JPC Masticatory Myositis

JPC SYSTEMIC PATHOLOGY

MUSCULOSKELETAL SYSTEM

March 2019

M-M12

 

Signalment (Slide A, JPC# 75-36): 3-year-old German shepherd dog

 

HISTORY: This dog had a two week history of hematuria, bilateral exophthalmos, conjunctivitis, and protrusion of the nictitating membranes.

 

HISTOPATHOLOGIC DESCRIPTION: Skeletal muscle: Multifocally expanding the epimysium, perimysium, and endomysium and separating, surrounding and replacing myocytes there are numerous eosinophils and plasma cells with fewer lymphocytes and macrophages, which are often perivascular, admixed with bands of fibrous connective tissue. Myocytes exhibit polyphasic degenerative and necrotic changes characterized by: a pale, swollen, and vacuolated sarcoplasm with disrupted myofibrils (degeneration); a hypereosinophilic, shrunken, and fragmented or hyalinyzed sarcoplasm with loss of cross striations, and a pyknotic or karyorrhectic nucleus (necrosis); or a lightly basophilic sarcoplasm and multiple internalized, linearly arranged, vesiculate nuclei with prominent nucleoli (regeneration). There is multifocal hemorrhage, edema, and few hemosiderin-laden macrophages and vessels are lined by hypertrophic (reactive) endothelial cells.

 

MORPHOLOGIC DIAGNOSIS: Skeletal muscle: Myositis, eosinophilic, lymphoplasmacytic and histiocytic, chronic, multifocal and polyphasic, marked, with myofiber degeneration, necrosis, loss, and regeneration, German shepherd dog, canine.

 

ETIOLOGIC DIAGNOSIS: Immune-mediated myositis

 

CONDITION: Masticatory myositis

 

SYNONYMS: Eosinophilic myositis, atrophic myositis (now grouped together as masticatory myositis)

 

Signalment (Slide B, JPC# 75-37): 18-month-old heifer

 

HISTORY: None

 

HISTOPATHOLOGIC DESCRIPTION: Skeletal muscle: Diffusely infiltrating and markedly expanding the epimysium, perimysium and endomysium and separating, surrounding, replacing, and resulting in fragmentation of myofibers are large numbers of eosinophils, fewer macrophages, and rare lymphocytes, which are often perivascular, admixed with bands of fibrous connective tissue. There is diffuse atrophy of myofibers and multifocally myocytes exhibit polyphasic degeneration and necrosis characterized by: a pale, swollen, and vacuolated sarcoplasm (degeneration) or a hypereosinophilic, shrunken, hyalinyzed and fragmented sarcoplasm with loss of cross striations, and a pyknotic or karyorrhectic nucleus (necrosis). Multifocally macrophages infiltrate individual necrotic myofibers. Multifocal myocytes are expanded by protozoal cysts up to 30-50 um in diameter that contain many basophilic, oval to crescent-shaped 1 X 3 um zoites. Vessels are lined by hypertrophic (reactive) endothelial cells. Multifocally edema expands the tunica media and perivascular areas of vessels within areas of inflammation. Within one focal area, myofibers are replaced by mature adipocytes.

 

MORPHOLOGIC DIAGNOSIS: Skeletal muscle: Myositis, eosinophilic and lymphocytic, chronic-active, diffuse, marked, with myofiber atrophy, degeneration, necrosis, loss and replacement with adipose tissue, and multiple intracellular sarcocysts, breed unspecified, bovine.

 

ETIOLOGIC DIAGNOSIS: Sarcocystic myositis

 

CAUSE: Sarcocystis sp.

 

CONDITION: Eosinophilic myositis

 

GENERAL DISCUSSION:

·      Eosinophilic myositis and Immune mediated myositis are two separate conditions with different etiologies and effecting a different spectrum of species, but which may have in common eosinophil infiltration and myofiber degeneration/necrosis in skeletal and/or cardiac muscle; immune mediated conditions will also have a lymphocytic component

Immune-mediated myositis:

·      Includes masticatory myositis of dogs and polymyositis in dogs

·      Muscle damage can be due to any of the following:

·      Circulating antibodies which target muscle cell components

·      Cytotoxic T lymphocytes which attack muscle cells

·      Immune-complex deposition leading to inflammation and ischemia of involved muscle fibers

·      Interstitial and perivascular lymphocytes and/or plasma cells

·      Must prove that cellular infiltrates are directly causing myofiber necrosis and did not migrate in secondary to primary muscle damage

·      Hallmark of primary myositis = mononuclear leukocytic cells invading intact muscle fibers (can be surrounding them or within them leaving a “cored out” appearance)

·      One of the main differentials is malignant lymphoma

Canine:

·      Masticatory myositis is an immune-mediated myopathy; causes progressive destruction of masticatory muscles (masseter, temporal, pterygoid) leading to fixation of the jaw

·      Auto-antibodies form against type 2M myosin, an isoform unique to the masticatory muscles in dogs

·      Recent research suggests that autoantibodies recognize a novel member of the myosin binding protein-C family (mMyBP-C), a single 150 kDa protein present within the muscle fiber and associated with the sarcolemma

·      Dogs with polymyositis most often do not have antibodies to 2M myosin

·      Previously designated as separate disorders, eosinophilic myositis and atrophic myositis are considered two ends of the spectrum of a single disease (masticatory myositis):

·      Eosinophilic myositis in the early end of the spectrum; eosinophils prominently infiltrate between individual myocytes

·      Atrophic myositis is the end result of prominent atrophy of the temporal and masseter muscles

·      Disorder occurs in many breeds; German shepherd dogs appear predisposed

 

Cattle and sheep:

·      Sarcocystis spp. are protozoal parasites of muscle which are similar to coccidia except they have to develop in 2 different hosts

·      Sexual stages in predators

·      Asexual stages in prey

·      Relatively rare condition in cattle and sheep < 2 years of age

·      Lesions usually identified at time of slaughter within skeletal muscle and myocardium; sudden deaths in both species has been ascribed to the myocarditis

·      May be caused by degeneration of Sarcocystis spp.; however, in some cases no degenerating parasites can be found

·      Thought to be an uncommon manifestation of Sarcocystis infection that may involve hypersensitivity

 

PATHOGENESIS:

Canine:

·      Bacterial infections leads to immune system recognition of endogenous antigens > antibodies form against type 2M myosin > inflammatory myopathy confined to temporalis and masseter muscles > bilaterally symmetric swelling of muscles of mastication > ischemia > necrosis and atrophy

·      If present, eosinophils will always be admixed with lymphocytes; lymphocytes are the primary inflammatory cell causing destruction of myofibers; there is a mixture of B and T lymphocytes with more CD4+ T cells than CD8+ T cells

·      Basal lamina is frequently damaged; although myocytes attempt to regenerate, healing by fibrosis is common

 

Cattle and sheep:

·      Life cycle of Sarcocystis spp.: sporocysts ingested by herbivore > sporozoites are released > invade tissues > 1-2 generations of schizogony within endothelial cells > schizonts develop within striated muscle as cysts containing metrocytes > divide to form bradyzoites > muscle is eaten by predator > sexual cycle in their intestines

·      Pathogenesis is unclear; eosinophilic inflammatory reaction possibly stimulated by parasite cyst rupture, and IgE resulting in eosinophil degranulation which causes damage to myofibers

·      Usually Sarcocytis cysts are incidental findings

·      Clinical disease occurs in intermediate hosts at either developmental stage:

·      occurs in intermediate hosts at either developmental stage:

§  Schizogonous (parasitemic) stage: fever, petechiation, edema, icterus, macrocytic hypochromic anemia (several episodes of intravascular coagulation); called “Dalmeny disease” in some animal species

§  Schizonts enter muscle at around 40 days after infection: there is extensive degeneration of myofibers and histiocytic and plasmacytic inflammation

TYPICAL CLINICAL FINDINGS:

Canine:

·      Acute: Bilaterally symmetrical swelling of, and pain in the temporalis and masseter muscles; inability to fully open jaws (trismus); possible difficulty prehending food

·      Chronic or insidious cases: progressive condition if not treated; bilaterally symmetric atrophy of the temporal and masseter muscles and decreased jaw mobility; pain may not be evident; concentric EMG often reveals foci of spontaneous activity, but may be normal, with normal velocity conduction

·      Can lead to permanent inability to fully open the jaw

·      Clinical pathology: Serum CK and AST are normal or only mildly elevated; moderate eosinophilia (10-40%); ALT may be elevated with significant muscle necrosis

 

Cattle and sheep:

·      Uncommon: Massive infection with Sarcocystic spp. may result in fever, anorexia and progressive wasting; sudden death possible from myocarditis, but usually asymptomatic

 

TYPICAL GROSS FINDINGS:

Canine:

·      Acute: Muscles are swollen, dark red, and doughy or hard; cut surface reveals hemorrhagic streaks and irregular, yellow-white patches

·      Chronic: Muscular atrophy and fibrosis; face has a “fox like” appearance from prominent zygomatic arches

 

Cattle and sheep:

·      Well-demarcated, green focal stripes or patches, which fade to off-white when exposed to air; may involve any muscle (including cardiac muscle)

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

Canine:

·      Multifocal and polyphasic necrosis; inflammatory infiltrates are interstitial and often perivascular

·      Predominant inflammatory cell type may vary; typically eosinophils and lymphocytes predominant – number of eosinophils variable, but always present with lymphocytes; may have numerous plasma cells; macrophages are present

·      Lymphocytes are a mix of T and B cells with more CD4+ T cells than CD8+ T cells (distinguishes from polymyositis which is more CD8+ cells)

·      Myofiber degeneration +/- regeneration, even without obvious inflammation, in light of consistent clinical history is suspicious for myositis

·      Fibrosis of the endomysium and perimysium

 

Cattle and sheep:

·      Combination of acute and chronic fibrous reactions

·      Large numbers of eosinophils separating endomysial sheaths and perimysial trabeculae

·      Sarcocystic remnants often in the center of lesions

·      Variable and sometimes absent muscle fiber degeneration

·      Lymphocytes, plasma cells, and histiocytes in chronic lesions; may look like a granuloma (central area of necrosis with degranulating eosinophils surrounded by epithelioid macrophages, multinucleated giant cells, and fibrous connective tissue), especially in young sheep

 

ADDTIONAL DIAGNOSTIC TESTS:

·      Serology for anti-type 2M myosin antibodies

·      Electromyography (EMG)

 

DIFFERENTIAL DIAGNOSIS:

Atrophy of muscles of mastication in dogs:

·      Polymyositis:

·      Common immune-mediated myopathy in dogs;

·      Do NOT have serum antibodies to 2M myosin - muscle fiber damaged mediated by CD8+ cytotoxic or suppressor T lymphocytes

·      Not limited to muscles of mastication - also affects diaphragm and esophagus leading to respiratory distress and esophageal fibrosis, dysfunction and megaesophagus, respectively

§  May occur with systemic lupus erythematosus (positive ANA titer)

§  May occur as a paraneoplastic disease with thymoma

·      Affects adult dogs of various breeds - German shepherd dogs and Newfoundlands (breed associated) are predisposed

·      Clinical signs are variable - may be bilateral; typically painful with deep palpation

·      Also is multifocal and polyphasic with interstitial and perivascular lymphocytic infiltrates (cytotoxic CD8+ T cells) and invasion of otherwise intact skeletal muscle

·      Regenerating fibers and eosinophils also commonly seen

·      X-linked muscular dystrophy: causes reduced jaw mobility, exercise intolerance, and a stiff-legged gait; clinical signs of neuromuscular weakness start around 8 weeks of age, progress until 12 months of age, when the disease tends to stabilizes; bilateral, non-painful to open jaw; best characterized in the golden retriever

·      Extraocular muscle myositis: Immune-mediated attack directed specifically at the extraocular muscles (rectus and oblique muscles); dogs are less than 2 years; Golden Retriever dogs appear predisposed

·      Present with acute bilateral nonpainful exophthalmos

·      Multifocal and polyphasic; interstitial lymphocytic inflammatory infiltrates causing myofiber necrosis and regeneration

·      Familial canine dermatomyositis of collies and shelties: Immune-mediated disease affecting cutaneous tissues, with subsequent muscle atrophy; especially head, esophagus and distal extremities; cell-poor vasculitis; circulating immune complexes and increased IgG levels; unilateral; non-painful

·      Denervation atrophy: Loss of connection with peripheral nerves cause rapid and severe atrophy; involves type 1 and type 2 fibers, although type 2 fibers are preferential affected; typically unilateral; non-painful

·      Pembroke Welsh Corgis in Japan have an inflammatory myopathy of the tongue leading to atrophy; histologically is severe myofiber atrophy with infiltration of fat and fibrosis; predominately B lymphocytes and macrophages; NO antibodies to 2M fibers

Infectious myositis:

·      Protozoa: Trichinella spiralis, Neospora caninum, Toxoplasma gondii, Hepatozoon canis, H. americanum, and Leishmania infantum

·      Larval Cestodes: Cysticercosis, hydatid disease, and coenuriasis

·      Bacteria/Rickettsia: Clostridium sp., Leptospira australis, L. icterohaemorrhagiae, and Ehrlichia canis (during acute phase of disease)

Granulomatous myositis in cattle:

·      Hairy vetch

·      Citrus pulp

 

COMPARATIVE PATHOLOGY:

·      Immune-mediated myositis:

·      Dogs: A bilateral extraocular muscle myositis is also described in dogs with lymphocyte infiltrates and a polyphasic pattern of degeneration/necrosis

·      Horses:

§  Exertional and postanesthestic myopathies: degenerative and not primary inflammatory myopathies

§  Immune complex disease from Streptococcus equi-associated purpura hemorrhagica:

·      Increased serum CK and AST

·      Hemorrhagic infarcts of affected muscles; fibrinoid necrosis of vessel walls and vasculitis

·      Infarcts in other organs; can culture Streptococcus equi from the guttural pouch or lymph nodes

·      Immune complexes composed of IgA and streptococcal M protein

·      Mink get similar immune-mediated myositis as dogs

·      Cats:

§  Most reported cases of polymyositis are actually degenerative polymyopathy due to hypokalemia

·      Sarcocytis spp. affecting domestic animals:

·      Horses:

§  Sarcocystis fayeri and S. bertrami (S. equicanis)

·      Both complete life cycle in the dog

·      The tongue is a common site for parasitic cysts; can result in eosinophilic glossitis with necrosis

·      Cattle:

§  Sarcocystis cruzi: life cycle completed in domestic and wild canids

·      Only one which causes significant disease in cattle

·      Clinical signs: hemolysis (during schizogonous stage); debilitation, abortion, drooling, lymphadenitis, sloughing of the tip of the tail, and possibly death

§  Sarcocystis hirsuta: life cycle completed in cats

§  Sarcocytis hominis: life cycle completed in people

·      Water buffalo:

§  Sarcocystis fusiformis: life cycle completed in cats

§  Sarcocystis levinei: life cycle completed in dogs

·      Sheep:

§  Sarcocystis tenella (S. ovicanis) and S. arieticanis: sheep-dog cycle

·      S. tenella is very virulent; lots of cysts in muscle

§  Sarcocystis gigantea and S. medusiformis: sheep-cat cycle

·      S. gigantea has very large cysts in the esophagus (adventitial surface)

§  Sarcocystis capricanis and S. hericanis: goat-dog cycle

§  Sarcocystis moulei: goat-cat cycle

·      Goats: none are naturally infective

·      Swine:

§  Sarcocystis miescheriana: pig-dog cycle

·      Only one to produce clinical signs – diarrhea, myositis, lameness

§  Sarcocytis porcifelis: pig-cat cycle

§  Sarcocystis suihominis: completes cycle in people

·      Dog and cat:

§  Rarely cause lesions in muscle, but can cause severe myositis

§  Microscopically there are often schizonts in endothelial cells which cause little inflammation and no evidence of endothelial cell damage

 

REFERENCES:

1.    Cooper BJ, Valentine BA. Muscle and tendon. In: Maxie MG, ed. Jubb Kennedy Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier; 2016: 226-227, 234-237.

2.    Cray MT, Spector DI, West CL. Acute masticatory muscle compartmental syndrome in a dog. J Am Vet Med Assoc. 2018; 253(5):606-610.

3.    Evans J, Levesque D, Shelton GD. Canine inflammatory myopathies: A clinicopathologic review of 200 cases. J Vet Intern Med. 2004; 18:679-691.

4.    Gardiner CH, Fayer R, Dubey JP. An Atlas of Protozoan Parasites in Animal Tissues. 2nd ed. Washington, DC: Armed Forces Institute of Pathology; 1998: 41-46.

5.    Herd HR, Sula MM, Starkey LA, et al. Sarcocystis fayeri-induced granulomatous and eosinophilic myositis in 2 related horses. Vet Pathol. 2015; 52(6):1191-1194.

6.    Kent M, Glass EN, Castro FA, Miller AD, de Lahunta A. Masticatory muscle myositis in a gray wolf (Canis lupus). J Zoo Wildl Med. 2017; 48(1):245-249.

7.    Needle DB, Hollinger C, Shelton GD, Fitzgerald SD. Necrotizing and eosinophilic masticatory myositis in farmed mink: A preliminary description. J Comp Path. 2014; 151:217-227.

8.    Pytel P, Anthony DC. Peripheral nerve and skeletal muscle. In: Kumar V, Abbas AK, Aster JC, eds. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Philadelphia, PA: Elsevier Saunders; 2015:1238-1240.

9.    Valentine BA. Skeletal muscle. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:927, 935, 942, 944-945, 949-953.

10. Wu X, Li Z, Brooks R, et al. Autoantibodies in canine masticatory muscle myositis recognize a novel myosin binding protein-C family member. J Immunol. 2007; 179(7):4939-4944.


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