CHAPTER THIRTEEN
MYOPATHOLOGY

INFLAMMATORY MYOPATHIES

Inflammatory myopathies are characterized pathologically by myonecrosis and mononuclear inflammatory infiltrates and clinically by weakness and soreness of muscles and elevated CK and erythrocyte sedimentation rate. The main inflammatory myopathies are polymyositis, dermatomyositis, and inclusion body myositis.

Polymyositis	Lymphocyte in myofiber

Polymyositis affects predominantly adults who present with subacute or chronic proximal weakness (without a rash) and elevated CK. The muscle biopsy shows endomysial mononuclear cells and myonecrosis. Polymyositis is a cell-mediated autoimmune disorder in which cytotoxic (CD8-positive) lymphocytes and macrophages invade and destroy myofibers expressing MHC-I antigens. The inflammatory cells are in the endomysium (between and around individual myofibers.) Inflammation may be focal and the MRI is useful in identifying affected areas for biopsy.

Dermatomyositis affects children and adults. It causes a purple (heliotrope) discolorarion of the upper eyelids, edema around the eyes and mouth, facial erythema, erythematous scaly papules over the knuckles and elbows (Gottron’s sign), muscle pain, weakness, and stiffness of muscles. Contractures, subcutaneous calcification, intestinal ulceration, and other extramuscular manifestations are frequent in children.

Dermatomyositis	Necrotic capillary	Tubuloreticular inclusion

TThe pathology of dermatomyositis includes inflammation, vasculitis, and perifascicular atrophy. The inflammatory cells are predominantly B-cells (with smaller numbers of CD4-positive T-cells) and are found around blood vessels, in the septa between muscle fascicles, and in fibroadipose tissue around muscle. The key pathological change of dermatomyositis is a vasculitis, which involves endomysial and perimysial capillaries and arterioles. This vasculitis begins with endothelial swelling and is followed by endothelial necrosis and capillary loss. Tubuloreticular cytoplasmic inclusions are often seen in endothelial cells. Similar inclusions are seen in lupus and other collagen vascular diseases. The vasculitis is thought to be caused by circulating anti-endothelial antibodies. Interaction of these antibodies with vascular antigens activates complement, leading to formation of the membranolytic attack complex (MAC), which destroys endothelial cells.

Perifascicular atrophy

A distinctive feature of dermatomyositis is atrophy and degeneration of myofibers at the periphery of fascicles (perifascicular atrophy), which occurs even in absence of inflammation. It has been proposed that perifascicular atrophy is caused by ischemia from loss of the endomysial capillary bed. This affects more severely the distal portion of the vascular field, which is the periphery of each fascicle. In support of this hypothesis, ischemic infarction of muscle is seen in some cases of dermatomyositis. Recent evidence indicates that the CD4-positive cells in dermatomyositis are plasmacytoid dendritic cells. These cells secrete type 1 interferons, which induce genes and molecular cascades that cause muscle injury. A key interferon-induced pathology is deficiency of titin, an intramuscular protein that is a scaffold for contractile filaments.

Dermatomyositis and polymyositis (and less frequently inclusion body myositis) are associated with scleroderma, mixed connective tissue disease, and cancer. The association with cancer is stronger with dermatomyositis. Patients with polymyositis and dermatomyositis may also have cardiac involvement leading to arrhythmia and heart failure, arthralgia, Raynaud’s phenomenon, interstitial pneumonitis, and renal involvement. Some of these extra-muscular manifestations are associated with circulating antibodies to anti-Jo-1 (an anti tRNA synthetase) autoantibodies.

Mixed CTD

The muscle biopsy in systemic lupus erythematosus and other connective tissue diseases (CTD) shows most often interstitial perivascular mononuclear infiltrates without vascular injury or myonecrosis. In some patients, however, manifestations of CTD overlap with inflammatory myopathy. This combination has been called mixed CTD, undifferentiated CTD, diffuse CTD, the overlap syndrome, and systemic rheumatic disease. Patients with mixed CTD have muscle pathology that closely resembles dermatomyositis. The inflammation of polymyositis, dermatomyositis, and collagen vascular disease subsides rapidly with corticosteroids, so the biopsy should be done before treatment is started.

Inclusion body myositis	Inclusion body myositis

Sporadic inclusion body myositis (IBM) is the most common muscle disease in old people. It causes progressive proximal and distal weakness with mild CK elevation. The pathological changes of IBM are highly characteristic. Light microscopy shows myofibers with vacuoles or cracks some of which are lined by basophilic granules. These are best seen in cryostat sections stained with modified Gomori trichrome. By electron microscopy, the abnormal fibers contain paired helical filaments similar to those of Alzheimer's disease, straight filaments, myelinoid membranous bodies, increased glycogen, and abnormal mitochondria. The filamentous inclusions of IBM have the optical properties of amyloid and contain beta amyloid, hyperphosphorylated tau protein, apolipoprotein E, presenillin 1, prion protein, and other proteins. Some of these are the same proteins that accumulate in the brain in Alzheimer's disease. The inflamatory component of IBM consists of cytotoxic T cells and macrophages, similar to polymyositis. The pathogenesis of IBM is not known but probably involves ageing of myofibers, oxidative damage, and an unknown trigger that initiates inflammation. There are hereditary myopathies with similar myofiber changes but without inflammation.

The diagnosis of PM, DM, and IBM should be based on the biopsy findings. PM and DM are treated with corticosteroids. Azathioprine , methotrexate, and cyclosporin are used in severe cases. IBM is refractory to corticosteroids and immunosuppressive agents.

MYASTHENIA GRAVIS

Myasthenia gravis is an autoimmune muscle disease characterized by progressively increasing weakness with exertion and recovery of strength with rest or following administration of anticholinesterase drugs such as neostigmine. Weakness affects most severely muscles that are innervated by brain stem nuclei, such as extraocular and facial muscles, and causes drooping of the eyelids, diplopia, and inability to chew. Death is due to respiratory compromise. Pathologically, the muscle is either normal or shows myofiber atrophy and aggregates of lymphocytes in the endomysium. In severe cases, there may be myonecrosis. Electron microscopy shows abnormal motor end plates. Axon terminals are normal and the number of synaptic vesicles is adequate, but there is loss of post-synaptic membrane such that the post-synaptic region is simplified, showing a few wide folds without branching. The primary synaptic cleft is widened. Ten percent of patients with myasthenia gravis, especially older males, have thymomas, and most other patients have follicular hyperplasia of the thymus.

Myasthenia gravis is caused by antibodies to the acetylcholine receptor (AChR) protein. Circulating IgG antibodies bind with the AChR and prevent acetylcholine from reacting with it. These antibodies also cause degradation of AChR and lysis of post-synaptic membranes. Improvement of strength following administration of edrophonium (Tensilon test) or neostigmine are diagnostic. Treatment consists of anticholinesterase drugs, corticosteroids and thymectomy.

Further reading

Dalakas M. Polymyositis and dermatomyositis. Lancet 2003; 362:971-82.PubMed

Mammen AL. Dermatomyositis and polymyositis. Clinical presentation, autoantibodies, and pathogenesis. Ann NY Acad Sci 2010; 1184:134-153. PubMed

Salajegheh M, Kong SW, Pinkus JL, et al. Interferon-Stimulated Gene 15 (ISG15) Conjugates Proteins in Dermatomyositis Muscle with Perifascicular atrophy. Ann Neurol 2010;67:53-63. PubMed

Updated April, 2010