Antimalarial Neuromyopathy

1. 42 yoWF with hx of hypothyroidism, depression has a 2 week hx myalgia, weakness and a CPK of 3000. Adm to PHD CPK of 13379 and AST 225, ALT 107, LDH 1380 and CRP 2.6 mg/dl. EMG was classic for DM. She was d/c on Prednisone 80 mg qd but worsened w/ difficulty with stairs, and combing her hair, proximal weakness and muscle pain. The patient also complains of subjective fever, fatigue, myalgia, indigestion, and depression. CPK worsened at home to 11000 and was re-admitted. Rx with steroids, IVIG and MTX • 21 yoBF with SLE x 2 yrs Rx with Plaquenil and Imuran. She developed progresive weakness in the arms over 2-3mos and was hospitalized with 2 pillow orthopnea and some RUQ pain and CPK of 12,112 and a Aldoase of 79. Started on prednisone 80 mg/day and Arava 100/wk and discharged with CPK 2000. She complains of difficulty with stairs, and combing her hair, and proximal weakness. She denies shortness of breath, dysphagia, and skin rash. Repeat CPK up to 5000. Steroid increased and pt put on MTX • 56 yoWF wih RA since 2003, On Plaquenil, MTX, failed Enbrel. 2/04, she reports progressive worsening of weakness to arms and legs. She has difficulty with stairs, getting off the toilet, chairs, upper pharyngeal dysphagia, mainly to pills and water, not food. Also c/o Weight loss of 15 lbs, SOB cough, dry eyes/moutn. found to have mild CPK elevation 458, mild LFTs elevation, with normal aldolase. EMG mixed myopathic/neuropathic. Bx showed autophagic vacuoloar myopathy

2. Antimalarial Neuromyopathy • Not dose or duration dependant • Insidious painless LE/UE weakness • Clinical myopathy 6.7%; Chemical myopathy 18.8% • Bx: classic vacuolar myopathy and EM curvilinear bodies/complex lysosomes • Rx: improvement within 2 mos of d/c Casado E. Ann Rheum Disease 2005

3. PolymyositisDermatomyositis • F:M = 2.5:1 • Acute onset; all ages (bimodal) • Incidence 2-7/million/year • Weakness (+ myalgia): Proximal > Distal • Skeletal muscle: dysphagia, dysphonia • Sx: Rash, Raynauds, dyspnea • 65% elevated CPK, aldolase • 50% ANA (+) • 90% +EMG; 85% + muscle biopsy

4. Proposed Criteria for Myositis • Symmetric proximal muscle weakness • Elevated Muscle Enzymes (CPK, aldolase, AST, ALT, LDH) • Myopathic EMG abnormalities • Typical changes on muscle biopsy • Typical rash of dermatomyositis • PM Dx is Definite w/ 4/5 criteria and Probable w/3/5 criteria • DM Dx Definite w/ rash and 3/4 criteria and Probable w/ rash and 2/4 criteria

5. Polymyositis ClassificationBohan & Peter • Primary idiopathic dermatomyositis • Primary idiopathic polymyositis • Adult PM/DM associated with neoplasia • Childhood Dermatomyositis (or PM) • often associated with vasculitis • Myositis associated with collagen vascular disease

6. MYOPATHY: HISTORICAL CONSIDERATIONS • Age/Sex/Race • Acute vs. Insidious Onset • Distribution: Proximal vs. Distal • Pain? • Drugs/Pre-existing Conditions • Neuropathy • Systemic Features

7. MYOPATHIES • Toxic/Drugs • Etoh, Cocaine, Steroids, Plaquenil, Penicilamine, Colchicine, AZT, Lovastatin, Clofibrate, Tryptophan • Infectious • Coxackie A9, HBV, HIV, Stept., Staph, Clostridial, Toxoplasma, Trichinella • Congenital neuromuscular disorders • Muscular dystrophies, hereditary myopathies • Neuropathic/Motor Neuron Disorders • Myasthenia gravis, amyotrophic lateral sclerosis • Endocrine/Metabolic • Glycogen storage diseases, mitochondrial

8. Drug-induced myopathy

9. NONMYOPATHIC CONSIDERATIONS • Fibromyalgia • Polymyalgia Rheumatica • Caucasians, > 55 yrs, M=F, ESR > 100, normal strength, no synovitis • RA • SLE • Adult Still's Disease • Vasculitis

10. INCLUSION BODY MYOSITIS • Bimodal age distribution, maybe hereditary • Slow onset, progressive weakness • Painless, distal and proximal weakness • Normal or mildly elevated CPK • Poor response to corticosteroids • Dx: light microscopy may be normal or show CD8+ lymphs. Tubulofilamentous inclusion bodies on electron microscopy • Role for amyloid?

11. Presentation of PM/DM

12. Skeletal Muscle Weakness • Painless; proximal > distal • Upper Extremity: combing hair, dressing • Lower: Stairs, toilet, car, falling, gait • Dysphagia, hoarseness, regurgitation • Inability to raise head from the pillow

13. DERMATOMYOSITIS5 Skin Features • Heliotrope Rash: over eyelids • Seldom seen in adults • Gottrons Papules (60-80%): MCPs, PIPs, MTPs, knees, elbows • V-Neck Rash (Shawl sign): violaceous erythema ant. chest w/ telangiectasias • Periungual erythema, digital ulcerations • Calcinosis • Mechanics Hands

21. Calcinosis

24. DIAGNOSTIC TESTING • Physical Examiniation: Motor Strength (Gowers sign), Neurologic Exam • Acute phase reactants unreliable • Muscle Enzymes • CPK: elevated >65%; >10% MB fraction is possible • Muscle specific- Aldolase, Troponin, Carb. anhydraseIII • AST > LDH > ALT • Beware of incr. creatinine (ATN) and myoglobinuria • Electromyogram: increased insertional activity, low amplitude, polyphasics, positive sharp waves • Beware of neuropathic changes, incremental/decremental MU changes

25. DIAGNOSTIC TESTING • Muscle Biopsy (an URGENT not elective procedure) • Call the neuropathologist! 85% Sensitive. • Biopsy involved muscle (MRI guided) • Avoid EMG/injection sites or sites of trauma • Magnetic Resonance Imaging - detects incr. water signal, fibrous tissue, infiltration, calcification • Investigational: Tc-99m Scans, PET Scans • Serologic Tests: ANA (+) 60%, Abs against t-RNA synthetases

26. INFLAMMATORY MYOSITISBiopsy Findings • Inflammatory cells • Edema and/or fibrosis • Atrophy/ necrosis/ degeneration • Centralization of nuclei • Variation in muscle fiber size • Rarely, calcification

29. Anti-synthetase syndrome: ILD, fever, arthritis, Raynauds, Mechanics hands

32. PULMONARY Intercostal, diagphragm involvement Aspiration pneumonitis Infectious pneumonitis Drug induced pneumonitis Fibrosing alveolitis RARE: Pulmonary vasculitis Pulmonary neoplasia Pulmonary hypertension CARDIAC Elev. CPK-MB Mitral Valve prolapse AV conduction disturbances Cardiomyopathy Myocarditis PM/DM Complications

33. MALIGNANCY & MYOSITIS • Controversial • Reports range from 10-25% • If real, men over age 50 yrs at greatest risk • Common tumors: Breast, lung, ovary, stomach, uterus, colon • 60% the myositis appears 1st, 30% neoplasm 1st, and 10% contemporaneously • Avoid invasive, expensive searches for occult neoplasia

34. RHABDOMYOLYSIS • Injury to the sarcolemma of skeletal muscle with systemic release of muscle macromolecules such as CPK, aldolase, actin, myoglobin, etc • Maybe LIFE-THREATENING: from hyperkalemia, met. acidosis, ATN from myoglobinuria • Common causes: EtOH, Cocaine, K+ deficiency, infection, PM/DM, infection (clostridial, staph, strept), exertion/exercise, cytokines

35. PM/DM Diagnosis • Symmetric progressive proximal weakness • Elevated muscle enzymes (CPK, LFTs) • Muscle biopsy evidence of myositis • EMG: inflammatory myositis • Characteristic dermatologic findings

36. INFLAMMATORY MYOSITISTreatment • Early Dx, physical therapy, respiratory Rx • Corticosteroids : 60-80 mg/day • 80% respond within 12 weeks • Steroid resistant • Methotrexate • Azathioprine • IVIG, Cyclosporin, Chlorambucil: unproven • No response to apheresis

37. PROGNOSIS • Poor in pts. with delayed Dx, low CPK, early lung or cardiac findings, malignancy • Neoplasia in 10% of adults • PT for muscle atrophy, contractures, disability • Kids:50% remission, 35% chr active disease • Adult < 20 yrs. do better than >55 yrs. • Adults: Mortality rates betw. 28-47% @ 7 yrs. • Relapses & functional disability are common • Death: due to malignancy, sepsis, pulm. or cardiac failure, and complications of therapy

38. Inflammatory Myositis • Polymyositis (PM) and dermatomyositis (DM) are types of idiopathic inflammatory myopathy (IIM). IIM are characterized clinically by proximal muscle weakness • Etiology: There is now known etiology. • Demographics: PM is more common than DM in adults. Peak incidence occurs between 40 and 60 yrs. F:M 2:1 • Muscles: Proximal muscle weakness, dysphagia, aspiration. respiratory failure or death. • Skin: Gottron's papules, heliotrope rash, "V" neck rash, periungual erythema, "Mechanic's hands", calcinosis • Dx: Muscle enzymes (CPK, aldolase), EMG, Biopsy • Rx: Steroids, MTX, Azathioprine, IVIG