Causes of Proximal Muscle Weakness That May Mimic Inflammatory Myopathy • Central

Creatine Kinase - Causes of Elevated CK Levels Acute CK Elevation (Pain > Weakness): • RHABDOMYOLYSIS - Drugs: cocaine, amphetamines, alcohol - Medications: statins, fibrates, colchicine, daptomycin - Illness: viral (COVID19, CMV/EBV, HIV), clostridial spp, mycoplasma, staph, strep) - Seizures: Trauma, burns, hyperthermia, immobility • Critical Illness Myopathy (ICU, steroids, mechanical ventilation) • Myocardial infarction, Acute renal injury, Strenuous exercise Subacute to Chronic Causes (Weakness > Pain): • PROXIMAL MUSCLE WEAKNESS - Endocrine: Hypo/hyperthyroidism, acromegaly - Electrolytes: hypo- phos, kalemia, calcemia, natremia - Muscular dystrophy - Metabolic Myopathies - Neuromuscular disorders - Vit D/E deficiency - Medications- Statins, fibrates, colchicine, daptomycin - Chronic Illness: HIV, Trichinella, toxoplasmosis - Inflammatory myopathy: dermatomyositis, polymyositis, necrotizing myopathy - Autoimmune: mixed connective tissue disorder, SLE • PROXIMAL AND DISTA: Inclusion body myositis • ASYMPTOMATIC: Macro CK Ann Marie Kumfer @AnnKumfer #Creatine #Kinase #Elevated #CK #differential #diagnosis #rhabdomyolysis

Weakness - Differential Diagnosis Framework Approach To Weakness: • Non-neuromuscular disorder (Cardiac, pulmonary etc) • CNS -> PNS -> NMJ -> Muscle • Muscle weakness (generalized, distal, proximal, or localized) 1. Upper Motor Neuron Impairment: • Acute stroke syndromes • Space occupying lesions of the central nervous system: Brain tumor • Lesions of the spinal cord • Inflammatory: Vasculitis • Infectious: Brain abscess • Toxic/drug: Radiation • Metabolic/endocrine: Vitamin B12 deficiency • Congenital leukodystrophies 2. Lesions Of The Peripheral Nervous System: • Symmetric polyneuropathy: DM • Mononeuropathy: Nerve compression • Mononeuritis multiplex (DM, Vasculitis-polyarteritis nodosa) • Toxic/drug: Lead • Neoplastic: Paraneoplastic syndrome • Inflammatory: Myeloma/amyloid • Infectious: Leprosy 3. Neuromuscular Junction: • Exercise-induced weakness: Fatiguability - Consider NMJ • Nerve Side Presynaptic: - Lambert-Eaton - Isaacs' syndrome - Tick-paralysis - Botulism - Aminoglycosides - Envenomation (venom from animal bites) • Synaptic Cleft: - Organophosphate toxicity - Carbamate toxicity • Muscle Side: - Postsynaptic: Myasthenia Gravis - Lack of UMN/LMN signs - Lack of sensory changes - Common pattern: Symmetric proximal weakness Myopathy: • Inflammatory disorders: Polymyositis • Immune mediated necrotizing myopathy • Autoimmune: Inclusion body myositis • Endocrinopathies: Hypothyroid • Metabolic myopathies: Hypoglycemia • Drugs and toxins: Steroids, Statins, amiodarone, Alcohol • Infections: - Viral - Influenza, parainfluenza, Coxsackie, HIV, CMV, EBV - Bacterial - Pyomyositis, Lyme myositis • Rhabdomyolysis • Neoplastic: Malignancy-associated myositis • Genetic: Muscular dystrophies Work Up: • Chem: CPK aldolase, lactate dehydrogenase, and the aminotransferases • Serology: - Anti-Ro/SSA, anti-La/SSB, anti-Sm, and anti-RNP - (Myositis) anti-histidyl-t-RNA synthetase [anti-Jo-1] - (Vasculitis) ANCA titers, hepatitis B and C serologies, and cryoglobulins • PNS, NMJ, Nerve: Nerve conduction and electromyographic (EMG) studies • MRI: Inflammation of the muscle • Muscle Biopsy: Dermatomyositis, polymyositis, inclusion body myositis, certain drug-induced myopathies, the muscular dystrophies, or vasculitis #Weakness #Differential #Diagnosis #neurology

Causes of Neuromuscular Weakness • Spinal Cord: Demyelinating Disease (MS), Epidural abscess, Infarction, Syringomyelia, Tetanus, Transverse Myelitis, Trauma, Tumor • Motor Nerves: ALS, Cervical spondylosis, Poliomyelitis, Guillain-Barre syndrome, Mononeuritis multiplex, Phrenic nerve injury, Sarcoid, Toxins (heavy metals), Critical illness neuromyopathy • Neuromuscular junction: Botulism, Lambert Eaton Syndrome, Myasthenia Gravis, Organophosphate poisoning, Scorpion sting, Shellfish poisoning, Meds (anticholinesterase inhibitors, aminoglycosides) • Muscles: Acid maltase deficiency, Malnutrition, Metabolic abnormalities (hyppK), Mitochondrial myopathy, Muscular dystrophy, Myotonic dystrophy, Polymyositis/dermatomyositis, Thyroid disease #Neuromuscular #Weakness #Causes #differential #diagnosis #neurology

Causes of Peripheral Weakness without Sensory Changes - Differential Diagnosis Algorithm No Objective Weakness • Cardio-pulmonary disease • Anemia • Chronic Infection • Malignancy • Depression • Deconditioning • Arthritis • Fibromyalgia • Endocrine Disease Motor Neuron and Motor Neuropathy - Atrophy, Fasciculations, Hyperreflexia • Lead toxicity • Progressive muscular atrophy • Hodgkin's lymphoma • Polio • Multifocal Motor Neuropathy • Spinal Muscular Atrophy Neuromuscular Junction - Fatigability, Variability, Oculomotor • Myasthenia Gravis • Lambert-Eaton Myasthenic Syndrome • Botulism • Congenital Myopathy - Proximal muscle involvement, elevated CK • Polymyositis • Duchenne Muscular Dystrophy • Statin Toxicity • Dermatomyositis • Viral infection #Peripheral #Weakness #Neurology #Differential #Diagnosis #Algorithm #Causes

Causes of Hypotonic Infant (Floppy Newborn) - Differential Diagnosis Algorithm Central Nervous System - Decreased LOC, Axial Weakness, Normal Strength, Normal Reflexes - Brain • Hypoxic-Ischemic Encephalopathy* • Trisomy 21* • Intracranial Hemorrhage • CNS Infection • Metabolic Diseases • Prader-Willi • Intracranial Mass/lesion • Other Congenital Syndromes - Spinal Cord • Spinal Muscular Atrophy • Trauma • Hematoma • Abscess • Arteriovenous Fistula • Infantile Neuronal Degeneration • Poliomyelitis Peripheral Nervous System - Alert, Responding to Surroundings, Profound Peripheral Weakness - Nerves • Congenital Hypomyelinating Neuropathy • Infantile Neuroaxonal Degeneration - Neuromuscular Junction • Congenital and Transient Myasthenia Gravis • Infantile Botulism • Magnesium Toxicity • Aminoglycoside Toxicity - Muscle • Congenital Myotonic Dystrophies • Metabolic Myopathies • Central Core Disease • Other Congenital Myopathies #Hypotonic #Infant #Floppy #Newborn #Differential #Diagnosis #Algorithm #Causes #Peds #Pediatrics

Autoimmune Myositis - Differential Diagnosis Framework Inflammatory Myopathies: Commonly symmetric proximal muscle weakness, no substantial muscle pain or tenderness; serum creatine kinase ↑ Muscle Tenderness → Consider infectious, thyroid, drug-induced myopathies Diagnostic Tests: • Measure CK • Aldolase levels • EMG DERMATOMYOSITIS: • Subacute • Proximal muscle (symmetric) • CK > 50 ULN Antibodies: • Anti-MDA5 (RP-ILD), dermato-rheumatologic symptoms • Anti-CADM-140 (amyopathic dermatomyositis) • Anti-Mi2 (skin lesions) • Anti-TIF1 (cancer-associated adult dermatomyositis) • Anti-NXP2 (ANA present 80% of the time) Dermatomyositis Symptoms: • Gottron rash (Gottron papules and Gottron sign) • Shawl sign • Heliotrope • Interstitial lung disease Malignancy Risk: Ovarian, lung, pancreas, stomach, colon, and lymphoma POLYMYOSITIS: • Progressive, symmetric, proximal muscle weakness • CK > 50 ULN Antibodies: • Anti-Synthetase Ab • Anti-Jo-1 antibodies (ANA present 80% of the time) Polymyositis Symptoms: • Muscle pain and tenderness • Muscle atrophy • Weakness of respiratory muscles • Interstitial lung disease • Dysphagia, dysmotility, and increased risk of aspiration pneumonia • Antisynthetase syndrome (also seen in association with dermatomyositis) Malignancy Risk: Ovarian, lung, pancreas, stomach, colon, and lymphoma Overlap Syndrome: Fever, joint pain and Raynaud phenomenon INCLUSION BODY MYOSITIS: • M > F • Age > 50 • Misdiagnosed as: Polymyositis or ALS • Very slow onset and pattern of muscle involvement/Early weakness • History of preexisting weakness averaging 5 years • Proximal + distal muscle involvement • Symmetric, but asymmetry may occur • Frequent falls due to quadriceps muscle weakness PE: Muscle weakness + atrophy- Hip flexors, quadriceps, finger flexors, and forearm flexors Labs: • Serum creatine kinase levels are elevated < PM and DM • CPK 10X ULN • + Camptocormia (bending forward of the spine) or head drop • ANA < 20 % IBM • Anti-cytoplasmic 5'-nucleotidase 1A (Anti cN-1A) 50% Cricopharyngeal muscle involvement -> dysphagia and increased risk of aspiration > 50% of pts ANTI-SYNTHETASE SYNDROME: • Fever • Interstitial lung disease • Myositis • Raynaud phenomenon • Nonerosive arthritis • Mechanic's hands Autoantibodies: • Anti-aminoacyl-tRNA synthetase enzymes • Anti-Jo-1 antibodies Symptoms: • Pericarditis/Pericardial tamponade • Conduction system abnormalities/Arrhythmias • Dysphagia, dysmotility, and increased risk of aspiration pneumonia (esophagus upper 2/3 striated muscle) NECROTIZING AUTOIMMUNE MYOPATHY: • Proximal muscle (symmetric) • Prominent myonecrosis on biopsy • Severe, rapidly progressive weakness • Very high serum CK levels 50X ULN • Myocyte necrosis and regeneration without significant inflammation • Extramuscular manifestations rare • Possible paraneoplastic syndrome • If myopathy improves within 4 to 6 weeks after discontinuation of statins - probably caused by toxic effects of the drug Antibodies: • Signal recognition particles (SRP's) • 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase ANTI-MITOCHONDRIAL MYOPATHY: • Chronic skeletal muscle disease/muscular atrophy • Chronic progressive respiratory muscle weakness • Severe cardiac involvement: (20-30%) arrhythmias, cardiomyopathy, and myocarditis Other Diseases: • PBC, autoimmune hepatitis, Psoriasis, Hashimoto's Antibodies: • Anti-mitochondrial antibodies #Autoimmune #Myositis #Myopathy #rheumatology #differential #diagnosis

Causes of Rhabdomyolysis - Differential Diagnosis • Drugs & Toxins (Statins, alcohol, cocaine) • Direct Muscle Damage (Trauma/crush injury, burns, extreme exercise) • Muscle Hypoxia (Prolonged immobilization) • Infections (Influenza, HIV, Legionella, S. pyogenes, Clostridium) • Temperature (Heat stroke, malignant neuroleptic syndrome) • Inflammatory Muscle Disease (myositis) • Metabolic Disorders (Diabetic ketoacidosis, hypothyroidism) • Genetic Defects (Deficiencies in glycolytic enzymes or lipid metabolism, mitochondrial) - BWH Medicine Chiefs @BrighamChiefs #Rhabdomyolysis #Differential #Diagnosis #Causes

Ptosis - Differential Diagnosis Framework Ptosis (Greek- to fall) Drooping of the upper eyelid that usually results from a congenital or acquired abnormality of the muscles that elevate the eyelid. When patients present with ptosis, it is important to think about three clinical diagnoses associated with ptosis: 1. CN III palsy 2. Horner’s syndrome 3. Myasthenia gravis Neurogenic Ptosis - Neurologic disease affecting the muscle, neuromuscular junction, cranial nerve, and the brainstem may lead to ptosis and weakness of the levator muscle of the upper eyelid: • Third nerve palsy • Horner syndrome • Myasthenia gravis • Botulinum toxin • Multiple sclerosis • Cerebral ptosis - Supranuclear lesions • Ophthalmoplegia migraine Myogenic Ptosis: • Mitochondrial myopathy • Myotonic dystrophy • Myasthenia gravis • Ocular myopathy • Oculopharyngeal muscular dystrophy • Blepharophimosis syndrome Aponeurotic Ptosis: • Spontaneous disinsertion or dehiscence of the levator aponeurosis (the tendon connecting the levator to the tarsal plate) • Involutional (senile) change • Contact lens wearing • Ocular surgery Congenital Ptosis - Absence or reduction of striated levator palpebrae superioris muscle: • Marcus Gunn jaw-winking syndrome Traumatic Ptosis - Direct or indirect trauma to the eyelid leading to: • Levator transection • Cicatrization • Eyelid laceration or orbital rooftop fracture with ischemia Mechanical Ptosis - Levator function is impaired due to the mass effect of some abnormal external structure/excess weight on the upper lid: • Neoplasm • Chalazion • Contact lens in the upper fornix • Scarring • Ocular pemphigoid • Trachoma Pseudoptosis: • Microphthalmos • Anophthalmos • Enophthalmos • Lid retraction of one eye causing ptosis in the contralateral eye • Redundant eyelid skin and prolapse of the orbital fat (dermatochalasis) • Lowering the ipsilateral eyebrow and raising the contralateral one • Duanes Syndrome #Ptosis #neurology #Differential #Diagnosis #ophthalmology #ocular

Rhabdomyolysis - Differential Diagnosis Framework and Management Summary Causes of Rhabdomyolysis: • Trauma: - Immobilization - Crush injury - Compartment syndrome - Electrical injury • Exertional: - Hyperthermia/Heat exhaustion, Heat injury, Heat stroke - Metabolic myopathies - Excess exertion/training - Seizures - Malignant hyperthermia - Neuroleptic malignant syndrome • Nontraumatic Nonexertional: - Electrolytes - Toxins - Drugs - Statins - ETOH - Infection - Viral (HIV, Influenza, TSS, Herpes, Coxsackie, etc) - Endocrine: Hypo/Hyperthyroidism - Autoimmune: Polymyositis/Dermatomyositis Clinical Features: • Triad of symptoms: - Muscle pain - Weakness - Dark urine • Other symptoms: - Malaise - Muscle swelling - Fever - Tachycardia - N/V - Abdominal pain Labs: • CPK 5X ULN • AST/ALT Elevation 4:1 ratio (AST declines > ALT) • AKI: BUN/Cr ↑ • Aldolase ↑ • LDH ↑ • Hyperkalemia • Hyperphosphatemia • Hypocalcemia/Late - Hypercalcemia • Hyperuricemia • Hyponatremia • HAGMA • Late complication: DIC • CPK - if doesn’t decline - suspect continued muscle injury or compartment syndrome • Myoglobinuria: UA positive for blood with no RBC’s, + myoglobin AKI Mechanism: 1. Shift of extracellular fluid into injured muscles - HYPOTENSION → renal vasoconstriction → decreased renal perfusion → renal ischemia 2. Cast formation: Renal tubular obstruction 3. Direct myoglobin nephrotoxicity to kidney tubular cells 4. Heme associated free radicals - oxidative injury Treatment: 1. Treatment of underlying disease 2. Prevent Prerenal azotemia: Isotonic fluid/Lactated ringers - Initial rate: 1-2 L/hour with goal urine output: 200 ml/hr 3. Monitor potassium and calcium several times per day until stable 4. Loop diuretics for fluid overload 5. Dialysis for severe hyperkalemia or ATN 6. Allopurinol for hyperuricemia if levels > 8 mg/dL #Rhabdomyolysis #Differential #Diagnosis #Management #causes #treatment #nephrology

Causes of Myocarditis 1. Infectious Myocarditis • Bacterial - Staphylococcus, Streptococcus, Pneumococcus, Meningococcus, Gonococcus, Salmonella, Corynebacterium diphtheriae, Haemophilus influenzae, Myobacterium (tuberculosis), Mycoplasma pneumoniae, Brucella • Spirochaetal - Borrelia (Lyme disease), Leptospira (Weil disease) • Fungal - Aspergillus, Actinomyces, Blastomyces, Candida, Coccidioides, Cryptococcus, Histoplasma, Mucormycoses, Nocardia, Sporothrix • Protozoal - Trypanosoma cruzi, Toxoplasma gondii, Entamoeba, Leishmania • Parasitic - Trichinella spiralis, Echinococcus granulosus, Taenia solium • Rickettsial - Coxiella bumetti (Q fever), R. rickettsia (Rocky Mountain Spotted fever), R. tsutsugamuschi • Viral - RNA viruses: Cox sackie viruses A and B, echo viruses, polio viruses, influenza A and B viruses, respiratory syncytial virus, mumps virus, measles virus, rubella virus, hepatitis C virus, dengue virus, yellow fever virus, Chikungunya virus, Junin virus, Lassa fever virus, rabies virus, human immunodeficiency virus-1 DNA viruses: Adenoviruses, parvovirus B 19, cytomegalovirus, human herpes virus-6, Epstein-Barr virus, varicella-zoster virus, herpes simplex virus, variola virus, vaccinia virus 2. Immune-mediated myocarditis • Allergens - Tetanus toxoid, vaccines, serum sickness. Drugs: Penicillin, cefaclor, colchicine, furosemide, isoniazid, lidocaine, tetracycline, sulfonamides, phenytoin, phenylbutazone, methyldopa, thiazide diuretics, amitriptyline • Alloantigens - Heart transplant rejection • Autoantigens - Infection-negative lymphocytic, infection-negative giant cell. Associated with autoimmune or immune-oriented disorders: Systemic lupus erythematosus, rheumatoid arthritis, Churg-Strauss syndrome, Kawasaki's disease, inflammatory bowel disease, scleroderma, polymyositis, myasthenia gravis, insulin-dependent diabetes mellitus, thyrotoxicosis, sarcoidosis, Wegener's granulomatosis, rheumatic heart disease (rheumatic fever) 3. Toxic myocarditis • Drugs - Amphetamines, anthracyclines, cocaine, cyclophosphamide, ethanol, fluorouracil, lithium, catecholamines, hemetine, interleukin-2, trastuzumab, clozapine • Heavy metals - Copper, iron, lead (rare, more commonly cause intramyocyte accumulation) • Miscellaneous - Scorpion sting, snake and spider bites, bee and wasp stings, carbon monoxide, inhalants, phosphorus, arsenic, sodium azide • Hormones - Phaeochromocytoma, vitamins: beri-beri • Physical agents - Radiation, Electric Shock #Myocarditis #Causes #differential #diagnosis #cardiology