A. Inflammatory Muscle Diseases [1,13]

1. Polymyositis
2. Dermatomyositis - may be associated with malignancy
3. Malignancy Associated Myositis
4. Juvenile Dermatomyositis
5. Collagen-Vascular Disease Associated Myositis (Overlap Syndromes)
   1. Systemic lupus erythematosus (SLE)
   2. Scleroderma
   3. Rheumatoid arthritis (RA)
   4. Sjogren Syndrome (SS)
6. Inclusion-body myositis
7. Miscellaneous
   1. Granulomatous Myopathy (sarcoid-like disease)
   2. Eosinophilic Myositis
   3. Eosinophilia-Myalgia Syndrome
   4. Myositis Ossificans (short metacarpals)
   5. Giant Cell Myositis
   6. Macrophage Myofasciitis
8. Infectious Myopathy
9. Drug and Toxin Myopathy
10. Critical Illness Myopathy (loss of myosin filaments) [4]

B. Characteristics of Necrotizing Myopathies [10]

1. Present with variable elevations of serum creatinine kinase, aldolase
2. Frank myoglobinuria occurs in severe cases
3. Show fibrillations and positive waves on electromyogram
4. Inflammatory myopathies are necrotizing and usually present with diffuse weakness
5. Careful evaluation for concomitant neuropathy and myopathy is important
6. Toxin myopathies should be considered, especially with rhabdomyolysis

C. Diagnostic Evaluation

1. ESR (and CRP) elevation inflammatory disease
2. Autantibodies
   1. Antinuclear Abs uncommon except in overlap syndromes (see below)
   2. Consider obtaining anti-U1-RNP if ANA is positive
   3. Anti-Jo1 and other anti-tRNA synthetase Abs also available
   4. Anti-GAD Abs associated with stiff man syndrome
3. Muscle enzyme elevation found in muscle destruction diseases
   1. Transaminases - AST (SGOT) found in muscle; ALT (SGPT) in lower levels in muscle
   2. Creatine kinase (CK) - is quickest and most sensitive for muscle disease
   3. Aldolase - most specific enzyme available for muscle tissue
   4. Lactate dehydrogenase (LDH) - least specific enzyme availabe
4. Myoglobinuria
   1. Positive urine dipstick hemoglobulin with no or few RBCs (microscopic negative)
   2. This is a false positive test, and is due to myoglobin (from muscle) in urine
5. Electromyographic (EMG) abnormalities
   1. Small amplitude, short duration, polyphasic motor potentials
   2. Spontaneous fibrillations with positive spike waves at rest
   3. Increased spontaneous spike waves and irritability
6. Nerve Conduction Studies (NCS)
   1. Absence of neuropathy (except in inclusion body myositis or some chemotherapy/toxin)
   2. Muscle loss can lead to denervation, which may show neuropathic results on NCS
   3. Concomitant nerve and muscle disorders are common and should be considered
7. MRI may be useful
   1. May show increased T2 signal in inflamed areas with true inflammatory disease
   2. May distinguish between inclusion body myositis and others
8. Muscle Biopsy - Gold Standard for Diagnosis

D. Differential Diagnosis of Myositis [1]

1. Electrolyte Disorders
   1. Hypokalemia - associated also with periodic paralysis (corresponds to low K+)
   2. Hypo- and hypercalcemia
   3. Hypophosphatemia
   4. Hypomagnesemia
2. Drugs and Toxins
   1. Alcohol - acute myopathy with weakness and muscle pain, rhabdomyolysis can occur; chronic muscle wasting also well documented
   2. Stimulants: Cocaine and MDMA ("Ecstasy")
   3. Colchicine - usually myopathy with mild distal polyneuropathy, minimal CK increases, pure myopathic changes in proximal limb with added neuropathic changes in distal areas [10]
   4. Niacin
   5. HMG CoA Reductase Inhibitors (statins; see below)
   6. Ipecac
   7. Glucocorticoids - usually without CK increase, weakness, no pain
   8. Hydroxychloroquine
   9. Penicillamine
   10. Tryptophan
   11. Valproate
   12. Zidovudine (AZT)
3. Statin Induced Myopathy [2,11]
   1. Serious myopathy ~0.4-1 case per 10,000 person years [11]
   2. Cerivastatin (Baycol®) was withdrawn from market due to ~10X higher rates [7,8]
   3. High lipophilicity, high doses, and drug-drug interaction potential correlate with risk
   4. Even high doses of atorvastatin, pravastatin, simvastatin when used alone (without fibrates or niacin) have very low rhabdomyolysis risk [11]
4. Infections
   1. Viral - coxsackievirus, EBV, influenza, HIV, echovirus (vacuolated), adenovirus, CMV
   2. Bacterial - pyomyositis; staphylococci, streptococci, clostridia
   3. Parasitic - toxoplasmosis, trichinosis, schistosomiasis, cysticercosis
5. Other Rheumatologic Disorders
   1. Polymyalgia rheumatica (PMR)
   2. Mixed Connective Tissue Disease (MCTD)
   3. Undifferentiated connective tissue disease
   4. Vasculitis
6. Neuromuscular Disorders
   1. Genetic Muscular Dystrophy
   2. Spinal Muscular Atrophy
   3. Peripheral Neuropathy - Guillain-Barre, Diabetes mellitus, porphyria, B12 Deficiency
   4. Neuromuscular Junction Disease - Myasthenia Gravis and Eaton-Lambert Syndrome
   5. Amyotrophic Lateral Sclerosis
7. Endocrinopathy
   1. Thyroid disorders
   2. Cushing's Syndrome (steroid myopathy)
   3. Addison's Disease
   4. Hyper- and hypoparathyroidism (due to calcium and phosphorus effects)
8. Metabolic Myopathy

D. Overlap Myositis Syndromes

1. Juvenile Dermatomyositis
   1. Children usually age 5-14 years
   2. Gottron and heliotrope rashes similar to adult form
   3. High incidence of perivascular lymphocyte infiltration; Ig and complement deposition
   4. Incidence of systemic vasculitis with GI, heart and retinal involvement higher than adult
   5. Muscle calcification is not uncommon and is distinct from adult form
2. Mixed Connective Tissue Disease
   1. Characterized by Raynaud's, myositis, arthritis (75%), Esophageal disease, Lung Disease
   2. Pulmonary hypertension is most common finding (probably related to Raynaud's)
   3. High Titer ANA, must have high titer anti-U1 RNP autoantibodies
   4. Myositis is similar to polymyositis
3. Myositis-Scleroderma Overlap
   1. Relatively common disease with overlap between scleroderma and polymyositis
   2. Anti-UQRNP, anti-U2RNP, anti-Ku are found in this (and other overlap syndromes)
   3. Anti-PM-Scl Ab appears specific for this syndrome; reacts with an 11-protein complex

E. Macrophage Myofasciitis [5,13]

1. Inflammatory myopathy of very recent discovery
   1. No infectious agents detected to date
   2. May be associated with intramuscular injection of aluminum-containing vaccines
2. Symptoms
   1. Myalgias
   2. Arthralgias
   3. Muscle weakness - typically deltoids and quadraceps
   4. Moderate to severe asthenia
   5. Fever (~30%)
   6. Children may present with hypotonia, developmental delay, inability to thrive
3. Laboratory
   1. Increased creatine kinase levels
   2. Elevated erythrocyte sedimentation rate (ESR)
   3. Myopathic EMG findings
4. Histopathology
   1. Infiltration of subcutaneous and all muscle tissue components with macrophages
   2. Macrophages are large with finely granular PAS+ content
   3. Occasional CD8+ T lymphocytes
   4. Absence of epitheliod and giant cells, necrosis, and mitotic figures
5. Glucocorticoids plus antibiotics improved or stabilized disease in all patients

F. Stiff Person (Man) Syndrome [6]

1. Characteristics
   1. Rare central nervous system (CNS) disorder of muscle controlling neurons
   2. Progressive rigidity in neck, trunk, and lower extremity muscles
   3. Intermittent superimposed spasms
2. Etiology
   1. Continuous contractions of agonist and antagonist muscles
   2. Due to involuntary firing of motor units at rest
   3. Reduced levels of inhibitors neurotransmitters gamma-aminobutyric acid (GABA)
   4. May also have reduced function or levels of inhibitory neurotransmitter glycine
   5. Lack of inhibition causes chronic (intermittent) contraction of muscles and/or skin
   6. Opposing muscle groups are often firing in parallel, leading to marked stiffness
   7. May be associated with malignancy (paraneoplastic syndrome)
   8. About 10% of patients have seizures, consistent with CNS hyperactivity
3. AutoAbs
   1. Most patients have auto-Abs to specific epitope of glutamic acid decarboxylase (GAD65)
   2. Anti-GAD65 Abs also found in Type I Diabetes, but directed against different epitope
   3. Titers of anti-GAD65 are ~100 fold lower in diabetes than in Stiff Man Syndrome
   4. The anti-GAD65 Abs are produced intrathecally
   5. Often found with other auto-Abs and other autoimmune disorders [3]
   6. Paraneoplastic SPS associated with autoantibodies to synaptic protein amphiphysin [12]
   7. Increased frequency of certain HLA-DR and -DQ phenotypes
4. Accompanying endocrine disorders, including polyendocrine failure, may be found [3]
5. Treatment
   1. GABA enhancing drugs such as valproate, diazepam, tiagabin, or vigabatrin help
   2. Doses of diazepam (~60mg) required for treatment are usually poorly tolerated
   3. Therefore, the newer anti-epilepsy medications are recomended
   4. Intravenous immunoglobulin (IVIg), plasmapheresis, and/or glucocorticoids
   5. High-dose IVIg (2gm/kg per month given monthly for 3 months) is well tolerated and effective for Stiff Person syndrome and anti-GAD65 Abs [9]

G. Other Types of Myositis [13]

1. Amyopathic Dermatomyostis
   1. Rash typical of dermatomyositis skin rashes without myopathy for at least 2 years
   2. More common in adults than children
   3. On biopsy, mild muscle inflammation often present but subclinical
   4. May be associated with calcinosis or arthritis
2. Focal Myositis
   1. Most often presents as an enlarging mass within affected muscle
   2. Often painful or tender on palpation
   3. Most commonly thighs or calves, followed by the neck
3. Orbital Myositis
   1. Subtype of focal myositis involving extraocular muscles
   2. Presents with orbital pain worse on eye movement
   3. Diplopia, proptosis, conjunctival injection, periorbital edema
   4. Narrowing of palpebral fissues and globe retraction also seen
   5. Occurs in children and adults
4. Inclusion-Body Myositis
   1. Most common myopathy in persons >50 years
   2. Slowly progressive proximal and distal weakness
   3. Generally not part of overlap syndrome
   4. Cytotoxic T lymphocytes target MHC-I antigen expressing muscle cells
   5. Low serum creatine kinase, rimmed vacuoles on trichome-stained muscle biopsy
5. Malignancy Associated Myositis
   1. Dermatomyositis is associated with a ~2-6X increased risk for malignancy
   2. Dermatomyositis most often found with ovarian, lung, pancreatic, gastric, colorectal, non-Hodgkin's lymphoma
   3. Polymyositis is associated with a ~1.5-2X increased risk for malignancy
   4. Polymyositis most often found with non-Hodgkin lymphoma, lung, and bladder cancers
   5. Patients with active neuropathy and myopathy have an increased risk for neoplasm
   6. 5-20% of patients >40 years old with dermatomyositis eventually develop neoplasms
   7. Inclusion body myositis associated with 2.4X increased risk of neoplasm [5]
6. Granulomatous Myositis
   1. Granulomas present on muscle biopsy
   2. Usually with distal weakness
   3. Idiopathic or related to sarcoidosis in pediatric cases

References

1. Polisson RP, Crocker JT, Mueller PR, et al. 2005. NEJM. 353(12):1275 (Case Record)
2. Rosenson RS. 2004. Am J Med. 116(6):408
3. Mueller-Schoop JW and Meyer M. 1996. Lancet. 348:1420 (Case Report)
4. Sandrock AW Jr, Cros DP, Louis DN. 1997. NEJM. 336(15):1079
5. Gherardi RK, Coquet M, Cherin P, et al. 1998. Lancet. 352(9125):347
6. Levy LM, Dalakas MC, Floter MK. 1999. Ann Intern Med. 131(7):522
7. Substituting for Cerivastatin (Baycol). 2001. Med Let. 43(1113):79
8. Thompson PD, Clarkson P, Karas RH. 2003. JAMA. 289(13):1681
9. Dalakas MC, Fujii M, Li M, et al. 2001. NEJM. 345(26):1870
10. Soto O and Hedley-Whyte ET. 2003. NEJM. 349(17):1656 (Case Record)
11. Graham DJ, Staffa JA, Shatin D, et al. 2004. Ann Intern Med. 292(21):2585
12. Sommer C, Weishaupt A, Brinkhoff J, et al. 2005. Lancet. 365(468):1406
13. Feldman BM, Rider LG, Reed AM, Pachman LM. 2008. Lancet. 371(9631):2201