Differential Diagnosis in Neurology

12.7. Inflammatory Myopathy

The three major categories of inflammatory myopathy are polymyositis, dermatomyositis, and inclusion body myositis. There are many conditions both myopathic and neuropathic that affect muscle in a similar pattern. Collagen vascular diseases frequently affects proximal musculature similar to and polymyositis and dermatomyositis but have extra muscular involvement that distinguishes them.

Polymyositis

• Genetics: sporadic
  • Possible increase incidence of HLA-B8 and B12 antigen
• Clinical presentation:
  • Onset subacute over weeks to months
    • Children 5–14 years of age
    • 45–64 years of age in adults
  • Incidence:
    • 1 per 100,000 people
    • Females greater than males, 2:1; black women patients
    • Weakness of neck flexor musculature
    • Symmetrical proximal girdle weakness
      • Rarely anterior tibialis and brachioradialis may be affected
    • Dysphagia occurs in 20–30% of patients:
      • Involvement of the striated posterior pharyngeal and cricopharyngeus muscles
    • Rare respiratory muscle involvement:
      • Does occur in severely patients affected late in their course
      • Rare mild facial muscle involvement
      • Extraocular muscles are not involved
    • Extra muscular involvement:
      • Interstitial lung disease:
        • Positive anti-Jo-1 antibody ( anti-aminoacyl transfer ribonucleic acid (+ RNA) synthetase
        • Occurrence possibly 5–10%
      • Cardiac involvement includes:
        • Congestive heart failure
        • Pericarditis (rare)
        • Valvular disease (rare)
• EKG abnormalities are common:
  • Non-specific ST-T wave abnormalities
  • Heart block
  • Bundle branch block
• Association with malignancy:
  • Rare (perhaps 3% of older patients)
  • Any type of malignancy
  • Sites are age related
  • Negative associations with malignancy:
    • Accompanying connective tissue disease
    • Pulmonary fibrosis
    • Myositis specific antibody
• Myositis specific autoantibodies:
  • Antisynthetase (anti-Jo-1)
    • Possibly 20% of PM
    • Acute onset in spring
    • Associated with interstitial lung disease
    • Nonerosive arthritis (associated)
    • Seen with relapse during prednisone taper
  • Anti-signal recognition particle (SRP)
    • 5% of PM
    • Onset in autumn
    • Associated with myocarditis
    • Severe weakness with myalgia
    • Poor response to prednisone
    • 25% five year survival

Polymyositis (PM) Associated with Connective Tissue Disease

General Features

• Polymyositis occurs in approximately 20% of associated connective tissue diseases
• Higher incidence of arthralgia and arteritis
• Milder muscle disease
• More responsive to immune suppressive therapy

PM with Scleroderma

• Proximal muscle weakness similar to PM
• Associated with other features of scleroderma:
  • Raynaud's phenomena
  • Kidney disease
  • Hypertension
  • Tendon sheath involvement
  • Vth nerve sensory involvement
  • Rare stroke
• Focal from of scleroderma (morphea):
  • Primarily affects children
  • Girls 3:1 over boys
  • Frequently affects the forehead; appears as a "sabre scar"

Laboratory Evaluation of Polymyositis

• Muscle enzymes:
  • Elevated 5 to 50 times normal
• Sed Rate:
  • May be normal; increased in associated connective tissue disease or malignancy
• EMG:
  • Membrane irritability
  • Myopathic motor unit potentials
• Muscle biopsy:
  • Inflammatory cells in the perimysium and endomysium
  • Prominent single fiber necrosis
  • Non-necrotic fibers are focally involved
  • Inflammatory aggregates contain a high percentage of activated T8 cells; small percentage of B cells
  • No perifascicular atrophy
  • No tubular aggregates in the cytoplasm of endothelial cells
  • Pathology confined to the skin, subcutaneous tissue and underlying muscle
  • Skin lesions are multiple or single; 0.5 to 15 cm in diameter
  • No symmetric proximal weakness
• Anti PM-Scleroderma associated antibody:
  • 50% have scleroderma
  • May be seen in other autoimmune diseases
  • May occur in scleroderma without myositis
• Antibodies:
  • Anti PM-Scl-myositis
  • SCL–70
  • Anti-nucleolar antibody
  • Anticentromere antibody with CREST that consists of:
    • Calcinosis cutis
    • Raynaud's
    • Esophageal dysfunction
    • Sclerodactyly
    • Telangiectasia
  • Anti-Ky antibody
• CK and aldolase: minimally elevated; may not be elevated
• EMG: myopathic
• Muscle biopsy:
  • Variation of fiber size
  • Occasional necrosis of single muscle fibers
  • Great increase of endomysial and perimysial connective tissue
  • Decreased capillaries in skeletal muscle
  • Increased thickness in the walls of intramuscular blood vessels; endothelial hyperplasia
  • Tubular aggregates in intramuscular capillary endothelial cells
  • T-cells predominate in the inflammatory infiltrate

Polymyositis Associated with Systemic Lupus Erythematosus

• Females 9:1 more affected than males
• Presents second to fifth decade
• Pericarditis, pleuritis, serosal surface involvement
• Arthritis
• Cerebral arteritis (generalized)
• Peripheral nerve involvement
• Muscle involvement same distribution as PM often less severe
• Laboratory evaluation:
  • IgG antibodies to double stranded DNA are most specific
  • CK and aldolase: mildly elevated
  • EMG: myopathic
  • Muscle biopsy:
    • Vasculitis of small blood vessels
    • Muscle changes similar to dermatomyositis
    • Immunoglobulin deposits and complement found in muscle
    • Multiple central vacuoles in some patients

Polymyositis with Rheumatoid Arteritis

• 0.7% have onset between 3–7th decade
• Severe joint involvement
• Pattern of weakness similar to PM
• Associated neuropathy; often severe intrinsic hand muscle weakness and atrophy
• C1–C2 dislocation; pannus formation at C2; destruction of the cruciate ligament
• Laboratory Evaluation:
  • Rheumatoid arteritis antigens
  • EMG: myopathic; evidence of sensorimotor neuropathy in some patients
  • Muscle biopsy:
    • Nodular vasculitis in the muscle
    • Necrotizing arteriolitis with fibrin deposits in the small blood vessels of muscles
    • Type II muscle atrophy
    • Immune complexes containing immunoglobulin and complement in blood vessel walls

Mixed Connective Tissue Disease

• General features:
  • Associated with anti-fibronuclear protein (RNP)
    • Not specific
  • The antibody is to a rilsonuclease selective antigen component of extratractable nuclear antigen
• Clinical presentation of MCTD; which has feature of:
  • SLE
  • Scleroderma
  • Dermatomyositis
  • SLE like rash
  • Fever, hepatomegaly, serositis, leukopenia
• Raynaud's phenomena
• Sclerodermatous hand findings
• Decreased esophageal motility
• Proximal muscle weakness and pain
• Laboratory evaluation:
  • EMG: myopathic
  • High aldolase and CDK
  • Muscle biopsy:
    • Muscle findings similar to those of dermatomyositis
    • Hyalinization of blood vessel walls

Sjögren's Syndrome

• General features:
  • Proximal and symmetric myopathy
  • Dryness of eyes, mouth and mucosal membranes
  • Arthritis
  • Multiple organ system involvement:
    • Vasculitis
    • Pancreatitis
    • Hepatobiliary disease
    • Interstitial nephritis
    • Thyroid abnormalities
  • PNS/CNS involvement:
    • Vth nerve involvement
    • Dorsal column dysfunction
    • Associated with higher incidence of primary progressive MS
• Sensory ataxia (dorsal root ganglionitis; large neurons)
• Sjögren's associated with:
  • Polyarteritis
  • Chronic active hepatitis
  • Interstitial pulmonary fibrosis
  • Lymphoproliferative neoplasia
• Laboratory evaluation:
  • Anti RO-SSA, anti-LA-SSB antibodies (anti-nuclear)
  • Serum antibodies against RNA, and antigens in the lacrimal, thyroid and salivary glands
  • Elevated smooth muscle and mitochondrial antibodies
  • EMG: myopathic
  • Muscle biopsy:
    • Changes in muscle similar to those of rheumatoid arthritis
    • Degeneration and regeneration of isolated muscle fibers
    • Inflammatory cells within the perimysium combined with a vasculitis
    • Immunoglobulins and C3 may be deposited within the walls and capillaries of the venules of skin and muscle

Variants of Polymyositis

Antisynthetase Syndrome

• Seen in 20% of PM and DM patients
• The anti-Jo-1 autoantibody is present
• Clinical features:
  • Acute myositis
  • Occurs in the spring
  • Associated with non-erosive small joint arthritis
  • Low grade fever
  • Raynaud's phenomena
  • Relapses with steroid taper
  • Interstitial lung disease (70% of patients)
  • Small number of patients have other features of the syndrome without the myositis

Anti-SRP Auto Antibody Syndrome

• Clinical Presentation
  • Severe polymyositis with myalgia
  • Present in the autumn
  • Myocarditis
  • Resistance to treatment (immunotherapies)
  • Poor prognosis

Dermatomyositis

• Clinical presentation:
  • Childhood variant: age 5–14
  • Adult: 45–64 years of age
  • No specific precipitative events; insidious onset with fatigue and weight loss
• Onset over weeks to months
• Rash may precede the onset of weakness by weeks to months
• Weakness is proximal, symmetrical and involves neck flexors
• Dysphagia occurs in approximately 30% of patients
• Muscle tenderness less than 50%; arms greater than legs
• Skin manifestations:
  • Acute stage:
    • Erythema and edema of subcutaneous tissue
    • Periorbital, perioral, malar, anterior neck and chest distribution:
      • Heliotrope suffusion primarily in children. Purplish discoloration of the eyelid and infraorbital skin
      • Groton's sign-erythematous symmetrical scaling lesions over bony prominences; knuckles and interphalangeal joints. SLE may affect areas between the joints
      • Dilatation and inflammation of capillaries at the base of the nail; SLE causes periungual telangiectasia
  • Chronic stage:
    • Scaling of the skin
    • Hyperpigmentation
    • Zones of brown induration (poikiloderma) in the extensor surfaces and back
    • Calcification of the skin in children
• Increased reflexes in the lower extremities (irritation of intrafusal) muscle fibers
• Systemic involvement:
  • Cardiac manifestation (5–10% of patients):
    • Atrial arrhythmias
    • Atrioventricular conduction defects
    • Bundle branch block
    • Congestive heart failure
  • Primary lung disease:
    • Interstitial pneumonitis:
      • Presenting manifestation or occurs late in the course of the disease
      • 5–10% of patients
    • Secondary lung disease:
      • Weakness of intercostals muscles
      • Chronic aspiration
      • Pyogenic or atypical lung infection (immunosuppressant treatment)
      • Methotrexate
  • Raynaud's phenomena
  • Arthritis 20–50% of PM greater than that which occurs in dermatomyositis

Dermatomyositis Associated with Malignancy

Associated malignancy in DM possibly as high as 40% in patients older than 40 ; PM only 3.4% malignancy at greater than 40 years of age. Earlier studies demonstrated approximately 10% of elderly patients develop malignancy (probably now closer to 5%). Malignancy occurs with IBM (inclusion body myopathy).

• Malignancy may precede or follow the onset of myopathy by months or years; usually occurs within two years of the diagnosis
• Any tumor type may be associated. Small cell squamous carcinoma of the lung in men and ovarian cancer in women appear most common. Stomach cancer has a greater incidence than colorectal malignancy.
• Less likely to have malignancy with myositis associated with connective tissue disease, pulmonary fibrosis or myositis specific antibody syndrome
• A few patients have had an explosive onset with malignancy
• Removal of the tumor may benefit the myopathy; recurrence of the myopathy may be the initial manifestation of tumor recurrence.
• Laboratory Evaluation:
  • CK and aldolase elevation occurs in the great majority of patients: exceptions are very early in the disease when only the rash is present and in very late illness. Usually 3–5 times normal. Antinuclear helicase antibody (anti-Mi-2) is detected in 5–10% of patients.
  • EMG:
    • Myopathic
    • Increased insertional activity, positive sharp waves; fibrillations particularly noted in paraspinal muscles
  • Long standing disease:
    • Signs of reinnervation with high amplitudes, long duration polyphasic MUAP
• Muscle biopsy:
  • Perivascular inflammatory cells in the perimysium that extend into the endomysium.
  • High percentage of B-cells and helper T cells in the infiltrate
  • Rare single fiber necrosis
  • Occasional necrotic or non-neurotic fibers surrounded by inflammatory cells
  • Tubular aggregates noted in the cytoplasms of endothelial cells of arterioles and capillaries
  • Capillary necrosis and degeneration

Pathology of PM/DM Associated with Malignancy

• Muscle pathology is similar to polymyositis
• Dermatomyositis:
  • Changes in muscle resemble dermatomyositis
  • Tubular aggregates are prominent within the endothelial cytoplasm of intramuscular arterioles, capillaries and vessels

Pathology of Dermatomyositis of Childhood

• Muscle pathology similar to that of the adult
• Perivascular collections of inflammatory cells
• Internal hyperplasia of the arteries and veins
• Small vessels occluded by fibrin thrombi
• Deposition of IgG, IgM, and C3 within the walls of intramuscular arteries and veins
• Deposition of complement membrane attack complexes in the walls of small intramuscular arteries

Childhood Dermatomyositis

• Affects children and young adults
• Clinical features:
  • Erythematous skin lesions over the extensor surface of joints
  • Malar rash
  • Aberrant skin calcifications
  • No precipitating cause
  • Muscle weakness and rash are associated
  • Duration of disease is variable; months to years
  • May have rapid course; respiratory failure is rare
  • Vasculitis of the gastrointestinal tract with perforation and hemorrhage are feared complications
• Skin rash may precede weakness, stiffness and painful muscles
• Muscle weakness is generalized; proximal shoulder and pelvic girdle muscles predominate:
  • Abductors of the legs greater than adductors
  • Extensors greater than flexors
  • Tip toe gait (children) due to gastrocnemius flexion contraction
  • May lose deep tendon reflexes with severe weakness
  • Severely affected children:
    • Incomplete muscle recovery
    • Progressive to bulbar musculature, phonation and respiration
    • Flexion contractions of elbows, hips, knees, and ankles
    • Brown erythematous skin thickening
    • Subcutaneous calcification with skin ulceration
    • Areas of hyperpigmentation and depigmentation
    • Groton papules in the knuckles

Inclusion Body Myositis

• General features:
  • Incidence is increasing; may be the second most common form of inflammatory myopathy
  • Most common inflammatory myopathy over age 50
• Clinical presentation:
  • Male predominance
  • Age of onset 60–70 years of age
  • Duration of symptoms prior to biopsy (mean of 7 years)
  • More common in white than black patients
  • Flexion contraction of forearm muscles and quadriceps
  • Swallowing abnormalities

Differential Diagnosis of PM/DM Complex

Criteria for Diagnosis of Definitive Polymyositis

• Presence of symmetrical weakness of limb girdle and neck flexor muscles
• Abnormal neck flexor muscles
• Increased CK
• Abnormal EMG with evidence of an irritative myopathy
• Chronic rash (DM)
  • 25–30% of patients fulfill the definitive criteria for PM

Less Restrictive Diagnostic Criteria for PM/DM Complex

Subacute Chronic Myopathy

• Course: rapid progression over weeks or months with reversibility
• Distribution: dysphagia, neck (flexor) and proximal limb weakness
• Myalgia and muscle tenderness
• Laboratory features:
  • Myopathic EMG
  • Elevated CK and aldolase
  • Impaired esophageal motility
  • Myopathic biopsy with presence of inflammatory cells

Evidence of Systemic Disease

• Clinical features:
  • Raynaud's
  • Arthralgia
  • Cardiac dysfunction
  • Interstitial lung disease
  • Fever
  • Weight loss
  • Esophageal dysmotility
• Laboratory:
  • Elevated sedimentation rate
  • Polyclonal hypergammaglobulinemia
• Exclusion of other disease:
  • Absence of family history (r/o dystrophies)
  • No cranial muscle weakness or cholinergic drug response (r/o MG)
  • Lack of endocrine disorder (r/o thyroid, Addison's disease, hyperparathyroidism)
  • No specific biochemical disorder on muscle biopsy
    • Rules out:
      • Carnitine deficiency
      • Acid maltase deficiency
      • Phosphorylase deficiency
      • Phosphofructokinase deficiency

Differential Diagnosis of Polymyositis

Criteria for Diagnosis of Polymyositis

• Myopathy similar to myopathy of dermatomyositis:
  • Course: rapid progression (weeks or months); reversibility
  • Distribution: dysphagia; neck and proximal limb weakness
  • Myalgia and tenderness (less than 50% of patients)
  • Laboratory evaluation:
    • Myopathic EMG
    • Myopathic biopsy: inflammatory cells (mononuclear endomysial infiltrates precuneate); variation of fiber size, muscle fiber degeneration and regeneration scattered throughout the fascicle)
    • Increased serum muscle enzymes
    • Impaired esophageal motility in 40% of patients
• Evidence of systemic disease:
  • Clinical; arthralgia, Raynaud's phenomenon, fever, weight loss
  • Laboratory evaluation; sedimentation rate elevation, hypergammaglobinemia
• Absence of other diseases, drugs and factors:
  • No family history (dystrophies)
  • No rash, calcinosis, heliotrope suffusion (PM)
  • No endocrine dysfunction
  • No biochemical abnormality on muscle biopsy: which rules out carnitine, phosphorylase, acid maltase, PFK
• Connective Tissue Diseases in which Polymyositis in associated:
  • SLE
  • Scleroderma
  • Vasculitis
  • Sjögren
  • Rheumatoid arthritis
  • Mixed connective tissue disease
• Infectious causes of Polymyositis:
  • Toxoplasmosis
  • Tania sodium
  • Schistosomiasis
  • Cysticercosis
  • Chagas disease
  • Legionnaire's disease
  • Candidiasis
  • Influenza
  • Hepatitis-B virus
  • Coxsackie virus
  • ECHO
  • HIV
  • Mycoplasma
• Drugs:
  • Ethanol
  • Penicillamine
  • Clofibrate
  • Statins
  • Emetine
  • Chloroquine
  • Aminocaproic acid
  • Rifampicin
  • Diuretics
  • Zidovudine
• Intramuscular Injectable Drugs:
  • Meperidine (Demerol)
  • Pentazocine (Talwin)
• Systemic Diseases:
  • Carcinoma (paraneoplastic)
  • Thymoma (paraneoplastic)
  • Sarcoid
  • Celiac Disease
  • Vitamin D deficiency states
• Endocrine diseases:
  • Hyperthyroidism
  • Hypothyroidism
  • Hyperadrenocorticism
  • Hyperparathyroidism
  • Hashimoto's thyroiditis
• Metabolic Diseases:
  • Protein malnutrition
  • Malabsorption
  • Hypocalcemia
  • Parenteral nutrition (phosphate depection)
  • Osteomalacia
  • Chronic renal disease
  • Hypokalemia
  • Carnitine deficiency
  • Acid maltase deficiency
  • Phosphorylase deficiency
  • Phosphofructokinase deficiency
• Hereditary Disorders:
  • Limb girdle dystrophies
  • Becker's muscular dystrophy
  • Mitochondrial myopathies
  • Fascioscapulohumeral dystrophy
• Inclusion in Body Myositis:
  • Steadily progressive; more slowly than PM/DM
  • Legs more affected than arms in many patients
  • Wasting of forearm, finger flexor muscles; weakness of wrist flexors, knee extensors, ankle dorsiflexors
  • May have generalized muscle weakness
  • Weakness is more often asymmetrical than symmetrical
  • Dysphagia is common
  • Scapular cervical and facial muscle may be involved; frequent falls from quadriceps weakness
  • Extraocular muscles are spared
  • Spinal, respiratory and abdominal muscles are rarely affected
  • Transient myalgias occur at the beginning or during the course of the illness
  • No sensory abnormalities
  • Deep tendon reflexes are normal or are slightly hyperactive; decreased knee jerks are seen with severe quadriceps atrophy
  • Higher incidence of peripheral neuropathy with sensory loss and decreased AJ
• Same relationship to other autoimmune diseases:
  • Scleroderma
  • Sjögren's
  • SLE
  • Monoclonal gammopathies
  • Antibodies to epitopes of myonuclei
• Steroids are minimally or not effective. IVIG is minimally to moderately effective
• Lack of steroid responsiveness in a patient appearing to have PM suggests the diagnosis
• Laboratory evaluation:
  • CK elevation: 3–5 times normal
  • Antinuclear helicase auto antibody (anti-M1-2) found in 5–10% of patients
  • EMG:
    • Short duration motor unit potentials
    • Increased polyphasic potentials
    • Fibrillation potentials; positive sharp waves are common
    • Normal nerve conduction velocities
  • Muscle biopsy:
    • Necrosis and regeneration scattered throughout the fascicle
    • Vacuoles in 5–10% of fibers; single or multiple
    • Fibrosis
    • Inflammatory changes are endomysial
  • Electron Microscopy:
    • Abnormal filamentous inclusions in the nucleus and cytoplasm
    • Neurofilaments are 15–18 mm in diameter
    • Membrane lined sarcoplasmic vacuoles
      • Contain membranous walls
      • Rimmed vacuoles with hematoxyphilic material

Differential Diagnosis of IBM

• Chronic polymyositis (rarely distal predominant, but usually affects the brachioradialis rather than finger flexors)
• Chronic spinal muscular atrophy
• Vacuolar myopathies (pathologic muscle biopsy differential)
  • Chloroquine myopathy
  • Colchicine myopathy
  • Vincristine myopathy
  • Acid maltase deficiency
  • Primary hypokalemic periodic paralysis
  • Juvenile Batten disease (lipocercoid fusionis)
  • Muscular dystrophy (rapidly progressive)
  • Oculopharyngeal dystrophy (AD)
  • Distal myopathy (sporadic or familial):
    • Rimmed vacuoles
    • Filamentous inclusions

Unusual Inflammatory Myopathies (Eosinophilic Polymyositis)

Hypereosinophilic Syndrome (HES)

• Heterogenous disorder
• Eosinophilia (often greater than 30,000 mm³)
• Diagnostic criteria:
  • Persistent eosinophilia greater than 1500 eosinophlis/mm³
  • Duration of greater than six months
  • No evidence of parasitic or other causes of eosinophilia
  • Organ system involvement
• Clinical features:
  • Insidious onset of proximal muscle
  • Skin involvement
  • Raynaud's phenomenon
  • Splinter hemorrhages of nail beds
  • Occasional ocular muscle involvement
  • Polymyositis may occur in the setting of hypereosinophilic syndrome (HES)
• Associated organ system involvement
  • Lung
  • Heart
  • Skin
  • Anemia
  • Eosinophilia
  • Hypergammaglobulinemic
  • Peripheral neuropathy
• Laboratory evaluation:
  • Elevated CK (serum)
  • Positive rheumatoid factor
  • EMG:
    • Myopathic
  • Rare EKG abnormalities:
    • Heart block
    • Arrhythmias
  • Chest X-ray:
    • Pulmonary infiltrates
  • Muscle biopsy:
    • Single fiber necrosis
    • Eosinophilic infiltration
    • Perivascular and interfascicular distribution of eosinophilic infiltration
• Differential diagnosis:
  • PAN
  • Hypersensitivity vasculitis
  • Allergic granulomatosis
  • Allergic eosinophilic gastroenteritis
  • Parasitic infection

Diffuse Fasciitis with Eosinophilia

• Clinical features:
  • Onset 30–60 years of age
  • Men greater than women
  • Onset may occur after unusual exertion; may occur without a precipitating event
  • Rapid evolution
  • Some patients have a prodromal period consisting of:
    • Low grade fever
    • Myalgias
    • Arthralgias
    • Cramps
    • Fatigue
  • Thickening of subcutaneous tissue:
    • Edema of arms and legs
    • Trunk may demonstrate mild edema
    • Face is spared
  • Restriction of movement of small joints of the hands, elbows, wrists, knees, and shoulders
  • Rare Raynaud's phenomenon
  • Visceral involvement is unusual
  • Proximal greater than distal muscle weakness
  • Spontaneous remission is common
  • Rapidly responsive to corticosteroids
  • Aplastic anemia may occur during the illness or following remission of the fascitis
• Laboratory evaluation:
  • Eosinophilia in the blood:
    • May be intermittent
    • Usually present (86% of patients)
  • Hypergammaglobulinemia occurs in approximately 75% of patients
  • 25% of patients have a positive ANA; occasional elevation of the rheumatoid factor; rare antimicrosomal and antithyroid antibodies
  • Elevation of circulating immune complexes
  • Elevated sedimentation rate
  • EMG:
    • Myopathic
  • Muscle biopsy:
    • Muscle tissue close to the fascia demonstrates endo and perimysial inflammation
    • Single fiber necrosis
    • Perifascicular atrophy
    • Deposits of IgG and C3 complement in deep muscle fascia

Focal Myositis

• Clinical features:
  • Asymmetric inflammatory myopathy
  • Weakness and wasting confined to a single limb muscle or one side of the body
  • Weakness may generalize
  • Weakness may remain confined for 1–20 years
• Laboratory evaluation:
  • Elevated serum CK
  • EMG of affected muscle:
    • Small motor unit potentials of brief duration
    • Fibrillation potentials
  • Muscle biopsy of the involved limb:
    • Perimysial inflammatory infiltrate of monocytes
    • Single muscle fiber necrosis

Proliferative Focal Myositis

• Clinical features:
  • Benign pseudosarcomatous mesenchymal lesions
  • Solitary discrete mass within muscle
  • Freely moveable
  • Painless focal swelling; rarely a dull or lancinating pain
  • Mass most frequently occurs in the shoulder, thorax or thigh
  • Grows rapidly; may double in size within days
  • No precipitating factor
  • No recurrence following excision
• Muscle biopsy:
  • Epimysium, perimysium and endomysium are thickened
  • Proliferation of fibroblasts and histiocytes
  • Myocytes, myotubes, and muscle giant cells are noted
  • Some patients:
    • Single fiber necrosis
    • Regeneration
    • Aggregation of lymphocytes, plasma cells and histiocytes in the endomyserium and perimysium

Localized Nodular Myositis

• General Clinical Features:
  • Primarily in men
  • Painful. nodular myopathy localized to an extremity
  • Evolves into diffuse myositis
  • Nodules disappear during the transition
  • Dysphagia occurs
• Muscle biopsy:
  • Nodules:
    • Large zones of necrotic muscle fibers
    • Inflammation in the zones
    • Similar pathology to infarction
  • Diffuse stages of the disease:
    • Histology is similar to PM/DM

Localized Myositis Ossificans

• Clinical features:
  • Swelling within muscle
  • Occurs in an area of injury; arm and thigh most frequently involved
  • Area is doughy; evolves into a firm and hard mass
  • Bone can be visualized greater than one month after disease onset
• Pathology:
  • Core of mass contains histiocytes and fibroblasts, giant cells and fibrin
  • Surrounding the core are compact layers of connective tissue
  • Periphery of the core is formed bone

Myositis Ossificans Progressiva

• Clinical features:
  • AD inheritance
  • Onset in first decade
  • Progressive widespread ossification of many muscles
    • Often starts in paraspinal muscles
  • Associated congenital defects:
    • Mono phalangeal digit of the great toe and thumb
    • Microdactyly
    • Wide separation of the great toe and first digit
    • Broad neck of the femur
    • Absence of two upper incisors
    • Hypogenitalism
    • Absence of the ear lobes
    • Deafness
  • Primary sign is subcutaneous masses of the posterior neck and shoulders:
    • Initially masses are warm and tender
    • Shrink and become bony hard
    • Masses may appear and then disappear
• X-Ray evaluation:
  • Configuration of bone resembles the shape of the muscle
  • Restriction of hip movement by age 20
  • Progressive involvement of muscles of the extremities, abdominal wall, chest and vertebral column
  • Most patients are wheelchair bound by the age of 30
  • Calcification occurs between muscle groups and across joints
  • Bone replaces tendons, fascia, ligaments and muscle
  • Occasional patients may display only skeletal alterations
• Pathology:
  • Primary changes are in connective tissue, dermis and fascia
  • Hemorrhage, inflammation and proliferation of collagen occurs
  • New cartilage and bone formation occur in the altered tissue

Muscle Involvement in Vasculitis

• Polyarteritis nodosa (PAN):
  • Muscle weakness may be symmetrical or asymmetrical
    • Affects approximately 40% of patients
  • Associated organ system involvement:
    • PNS – 60%; mononeuritis multiplex, GBS picture, sensorineural neuropathy
    • CNS – rare stroke of large vessels
    • Kidneys – 70%; severe hypertension particularly virulent from in young black patients
    • GI – tract involvement in 30% of patients; hepatic lobe infarction
    • Skin involvement in 50%; palpable vessel enlargement (often on quadriceps)
    • Testis – 5–30% may suffer infarction
    • Heart-myocardial infarction in approximately 15%; secondary to prolonged hypertension in some
• Laboratory evaluation:
  • Sedimentation rate increased in greater than 90% of patients
  • Increased rheumatoid factor in 50%
  • Decreased complement in approximately 25%
  • Hepatitis-B antigen positive in 30%
  • Hepatitis-C positive antigen in 5–20%
  • ANCA + in 70%
  • Persistent eosinophilia in 77%
  • Arteriogram positive
    • Aneurysmal dilatation of medullary kidney arteries
• Pathology:
  • Involvement of small and medium sized arteries and adjacent veins
  • The inflammatory cells is the neutrophilic leukocyte
  • Splitting and fragmentation of the internal elastic membrane of vessels
  • Arterial walls are thickened and nodular
  • Aneurysmal dilatation of arterioles; seen on renal arteriograms in the medullary arteries
  • Fibrinoid necrosis of arteries
• Microscopic Polyangiitis:
  • 20% of patients suffer a mild symmetric limb girdle weakness
  • Associated organ involvement:
    • Glomerulonephritis in 100% of patients
    • Lung involvement (interstitial) 40–50% of patients
    • Skin involvement in 40% of patients
    • Eye – 30% of patients
    • Spleen – 30% of patients
    • CNS – small vessel stroke
    • PNS – mononeuritis multiplex; sensorimotor neuropathy
• Allergic Arteritis/Granulomatosis:
  • Muscle involvement is proximal
  • Most frequently occurs in asthmatics
  • Clinical evolution is rapid
  • Preceding infection is common
  • Fever
  • Eosinophilia
  • Prominent lung involvement
  • Subcutaneous nodules
  • Non-thrombocytopenic purpura
• Pathology:
  • Disseminated necrotizing arteritis with involvement of:
    • Medium and small arteries
    • Veins and arterioles
  • Acute and chronic lesions
  • Necrotizing extravascular granulomata
  • Lung, heart, skin and muscle involvement

Wegener's Granulomatosis

• Clinical features
  • Onset after 40 years of age
  • Sinus and upper respiratory tract involvement in 79% of patients
  • Lung diffusely involved (85%)
  • Eye and skin involvement in 50%
  • Glomerulonephritis in 70% of patients
  • PNS-cranial nerve involvement; mononeuritis multiplex, sensorimotor neuropathy – 45%
  • CNS, stroke; occurs conducting vessels in 4–8% of patients
  • Muscle-direct extension of the vasculitis
• Laboratory evaluation:
  • ANCA: 50–90% of patients
  • RF: 60% of patients
• Pathology:
  • Small arteries, arterioles, venules and capillaries are involved
  • Fibrinoid necrosis of small arteries and veins
  • Granulomata are interspersed among acute lesions; they are intramural and perivascular
• Muscle:
  • Involved by spread from adjacent tissue
  • Necrotizing granulomata in vascular and extravascular distributions

Rheumatoid Vasculitis

• Clinical features:
  • Muscle involvement occurs in long standing patients:
    • Intrinsic hand muscle wasting is prominent (may have associated neuropathy)
    • Symmetrical proximal weakness
      • Steroid causes Type II muscle atrophy
  • Associated organ involvement
    • Skin: 70%
    • Muscle: 55%
    • Lungs: 25%
    • Kidneys: 25%
    • GI: 10%
    • Serositis: 10%
    • PNS, sensorimotor neuropathy; mononeuritis multiplex: 40–50%
    • CNS: 10–15%; medium sized vessel stroke; thickened meninges; occasional seizure from cortical encroachment of meninges
• Laboratory evaluation:
  • RF: 90–95%
  • Increased sedimentation rate: 85%
  • Decreased complement: 45%
  • ANCA: 40%
  • ANA: elevated 50%
  • Eosinophilia: 5–10%
• Pathology:
  • Necrotizing vasculitis
  • Internal hyperplasia of small vessels

Hypersensitivity Vasculitis

• Criteria:
  • Lesions are of one age
  • Involvement of small blood vessels
  • Non-granulomatous reaction
• Components of hypersensitivity vasculitis are seen in:
  • Rheumatoid arteritis
  • SLE
  • Cryoglobulinemia
• Clinical features:
  • Skin lesions predominate:
    • Purpura, urticaria, ecchymosis, papules, vesicles, necrotic ulceration
    • Lesions are symmetrical
    • Legs, ankles and feet are primarily involved
  • Renal disease is common
  • Myalgia and arthralgia may be prominent
• Pathological features:
  • Small blood vessels, arterioles, venules and capillaries are involved
  • Non-granulomatous inflammation
  • Muscle biopsy:
    • Inflammatory reaction occurs in one stage
    • Involvement of blood vessels, perimysium and endomysium
    • Immune complexes are seen in the walls of blood vessels
• Laboratory evaluation:
  • Increased sedimentation rate: 40–70%
  • RF: 15%
  • ANA elevated: 15%
  • Decreased complement (rare)

Sjögren's

• Clinical features:
  • Muscle involvement occurs in approximately 50% of patients
  • Autoimmune dysfunction of salivary and sweat glands; dry mouth, eyes and vagina
  • PNS involvement in 35% of patients; characteristic Vth nerve involvement; sensorimotor neuropathy; sensory neuropathy, mononeuritis multiplex
  • CNS (rare stroke)
  • GI: 50%
  • Glomerulonephritis: 50%
  • Lungs, spleen: involvement is rare
• Laboratory evaluation:
  • ANA positive in 90% of patients
  • SSA/RO: 60–70% of patients
  • SSB/LA: 40–60% of patients
  • RF: 60–90% of patients
  • Decreased complement: noted in greater than 50% of patients
  • Cryoglobulins: 15% of patients
  • ANCA: 10% of patients

Systemic Lupus Erythematosus

• Clinical features:
  • Proximal myopathy occurs in the setting of active generalized disease
  • CNS manifestations:
    • Seizures
    • Psychosis
    • Small vessel strokes
    • Chorea
    • Migraine
    • Emboli from verrucous endocarditis
  • PNS and systemic manifestations
    • Generalized vasculitis neuropathy; legs greater than arms
    • Mononeuritis multiplex
    • Rare cranial neuropathy; CN-II > III > VI
    • Skin: malar rash; interphalangeal rash; discoid lesions
    • Arthritis and arthralgia of small joints: 85%
    • Kidney involvement: 50%
    • Pleuritic involvement: 35%
    • h Raynaud's: 30%
    • Pericarditis with effusion: 20%
• Laboratory evaluation of antibody prevalence:
  • ANA+ > 90%
  • ds DNA: 60–70%
  • SM: 30–40%
  • RO: 25–40%
  • RF: 40%
  • ANCA: 15%

Giant Cell Arteritis

• Clinical features:
  • Occurs in patients older than 50 years of age
  • Male = female in incidence
  • Muscle involvement:
    • 50% of patients have polymyalgia rheumatica
    • Inflammatory reaction of vessels extends into muscle and adjacent connective tissue
  • Intermittent claudication of mastication
  • Visual loss: infarction of the optic nerve head (posterior ciliary arteries)
  • Perforation of the nasal septum
  • Tender palpable external carotid arteries (less than 30% of patients)
  • Head; burning scalp pain: 30–50% of patients
  • Involvement of other major arteries in 10% of patients:
    • Carotid
    • Subclavian
    • Brachial
    • Abdominal
• Laboratory evaluation:
  • Increased sedimentation rate: 70% of patients
  • ANCA rarely positive
  • Arteriogram of extend carotid system positive in 50% of patients
• Pathology:
  • Necrotizing vasculitis
  • Medium to large arteries are involved
  • Giant cells in about 50% of patients
  • Internal elastic membrane is fragmented early
  • Granulomatous infiltration of the involved artery (lymphocytes and eosinophiles)

Laboratory Differential Diagnosis of Vasculitis Affecting Muscle

• PAN:
  • Elevated sedimentation rate
  • Leukocytosis
  • Anemia
  • Dilatation and aneurysmal formation of intramedullary renal arteries
  • Aneurysmal dilatation of arteries in skin nodules
• Allergic granulomatosis/arteritis:
  • Peripheral eosinophilia
• SLE:
  • Circulating DNA (particularly when there is associated vasculitis)
• Differential diagnosis of circulating DNA:
  • Chronic hemodialysis
  • Pulmonary embolism
  • Neoplasms
  • Circulating DNA seen primarily with associated vasculitis
• Hepatitis-B antigen seen in:
  • Small and medium vessel vasculitis
  • Associated with immunoglobulin and complement and necrotizing small and medium vessel disease
• ANCA+: Wegener's disease
• SSA/RO; SSB/2A-Sjogren's disease

The Borderline of Muscle Vasculitis

• Clinical features:
  • Follows infection with group A streptococcus
  • No muscle symptoms or myalgia
• Pathology:
  • Perimysial and epimysial connective tissue infiltration
  • Mononuclear and inflammatory cells, proliferation of collagen; Aschoff giant cells in perimysium and epimysium

Polymyalgia Rheumatica (PMR)

• Clinical Features
  • Affects middle aged and elderly patients
  • Peak incidence 70–75 years of age
  • Diffuse aching and stiffness in the neck and shoulders initially
  • Later involvement of the pelvic girdle, torso and thighs
  • Minimal (secondary to pain) or no weakness
  • Associated temporal arteritis (16% of PMR patients)
  • Increased incidence of rheumatoid arthritis
  • Median duration of the disease is eleven months
  • Dramatically responsive to a small dose of steroids (5 mg of prednisone)
• Laboratory evaluation:
  • Sedimentation rate greater than 49 mm/h (during active disease)
  • Elevated immunoglobulin and fibrinogen levels

• Pathology:
• Muscle biopsy:
  • No significant pathological change
• Deep Abscesses:
  • Tropical climates
  • Young patients
  • Thighs most common site
• Intramuscular abscess:
  • From of tropical myositis
  • Small abscess with less swelling
  • Parasitic etiology
  • Nigeria (dracunculus medinensis) worm
• Burned patients
  • Pyomyositis: direct linear extension of suppuration from the surface to the muscle
  • Core of destruction contains degenerating neutrophiles surrounded by granulomatous tissue
  • Perivascular monocytes at the periphery of the lesion

Pyomyositis

• General Features:
  • Affects patients in the late stage of immunosuppression
  • Median CD4 count of 50 mm3
  • Underlying muscle disease, trauma from exercise, hematogenous spread of infection are risk factors
• Clinical Presentation:
  • Localized pain and swelling
  • Increased CK
  • Fever and leukocytosis may be minimal
  • Multiple abscesses occur

Bacterial Pyomyositis

• General Features:
  • Common in the tropics
  • Organisms:
    • Staphylococcus aureus (90%)
    • A and B hemolytic streptococci
    • Escherichia coli
    • Streptococcus pneumonia
    • Yersinia
    • Legionella
    • Neisseria gonoccous
    • Staphylococcus epidermitis
    • Proteus mirabilis
    • Pseudomonas
    • Salmonella
    • Bacteroides
  • Risk factors:
    • Local trauma
    • HIV infection
    • IV drug abuse
    • Steroids
    • Diabetes mellitus
• Clinical presentation:
  • Most common areas of involvement are the quadriceps, deltoids and gluteal muscles
  • Paraspinal involvement presents with back pain
  • Group A and B-hemolytic streptococci pyomyositis may be associated with septicemia; also abscess of muscle
  • Clostridial myositis:
    • Most lethal
    • Clostridium perfringens is most common organism
    • Incubation period is 2–4 days
    • Acute onset of edema and local tenderness; later a serosanguineous discharge, blebs and green-black cutaneous necrosis; crepitus of the involved tissue
    • High fever followed by DIC in severe cases
• Laboratory evaluation:
  • Neutrophilic pleocytosis
  • Elevated ESR
  • Serum CK is usually mildly elevated

Orbital Myositis (Orbital Pseudotumor)

• Clinical presentation:
  • Inflammation of some or all of the orbital structures
  • Acute onset of unilateral periorbital pain
  • Diplopia
  • Swelling of the eyelid
  • Chemosis and conjunctival infection adjacent to the insertion of the extraocular muscles
  • Ptosis
  • Both orbits are involved seriatim; involvement may be weeks apart
  • Patients may have symptomatic complaints:
    • Headache
    • Fever
    • Vomiting
    • Anorexia
    • Pharyngitis
    • Abdominal pain
    • Lethargy
  • Iritis is common (severe photophobia)
  • Papilledema in approximately 40% of patients
  • Precipitating event:
    • Upper respiratory illness
    • Streptococcal pharyngitis
  • Excellent response to steroids
• Laboratory evaluation:
  • CT or MRI findings of enlargement of a single or multiple muscles
  • Specific radiologic characteristics:
    • Involvement of the tendon (insertion on the globe)
    • Enhancement of the sclera and Tenon's capsule
    • Irregular enlargement of the muscle
    • Extension of the inflammation to the orbital fat
    • No bone involvement
    • ESR elevated during the acute stage
    • Eosinophilia and antinuclear antibodies are occasionally noted
• Pathology:
  • Lymphocytes, plasma cells and eosinophils are the muscular inflammatory infiltrate
• Differential Diagnosis:
  • Grave's Disease
  • Tumor infiltration
  • Orbital myositis
  • Carotid cavernous fistula
  • AVM
  • Parasellar mass (compresses venous outflow from the orbit)

Grave's Disease

• Inferior rectus may enlarge first; collier's sign (pathologic lid retraction; early)
  • May be unilateral

Tumor Infiltration

• Lymphoma-superior rectus muscle involved first
• Rhabdomyosarcoma (underlying tuberous sclerosis)
• Metastatic:
  • Breast cancer; scirrhous from pulls the eye in
  • Small cell cancer of the lung
  • Melanoma
• Usually a separate lesion that compresses or enlarges the muscle

Carotid Cavernous Fistula

• Traumatic precipitating cause
• Arterialized con junctural veins that reach the iris (in an infection, veins do not reach the iris)
• Bruit over the orbit
• Enlargement of the superior or inferior ophthalmic vein on MRV

AVM

• Chemosis
• Proptosis
• Partial ophthalmoplegia
• Arterialized venous blood on the sclera

Parasellar Mass

• Cranial nerve involvement (III or IV)
• May involve optic nerve and chiasm

Infection (Bacteria, Fungi, Parasites)

• Bacteria:
  • Gain access to the orbit through the lamina papyracea of the medial wall of the ethmoid sinus
  • Severe orbital and periorbital edema and pain
• Fungus:
  • Mucormycosis (Rhizopus):
    • Immunosuppressed patient
    • Ophthalmoparesis
    • Venous sinus occlusion (black palate-occlusion of sigmoid and jugular sinuses)

Wegener's Granulomatosis

• Acute orbital pain
• Ocular pareses
• Destruction of the sinuses and the nasopharynx

Pseudothrombophlebitis Syndrome Affecting Muscle

• Mimics signs and symptoms of deep vein thrombophlebitis
• Clinical features:
  • Swelling; warmth and tenderness of the calf
  • Positive Homan's sign
  • Pedal edema
  • Popliteal mass
• Etiology is popliteal synovial cyst:
  • Ruptured or has dissected into the calf
  • Associated with inflammatory joint disease
  • Rupture precipitated by exercise or knee injury
  • Rule out localized polymyositis