JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

January 2023

N-B09

 

Signalment (JPC #2641247): 9-year‑old male chow chow dog 

 

HISTORY: This dog had a one month history of weight loss.  Three days prior to euthanasia, the dog developed episodic blindness, pacing, head pressing, seizures, lethargy, and high fever (106°F).

 

HISTOPATHOLOGIC DESCRIPTION: Cerebrum, level of the hippocampus:  Multifocally affecting periventricular, cerebral, choroidal, and meningeal small veins, capillaries, and arterioles, there is vasculitis characterized by occasional discontinuity of the endothelium and multifocal transmural replacement by eosinophilic cellular and karyorrhectic debris and numerous viable and necrotic neutrophils, macrophages, and lymphocytes with fewer plasma cells (necrotizing vasculitis) with occasional hemorrhage, as well as frequent expansion of the tunica media and tunica adventitia by brightly eosinophilic, hyalinized to fibrillar material (fibrin; fibrinoid vasculitis). Previously described inflammatory cells often expand the Virchow-Robins space and multifocally infiltrate the surrounding leptomeninges, choroid plexus, and neuropil. Occasionally, adjacent to the most severely affected vessels, there is rarefaction characterized by edema and vacuolation of the neuropil (necrosis) and infiltration by moderate numbers of foamy gitter cells, neutrophils, lymphocytes, fibrin, and necrotic debris. Less severely affected vessels are often lined by hypertrophied endothelial cells (reactive).  

 

MORPHOLOGIC DIAGNOSIS: Cerebrum, level of the hippocampus: Vasculitis, fibrinonecrotizing, periventricular, cerebral, choroidal, and meningeal, multifocal, severe, with rarefaction and moderate neutrophilic and lymphohistiocytic choroiditis, meningoencephalitis, and ventriculitis, chow chow, canine.

 

ETIOLOGIC DIAGNOSIS: Rickettsial vasculitis and choriomeningoencephalitis

 

CAUSE: Rickettsia rickettsii

 

CONDITION: Rocky Mountain spotted fever (RMSF), Brazilian spotted fever (BSF)

 

GENERAL DISCUSSION:

• R. rickettsia is a tick-borne rickettsial disease that causes vasculitis and thrombosis in many organs, especially those with abundant endarterial circulation (e.g. brain, dermis, gastrointestinal tract, heart, lung, kidneys, and skeletal muscle)
• Order Rickettsiales, family Rickettsiaceae includes genera (1) Rickettsia; (2) Ehrlichia; (3) Neorickettsia; (4) Anaplasma; (5) Cowdria; and (6) Aegyptianella 
• Rickettsia rickettsii infects dogs and humans in North and South America 
• Ticks serve as vectors, reservoirs, and natural hosts (regionally variable):

• Dermacentor variabilis (American dog tick):  Eastern North America
• Dermacentor andersoni (wood tick):  Western North America 
• Amblyomma americanum (Lone Star tick) and Rhipicephalus sanguineus (brown dog tick) can also serve as vectors

 

PATHOGENESIS:  

• Tick-to-tick transmission is both horizontal and vertical; maintained primarily through the sylvan cycle in small rodents
• Infection is usually from tick bites (although in humans infection can occur from contact with infected hemolymph or excreta during tick removal) and usually during tick season (April to September); dogs can develop a high and persistent rickettsemia and are a potential public health danger
• Rickettsiae invade and replicate within endothelial cells of small blood vessels
• Enters endothelial cells of small blood vessels > escapes endosome before formation of acidified phagolysosome > proliferates in cytoplasm > endothelial swelling and necrosis (likely mediated by phospholipase A and a trypsin-like protease of either host or rickettsial origin) and platelet activation > increased vascular permeability and exposure of basement membrane > activates kallikrein-kinin system and coagulation and fibrinolytic cascades > end result - tissue necrosis, thrombosis, microinfarction, and hemorrhage > migration to other organs via the blood stream
• Vasculitis due to endothelial swelling and necrosis with secondary contributions from host immune and phagocytic responses

 

TYPICAL CLINICAL FINDINGS:

• Most common in dogs less than 2 years of age; purebred dogs>mix breeds, especially German shepherds 
• Cutaneous lesions: petechiae, edema, necrosis, and ulceration as a result of direct endothelial cell damage and vasculitis
• Petechial and ecchymotic hemorrhages – ocular (retinal hemorrhage +/- uveitis occur in 80% of canine cases), oral, and genital mucous membranes
• Neurologic signs - lethargy, confusion, stupor, vestibular disease, nystagmus, ataxia, and circling; edema of the medulla oblongata may contribute to cardiorespiratory depression; death from rapidly progressive meningoencephalitis
• Listlessness and depression, high fever, history of ticks, anorexia, myalgia/arthralgia, lymphadenomegaly, vestibular deficits, dyspnea, conjunctivitis, paralumbar hyperesthesia 
• Febrile exanthema, edema, and hyperemia of the lips, prepuce, scrotum, pinna, and dependent portions of the body
• Hemorrhagic diathesis or thrombosis can result in death
• Dyspnea and coughing
• Lameness from joint or muscle pain; necrosis of extremities
• Clinical pathology: 

• CBC

• Thrombocytopenia – consumption secondary to vasculitis; possible immune-mediated platelet destruction
• Leukopenia (initially) then progressive, moderate leukocytosis with a minimal left shift
• Mild normocytic-normochromic anemia

• Serum chemistry – hypercholesterolemia, hypoproteinemia, hypoalbuminemia, hyponatremia, hypocalcemia (often related to hypoalbuminemia), mild increase in liver enzymes
• Coagulation abnormalities – hyperfibrinogenemia, prolonged aPTT; fulminant DIC is uncommon, but can occur with concurrent sepsis

 

TYPICAL GROSS FINDINGS:

• Edema and hyperemia: Lips, muzzle, pinna, scrotum, and dependent portions of the body
• Widespread petechial and ecchymotic hemorrhages in all tissues, especially caudal abdominal skin, mucous membranes, gastric wall, and pleura
• Generalized hemorrhagic lymphadenomegaly and splenomegaly
• Ulcerative glossitis, scrotal dermatitis, hemorrhagic colitis
• Retinal hemorrhage and uveitis

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Necrotizing vasculitis of small veins, capillaries, and arterioles, with perivascular lymphohistiocytic infiltrates of lymphocytes and macrophages
  • Most common in skin, testes, digestive tract, pancreas, kidneys, urinary bladder, heart, meninges, retina, and skeletal muscle
• Characteristic retina changes are multifocal retinal hemorrhage, perivascular retinal edema, and necrosis of endothelium in retinal venules and arterioles 
• +/- Acute meningoencephalitis, splenitis, interstitial pneumonia, myocardial necrosis, adrenal necrosis, hepatic necrosis, glomerulonephritis 

 

ADDITIONAL DIAGNOSTIC TESTS:

• Serology: Comparison of acute and convalescent (paired) titers; species-specific microimmunofluorescent method is most reliable serologic test; initially high antibody titers that wane after 3-5 months
• Direct fluorescent antibody staining of skin biopsy (positive in up to 80% of cases); coccobacillary organisms present in endothelial cells and vessel walls
• PCR of agent in peripheral blood
• Special histologic stains - Giemsa, Gimenez, Macchiavello 
• Aspirates of enlarged lymph nodes will be consistent with a hyperplastic lymph tissue

 

DIFFERENTIAL DIAGNOSIS

Gross: 

Microscopic:

• Ehrlichia canis: perivascular plasmacytosis
• Neorickettsia helmintheca (salmon disease): Vasculitis not characteristic; non-suppurative leptomeningitis in CNS

 

REFERENCES:  

1. Blauvelt M, Messick JB. The Lymph Nodes. In: Valenciano AC, Cowell RL eds. Cowell and Tyler’s Diagnostic Cytology and Hematology of the Dog and Cat. 5^th ed. St. Louis, MO: Elsevier; 2020:176.
2. Kramer JA, Bielitzki. Integumentary System Diseases of Nonhuman Primates. In: Abee CR, Mansfield K, Tardif S, Morris T eds. Nonhuman Primates in Biomedical Research Volume 2: Diseases. 2^nd ed. Waltham, MA: Elsevier; 2012:574.

1. Robinson WF, Robinson NA. Cardiovascular system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. St. Louis, MO: Elsevier; 2016:82-83.

1. Wilcock BP, Njaa BL. Special Senses. In: Maxie MG ed. Jubb, Kennedy, and Palmer's Pathology of Domestic Animals. Vol 3. 6th ed. St. Louis, MO: Elsevier; 2016: 474-475. 
2. Welle MM, Linder KE. The Integument. In: Zachary JF eds. Pathologic Basis of Veterinary Disease. 7th ed.  St. Louis, MO; 2022: 1238.

 

 

 

 

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