JPC SYSTEMIC PATHOLOGY
Signalment (JPC #2320162): 9-month-old male sheepdog
HISTORY: This dog presented with progressive signs of CNS disease including ataxia, incoordination and hyperreflexia.
HISTOPATHOLOGIC DESCRIPTION: Cerebellum and brainstem: Affecting over 50% of the cerebellar white matter, myelin sheaths are lost with replacement by gitter cells (demyelination), or are markedly dilated (spongiosis) and contain swollen hypereosinophilic axons (spheroids) or gitter cells and cellular debris (digestion chambers or ellipsoids) (Wallerian degeneration). Within the most severely affected white matter, primarily at the tips of folia, but occasionally extending into the overlying gray matter, there is rarefaction and replacement by numerous gitter cells, fewer gemistocytic astrocytes, lymphocytes and plasma cells, occasional syncytia with up to 5 nuclei and small amounts of karyorrhectic debris and edema fluid (necrosis). Multifocally, Purkinje cells are degenerate, with markedly swollen, hypereosinophilic, fusiform proximal axons in the granule cell layer (torpedoes), or are lost, leaving circular clear spaces in the Purkinje cell layer (empty baskets), and the adjacent granule cell layer is often paucicellular. Numerous inflammatory cells, astrocytes, Purkinje cells and small neurons in the granular cell and molecular layers contain intranuclear and fewer intracytoplasmic, 3-5 um diameter, irregularly ovoid, eosinophilic viral inclusions that marginate the chromatin. There is mild focally extensive gliosis in the brainstem. Multifocally, vessels within the affected gray, white matter and leptomeninges are mildly congested, lined by reactive endothelium and Virchow-Robbins space is expanded by many lymphocytes and plasma cells and fewer macrophages (perivascular cuffing).
MORPHOLOGIC DIAGNOSIS: Cerebellum and brainstem: Demyelination and necrosis, multifocal, severe, with Purkinje cell degeneration and loss, spongiosis, lymphoplasmacytic perivascular meningoencephalitis, viral syncytia and eosinophilic intranuclear and intracytoplasmic viral inclusions, sheepdog, canine.
ETIOLOGIC DIAGNOSIS: Morbilliviral meningoencephalitis
CAUSE: Canine distemper virus (canine morbillivirus)
CONDITION: Canine distemper; Carre"s disease
· Canine distemper is an important, ubiquitous infectious disease of dogs, other canids, wild felids, mustelids (ferrets, mink), procyonids (raccoons) and pinnipeds worldwide
· Systemic disease often with respiratory, gastrointestinal and central nervous system (CNS) involvement
· CDV is a pantropic, negative-sense, single-stranded, enveloped RNA virus, 150-300 nm diameter, genus Morbillivirus, family Paramyxoviridae
· One recognized serotype; variable strain pathogenicity and tissue tropism
· Four distinct forms of CNS disease: Classic CDV encephalitis; multifocal distemper encephalomyelitis in mature dogs; post-vaccinal canine distemper encephalitis; “old dog” encephalitis (ODE)
· Virulence factors: Hemagglutinin glycoproteins on viral envelope mediate attachment to host cells; fusion glycoproteins allow penetration of host cells and fusion of infected cells with uninfected cells
· Receptors: Signaling lymphocyte activation molecule (SLAM, CD150; leukocyte-restricted, mediates entry into cells); CD46 (widespread)
· Overall pathogenesis: Inhalation > virus infects macrophages in upper respiratory tract or lungs > viral replication in tonsils and lymph nodes in first 24 hours > cell-associated viremia by 2 days PI > spread to all lymphoid tissues and blood lymphocytes by 2-5 days PI > lymphocytolysis and leukopenia > immunosupression > animals with:
· Adequate humoral/cellular immunity: Neutralize virus by 14d PI; may not shed virus
· Delayed / intermediate humoral / cellular immunity: Viral infection / persistence in mucosal epithelium and brain > may develop neurologic disease +/- disease associated with epithelial infection
· Failure to develop neutralizing antibody by 8 or 9 days PI: Virus disseminates to respiratory, GI, urogenital, and central nervous systems; integumentary, exocrine and endocrine systems also affected > virus shed in all excretions during the systemic phase of infection > secondary infections common
· Common secondary infections: Adenovirus, Bordetella sp., Clostridium piliforme, Cryptosporidium sp., E. coli, Encephalitozoon sp., Pneumocystis sp., Sarcocystis sp., and Toxoplasma sp.
· Pathogenesis of CNS lesions: CNS signs develop 1-3 weeks after systemic signs or may seemingly occur de novo after a subclinical infection
· Virus spread through leukocyte trafficking and cell-free viremia hematogenously to brain and choroid plexus > infected cells migrate through endothelium and virus replicates in endothelial cells à perivascular lymphocytic cuffing > virus replicates in pericytes, microglial cells, astrocytic foot processes, choroid plexus epithelial cells > characteristic white matter vacuolation (intramyelinic edema) thought to result from a direct effect of the virus on oligodendrocytes
· ODE may be a consequence of long-term subclinical, persistent infection of CDV in a replication-defective state.
· Post-vaccinal CDV: Vaccination with modified live vaccines (MLV) is often fatal in exotic carnivores (e.g., ferret, mink, lesser panda, grey fox); rarely causes fatal encephalitis in young dogs, possibly due to immune stimulation by other canine viruses (e.g., canine parvovirus) at time of vaccination; vaccination of pregnant dogs can cause disease in puppies or abortion
TYPICAL CLINICAL FINDINGS:
· Classic canine distemper:
· Disease most common in 12-16 week-old puppies (waning passive immunity)
· Early: Fever, conjunctivitis, cough, vomiting, diarrhea, depression, anorexia, serous to mucopurulent oculonasal discharge, death
· Clinical pathology: Lymphopenia, thrombocytopenia (virus-antibody immune complexes on platelets and direct infection of megakaryocytes), regenerative anemia, hypoalbuminemia, hypergamma- and alpha-globulinemia
· Later (1-4 weeks and if animal did not die in early stage): Neurologic disease (seizures, cerebellar or vestibular ataxia, paraparesis, myoclonus); may see minimal or no signs of epithelial infection and only neurologic signs in some dogs; hyperkeratosis of footpads and nose, and enamel hypoplasia are late manifestations
· 50-70% of infections are subclinical
· Multifocal distemper encephalomyelitis in mature dogs:
· Occurs when CDV infects dogs at 4-8 years of age
· Rare, chronic, progressive disease
· Not preceded by signs of classic distemper
· Slow, progressive course of weakness and incoordination, but no seizures
· “Old dog” encephalitis (ODE):
· Extremely rare; most cases occur in dogs past middle age
· Insidious onset of circling, incoordination, compulsive walking and pushing against fixed objects
· No paralysis or convulsions
· Progression over 3-4 months to coma or death
· Post-vaccinal canine distemper encephalitis:
· Affects young dogs 1-3 weeks post-vaccination with MLV CDV vaccines
· Acute/subacute (1-5 days) clinical course
· Signs reminiscent of furious form rabies; aggressive/attack behavior
TYPICAL GROSS FINDINGS:
· CNS: Lesions are uncommon; white matter softening with brown discoloration +/- hemorrhage; brain reduced in size with moderately dilated ventricles in ODE
· Lungs: Patchy red-tan, rubbery subpleural and marginal lesions (bronchointerstitial pneumonia); may be edematous and consolidated (secondary bronchopneumonia)
· Eyes/conjunctiva: Conjunctivitis, keratitis
· Integument: Hyperkeratosis of footpads and nose; +/- secondary pyoderma (pustular dermatitis, especially ventral abdomen)
· Lymphoid tissues: Tonsillar enlargement, thymic atrophy
· Teeth: Enamel hypoplasia
· Long bones: Metaphyseal osteosclerosis (young growing dogs)
TYPICAL LIGHT MICROSCOPIC FINDINGS:
· Eosinophilic intracytoplasmic (IC) and/or intranuclear (IN) inclusion bodies:
· Most numerous 10-14 days PI
· Most obvious in brain (often INIBs) and epithelium (usually ICIBs), especially in urinary bladder; less obvious in lymphoid tissues
· Central nervous system:
· Classic canine distemper:
· Lesions usually involve both gray and white matter, but predominate in one over the other
· White matter: Demyelination (with early axon sparing) and status spongiosis of white matter with axonal degeneration and necrosis (most severe in cerebellar peduncles, rostral medullary velum, optic tracts, hippocampal fornix, spinal cord, surrounding the fourth ventricle); nonsuppurative encephalitis, gitter cells, astrocytosis, syncytia
· Gray matter (lesions less common than white matter lesions): INIBs +/- ICIBs in neurons > neuronal necrosis > mononuclear infiltrate surrounding necrotic neurons > nonsuppurative perivascular encephalitis +/- mild meningitis; rare cases with severe seizure activity feature bilateral polioencephalomalacia involving pyriform lobes and hippocampus
· Multifocal distemper encephalomyelitis in mature dogs:
· Lesions are restricted to CNS and most prevalent in cerebellum and white matter of spinal cord; cerebral cortex often spared (in contrast to ODE)
· Multifocal necrotizing nonsuppurative encephalitis with rare intra-astrocytic INIBs; demyelination in internal capsule and corona radiate
· “Old dog” encephalitis:
· Cerebral cortex, thalamus, and brainstem are consistently affected (in contrast to multifocal distemper encephalomyelitis in mature dogs)
· Most obvious change is large lymphocytic perivascular cuffing at grey-white matter junction
· Uniform sclerosis and demyelination of white matter
· Characteristic feature is widespread nonsuppurative perivascular encephalitis; IN& ICIBs in astrocytes and neurons; neuronal necrosis; viral antigen detectable by IHC, but cannot isolate virus from the brain (viral antigen not in cerebellum)
· Post-vaccinal canine distemper encephalitis:
· Lesions always restricted to CNS
· Similar to classic CDV lesions, but with relative sparing of white matter
· Eyes: acute lymphoplasmacytic chorioretinitis and optic neuritis, perivascular cuffing and edema, exudative retinal separation, eosinophilic INIBs in ganglion cells and astrocytes; multiple random foci of retinal degeneration (usually full thickness)and scarring are more prevalent lesions
· Lungs (common): Bronchointerstitial pneumonia
· Patchy bronchiolar necrosis/attenuation
· IBs are most obvious in airway epithelium (persist longer than in CNS)
· Alveoli: Edema, fibrin, mononuclear cells, necrosis; type II pneumoncyte hyperplasia, IBs common in type II pneumocytes and alveolar macrophages, alveolar epithelial syncytia
· Integument: Orthokeratotic and/or parakeratotic hyperkeratosis of footpad, nose, rarely haired skin
· +/- Epidermal syncytia; INIBs / ICIBs in epithelial cells and syncytia
· +/- Secondary pustular dermatitis (pyoderma)
· Lymphoid tissues: Early lymphoid depletion and lymphocytic necrosis > syncytia +/- IBs > histiocytic cell hyperplasia; thymic atrophy particularly common in puppies
· Teeth: Cystic degeneration of ameloblastic epithelium, syncytia and ICIBs > enamel defects / hypoplasia
· Other epithelia (urinary bladder; renal pelvis; gastric surface, chief, and parietal cells; cholangiolar epithelium; pancreatic ductular epithelium; epididymis; testis): Degeneration, mononuclear infiltrates, ICIBs +/- INIBs
· Heart: Myocardial necrosis and mineralization
· Bone: Growth retardation lattices; Osteoclast necrosis à impaired osteoclastic resoprtion of primary spongiosa
· Tubular CDV nucleocapsids are seen in non-membrane bound intracytoplasmic aggregates; similar tubular structures may be seen in the nucleus (despite lack of viral replication in the nucleus)
· Destruction of ensheathing myelin envelope
ADDITIONAL DIAGNOSTIC TESTS:
· Virus isolation, immunohistochemistry (IHC), fluorescent antibody test
· IHC on skin lesions shows CDV antigen at all levels of the epidermis but most abundant in stratum spinosum, granulosum, and in epithelium of eccrine sweat glands; rare in basal layer
For CNS lesions:
· Toxoplasma gondii / Neospora caninum: Random, multifocal, necrotizing foci in the grey and white matter; protozoa at the margins of the lesions
· Rabies (Rhabdoviridae; lyssa virus): ICIBs in hippocampal neurons and Purkinje cells; occasional lymphocytic perivascular cuffing
· Pseudorabies (Alphaherpesvirus, suid herpesvirus 1): Polioencephalomyelitis +/- ganglionitis, INIBs in neurons of spinal ganglia, spinal cord, medulla, pons
· Granulomatous meningoencephalitis: Progressive neurological disease of adult dogs with granulomatous inflammation
· Canine adenovirus type I (Infectious canine hepatitis): Brainstem hemorrhages with mild vasculitis and intranuclear inclusions in endothelial cells
· Canine herpesvirus: Usually puppies less than 21 days old; multifocal necrotizing lesions in many organs including lung, liver, kidneys and CNS
· Case report of several neonatal pups with CDV developing respiratory tract lesions without central nervous signs; distemper should be considered a differential for neonatal canine mortality / fading puppy syndrome
Other viruses causing IBs in bronchiolar or airway epithelium:
· Canine adenovirus-2
· Canine herpesvirus-1
· Canine minute virus (canine parvovirus 1)
Other species affected with CDV:
· Mustelidae: One of the most important viral diseases in ferrets, also weasels, mink, skunk, badger, marten, otter
· Canidae: Dingo, fox, coyote, jackal, wolf
· Procyonidae: Raccoon, coati
· Ailuridae: red panda
· Ursidae: Bears, panda
· Viverridae: civet, mongoose
· Felidae: Lions, leopards, cheetahs, tigers
o Large felids: Fatal neurologic disease due to a distinct CDV variant
o African lions contract the virus from hyenas and feral dogs
o Hard pads are rare; CNS signs most common
· Phocids (e.g. Baikal seals) susceptible to CDV and phocine distemper virus
· Rodents: Marmots
· NHP: Rhesus monkeys
· Other morbilliviruses:
o Rinderpest: Primarily large ruminants – oral mucosal erosions, diarrhea
o Peste-des-petits-ruminants: Small ruminants – respiratory signs, oral erosions, diarrhea
o Cetacean morbillivirus (dolphin morbillivirus and porpoise morbilliviruses are two strains of the same species): Closely related to RP and PPRV
o Phocine distemper virus (PDV): Closely related to CDV
o Measles virus: Humans and non-human primates
1. Boes KM, Durham AC. Bone marrow, blood cells, and the lymphoid/lymphatic system. In: Zachary JF, eds. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier Mosby; 2017:759-760.
2. Cantile C, Youssef S. Nervous system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier; 2016:384-385.
3. Caswell JL, Williams KJ. Respiratory system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. St. Louis, MO: Elsevier; 2016:574-576.
4. Cheville NF. Ultrastructural Pathology: The Comparative Cellular Basis of Disease. Ames, IA: Wiley-Blackwell; 2009:360-363.
5. Craig LE, Dittmer KE, Thompson KG. Bones and joints. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier; 2016:104-105.
6. Greene CE, Vandevelde M. Canine distemper. In: Greene CE, ed. Infectious Diseases of the Dog and Cat. 4th ed. St. Louis, MO: Saunders Elsevier; 2012:25-42.
7. Headley SA, Amude AM, Alfieri AF, Bracarense AP, Alfieri AA, Summers BA. Molecular detection of canine distemper virus and the immunohistochemical characterization of the neurologic lesions in naturally occurring old dog encephalitis. J Vet Diagn Invest. 2009;21(5):588-597.
8. Kiupel M, Perpiñán. Viral diseases of ferrets. In: Fox JG, Marini RP, ed. Biology and Diseases of the Ferret. 3rd ed. Ames, IA: John Wiley & Sons, Inc.; 2014:439-450.
9. MacLachlan NJ, Dubovi EJ. Paramyxoviridae. In: MacLachlan NJ, Dubovi EJ, eds. Fenner’s Veterinary Virology. 4th ed. San Diego, CA: Academic Press; 2011:317-320.
10. Miller AD, Zachary JF. Nervous system. In: Zachary JF, eds. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier Mosby; 2017:890-891.
11. Origgi FC, Sattler U, Pilo P, Waldvogel AS. Fatal combined infection with canine distemper virus and orthopoxvirus in a group of Asian marmots (Marmota caudata). Vet Pathol. 2013;50(5):914-920.
12. Pandher K, Podell B, Gould DH, Johnson BJ, Thompson S. Interstitial pneumonia in neonatal canine pups with evidence of canine distemper virus infection. J Vet Diagn Invest. 2006;18(2):201-204.
13. Pesavento PA, Murphy BG. Common and emerging infectious diseases in the animal shelter. Vet Pathol. 2014;51(2):478-491.
14. Qiu W, Zheng Y, Zhang S, et al. Canine distemper outbreak in rhesus monkeys, China. Emerg Infect Dis. 2011;17(8):1541-1543.
15. Spitzbarth I, Baumgartner W, Beineke A. The role of pro- and anti-inflammatory cytokines in the pathogenesis of spontaneous canine CNS diseases. Vet Immunol Immunopathol. 2012;147(1-2):6-24.
16. Summers BA, Cummings JF, de Lahunta A. Inflammatory diseases of the central nervous system. In: Summer BA, Cumming JF, de Lahunta A, eds. Veterinary Neuropathology. St. Louis, MO: Mosby-Year Book; 1995:102-110.
17. Wenzlow N, Plattet P, Witter R, Zurbriggen A, Grone A. Immunohistochemical demonstration of the putative canine distemper virus receptor CD150 in dogs with and without distemper. Vet Pathol. 2007;44(6):943-948.
18. Wilcock BP, Njaa BL. Special senses. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier; 2016:474.
19. Zachary JF. Mechanisms of microbial infections. In: Zachary JF, eds. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier Mosby; 2017:225-226.