a limb-girdle muscular dystrophy and a congenital myopathy. History H&E Trichrome Electron Microscopy Case 11 History Newborn, 37 weeks gestation, with marked hypotonia Etiology uncertain clinically Muscle biopsy performed H&E Trichrome Case 12 History - A -Newborn; delivered at 36 weeks gestation due to a breech position -Respiratory distress was noted at birth -Hypotonia -Congential bilateral hip dislocations -There is no known family history Trichrome ATPase pH 4.3 H&E NADH Electron Microscopy -- 54-year-old man -- Life-long history of exertional fatigue and muscle tightness -- With multiple episodes of rhabdomyolysis / myoglobinuria -- He has a 5-year-old son -- Easily fatigued -- Proximal weakness History - B Histology Thick Section, T. Blue NADH Electron Microscopy NADH Trichrome ATPase 4.3H&E Case 13 35-year-old man Past Medical History: Unremarkable Medications: None Presentation: Diffuse muscle pain / soreness, proximal and distal Neurologic Examination: Pain in multiple muscles; no weakness Laboratory Evaluation: CPK 600 Social History: Hunter in the Upper Peninsula of Michigan History Case 14 History - 56-year-old woman - Past medical history: lupus erythematosus X 5 years - Medications: Immunosuppressives including corticosteroids - Symptoms: Progressive weakness, profound - Proximal-predominant ATPase pH 9.4 Histochemical Fiber Typing Type 1Type 2 TwitchsLowfast Turkey MeatDark drumstickWhite Breast analogy(weight bearing)(rapid / skilled movement) MetabolismOxidativeGlycolytic FatMoreLess GlycogenLessMore NADH (oxidative)DarkLight ATPase 4.3DarkLight 9.4LightDark One Slow Fat Red Ox Case 15 56-year-old man Past Medical History: Unremarkable Medications: None Presentation: Slowly progressive weakness, left leg, then right leg and arms; difficulty swallowing Neurologic Examination: Weakness, distal and proximal Laboratory Evaluation: CPK 150 (normal < 220) History Esterase Fiber type grouping groups of type 1 and type 2 fibers (ATPase pH 9.4 type 2 fibers dark) Neurogenic Changes Case 16 60 year old woman with a history of chronic obstructive pulmonary disease. Suffered an episode of respiratory failure that required intubation approximately 3 weeks prior to biopsy She has received Neuromuscular blocking agent High dose corticosteroid therapy She has now been extubated and is manifesting significant weakness, legs greater than arms. History Electron Microscopy Electron Microscopy, X Magnification: Evaluation of intact (left) and affected (right) myofibers. ANSWERS 1. Myofiber necrosis from statin medication 2. Vacuolar myopathy 3. Duchenne muscular dystrophy 4. Congenital muscular dystrophy, merosin negative 5. Dermatomyositis 6. Inclusion body myositis 7. Sarcoid 8. Mitochondrial disease 9. McArdle's Disease 10. Nemaline myopathy 11. Centronuclear myopathy 12. Central core disease 13. Trichinella spiralis 14. Steroid-induced atrophy 15. ALS 16. Critical Care myopathy