Skeletal Muscle Diseases

Depends on the specific disease process

Myopathies usually present with the following:

• Proximal muscle weakness, usually symmetric

• Malaise and fatigue

• No sensory complaints or paresthesias

• Atrophy and hyporeflexia are late findings

• Serum creatine kinase (CK) levels are usually elevated

• Electromyography (EMG) shows “myopathic” changes

Neurogenic muscle disorders present with the following:

• Usually distal muscle weakness

• Sensory complaints and paresthesias

• Atrophy and hyporeflexia early in the disease course

• Serum CK levels are usually normal

• Electromyography shows “neurogenic” changes

Depends on the specific disease process

There are no specific imaging findings that help differentiate between myopathic and neurogenic muscle changes

Myopathic features include the following:

• Variability in fiber size and shape with rounded myofibers

• Large and small myofibers are randomly and diffusely distributed

• Type 1 fiber predominance

• Increased internal nuclei (more than 3%) and nuclear chains

• Myofiber necrosis (pale staining or hyaline fiber) and phagocytosis

• Regenerating (basophilic) myofibers

• Fiber splitting

• Increased endomysial connective tissue and deposition of adipose tissue

• Endomysial, perimysial, or perivascular infiltrates of T lymphocytes and macrophages are prominent in some myopathies

• Myofibrillar architectural changes such as moth-eaten fibers, ring fibers, lobulated and whorled fibers

• Sarcoplasmic inclusions and vacuoles are characteristic of some myopathies

Neurogenic features include the following:

• Variability in myofiber size and shape with angulated fibers

• Two populations of myofibers are seen in denervated muscle: atrophic fibers (denervated) and normal or hypertrophied fibers

• Atrophic fibers are generally clustered in groups (small group atrophy)

• Large group atrophy occurs when an entire fascicle becomes atrophic

• Fiber type grouping (groups of both types have to be identified in the biopsy)

• Hypertrophic myofibers are usually type 1

• Atrophic angulated myofibers are of both types

• Pyknotic nuclear clumps

• Atrophic angulated myofibers stain intensely with oxidative stains

• Myofiber architectural changes including target fibers and targetoid fibers

Oxidative enzymes such as NADH-TR highlight myofiber architectural changes in both myopathic and neurogenic muscle

Specific immunostudies (inflammatory stains, sarcolemmal proteins) depending on the histologic features and clinical impression

Myopathic changes are seen in a wide range of acquired and inherited disorders including inflammatory myopathies, metabolic disorders, muscular dystrophies, and toxic exposure, among others

Neurogenic changes are seen in numerous inherited and acquired clinical disorders caused by defects in upper or lower motor neurons or the peripheral nerve including, but not limited to, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), hereditary motor and sensory neuropathies (HMSN), and inflammatory peripheral neuropathies

Rare disease with an estimated incidence of 9.63 cases per million people

More common in women (women-to-men ratio of 2 : 1)

Adult-onset dermatomyositis has peak onset age of 50 years

Juvenile dermatomyositis affects children, usually between 5 and 10 years

Heliotrope (violaceous) skin rash over the upper eyelids

• Skin findings usually antedate muscle manifestations

Groton papules or scaly erythematous eruptions over the extensor surfaces of the knuckles, elbows, or knees

Progressive symmetric proximal limb muscle weakness with insidious onset, myalgia, tenderness, and dysphagia

• Neuromuscular symptoms similar to polymyositis

Involvement of organ systems such as the lung, heart, and kidneys may occur

Strong association with the development of malignancies

Juvenile dermatomyositis

Variable muscle weakness

Associated with general symptoms of malaise, fever, lethargy

Calcinosis in chronic cases

Laboratory abnormalities include increased serum creatine kinase (CK) usually 5 to 50 times the reference range, increased serum aldolase, increased erythrocyte sedimentation rate (ESR), and myoglobulinuria

Antibodies may be detected in the serum, including antinuclear antibodies (ANA), myositis-specific antibodies, and anti-RNA antibodies such as Jo-1 and Mi-2 antibodies

Electromyography (EMG) reveals a combination of spontaneous fibrillation potentials, positive sharp waves, and polyphasic, short duration potentials on voluntary contractions indicative of irritable myopathy

Muscle disease responds to corticosteroid therapy

Other immunosuppressive agents (azathioprine, cyclophosphamide, cyclosporine) may be used in patients unresponsive to corticosteroids and to treat skin disease

Prognosis is generally favorable; however, recovery may be slow and incomplete

MRI findings are nonspecific and reveal increased signals in areas of edema and inflammation

May be used to select the site of biopsy

Perifascicular myofiber atrophy

Inflammation is focal and predominantly perivascular and perimysial

Inflammatory infiltrates are composed predominantly of macrophages, B cells, and CD4+ T lymphocytes

Decreased capillary density especially in the perifascicular region, which may lead to myofiber infarction

Electron microscopy reveals tubuloreticular inclusions in endothelial cells of intramuscular arterioles and capillaries

Humoral mediated immune reaction against capillaries with activation of complement, deposition of C5b-9, lysis of endothelial cells, and loss of capillaries with resulting ischemia

Immunostudies demonstrate a predominance of B cells and CD4+ cells (both T lymphocytes and dendritic cells) in the inflammatory infiltrate

Deposition of the membrane attack complex of complement (C5b-9) in capillaries is an early event

Aberrant sarcolemmal expression of major histocompatibility complex I (MHC-I) may be seen, especially in the perifascicular region

Connective tissue disorders with muscle and skin involvement such as systemic lupus erythematosus

Rare disease with an incidence of 0.5 to 8.4 cases per million people

More common in women (women-to-men ratio of 2 : 1)

Peak incidence between 45 and 60 years; it rarely affects children

Progressive symmetric proximal limb muscle weakness with insidious onset

Myalgia and tenderness may be present

Dysphagia is present in one third of patients

Extraocular muscles are usually spared

Involvement of organ systems such as the lung, heart, and kidneys is uncommon

Laboratory abnormalities include increased serum creatine kinase (CK) usually 5 to 50 times the reference range, increased serum aldolase, increased erythrocyte sedimentation rate (ESR), and myoglobulinuria

In some cases, antibodies may be detected in the serum, including antinuclear antibodies (ANA), myositis-specific antibodies, and anti-RNA antibodies such as Jo-1 and signal recognition particle (SNP) antibodies

Electromyography (EMG) reveals a combination of spontaneous fibrillation potentials, positive sharp waves, and polyphasic, short duration potentials on voluntary contractions indicative of irritable myopathy

Polymyositis may be associated with other connective tissue diseases

Majority of cases respond to corticosteroid therapy

Other immunosuppressive agents (azathioprine, cyclophosphamide, cyclosporine) may be used in patients unresponsive to corticosteroids

Prognosis is generally favorable; however, recovery may be slow and incomplete

MRI findings are nonspecific and reveal increased signals in areas of edema and inflammation

May be used to select the site of biopsy

Myopathic features

Evidence of myofiber necrosis, phagocytosis, and regeneration

Prominent endomysial inflammatory infiltrates composed predominantly of T lymphocytes and macrophages

T lymphocytes also surround and invade non-necrotic myofibers

Inflammatory infiltrates can be small and multifocal

Evidence suggests an antigen-directed and MHC-I restricted cytotoxicity mediated by CD8+ T cells

Immunohistochemical studies for CD3 (T lymphocytes) and CD68 (macrophages) are useful for identification and localization of inflammatory cells

CD8+ T lymphocytes predominate

Major histocompatibility complex I (MHC-I) is abnormally up-regulated on the sarcoplasm of myofibers even in areas devoid of inflammation

Inclusion body myositis

Limb-girdle muscular dystrophy

Toxic or drug-induced myopathies (alcohol, statins)

Accounts for 16% to 28% of inflammatory myopathies in North America

Affects individuals older than 50 years (mean age of onset is 56 to 60 years)

Men are more commonly affected than women (ratio of 3 : 1)

Hereditary inclusion body myopathies:

• Hereditary group of disorders characterized by progressive muscle weakness

• Most are of late onset, but congenital and childhood forms have been described

• Muscle biopsy reveals rimmed vacuoles with accumulation of the same proteins as in sporadic inclusion body myositis but no inflammatory infiltrate

• Several genetic defects have been identified

Insidious onset of proximal leg and distal arm weakness with marked asymmetry

Dysphagia is present in a majority of patients

May be associated with autoimmune disorders (systemic lupus erythematosus [SLE], Sjögren syndrome, and sarcoidosis, among others)

Strong association to MHC antigens HLA-DR3, DR52, and B8

Serum creatine kinase (CK) may be normal or elevated (up to 10 times the upper normal limit)

Myositis-associated autoantibodies are usually not found

Electromyography (EMG) reveals increased insertional activity and short duration polyphasic motor unit potentials

Nerve conduction studies are consistent with superimposed peripheral neuropathy

Refractory to immunosuppressive therapy

Prognosis is that of slow progression to disability

MRI is of limited diagnostic value

Myopathic features

Small angulated myofibers may be scattered through the biopsy or in clusters

Endomysial mononuclear cell inflammatory infiltrate with invasion of non-necrotic myofibers

Gomori trichrome stain reveals rimmed vacuoles and ragged-red areas

Intracellular amyloid deposits (Congo red positive)

Eosinophilic intracytoplasmic inclusions

Occasional cytochrome oxidase (COX) negative fibers

Electron microscopy reveals 15- to 21-nm tubulofilaments in the sarcoplasm and structurally abnormal mitochondria

Inflammatory infiltrate is predominantly composed of CD8+ T lymphocytes

MHC-I expression in the sarcolemma

The vacuoles may be immunoreactive for β-amyloid, β-amyloid precursor protein, ubiquitin, α-synuclein, phosphorylated tau, TDP-43, and prion protein, among others

Unknown

Immune-mediated causes and degenerative processes have been proposed

Polymyositis

Amyotrophic lateral sclerosis (ALS)

Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy

Prevalence of 1 in 3500 live male births worldwide (63 cases per million)

Becker muscular dystrophy (BMD) has a prevalence of approximately 24 cases per million

Almost exclusively affects males because of X-linked inheritance pattern