AFIP SYSTEMIC PATHOLOGY

JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

April 2017

N-V01

 

Signalment (JPC 1492905):  Full-term calf

 

HISTORY:  This calf was unable to stand and nurse.  A section of cerebellum from a normal calf is on the slide for comparison.

 

HISTOPATHOLOGIC DESCRIPTION:  Cerebellum:  There is diffuse cerebellar hypoplasia characterized by shortened and blunted cerebellar folia with blending of the layers, a marked decrease in cellularity of the granular cell layer with few individual necrotic external granular cells, a paucity of Purkinje cells, and a markedly thin molecular layer that is approximately one-third normal size.  Multifocally, remaining Purkinje cells are often disorganized, located within both the internal granular layer and molecular layer (ectopic Purkinje cells), are swollen with vacuolated cytoplasm (degenerate), angular with deeply eosinophilic cytoplasm and pyknosis (necrotic), or absent, with only a clear space remaining (empty basket).  Multifocally, the meninges are expanded by few lymphocytes, macrophages and fibroblasts. 

 

MORPHOLOGIC DIAGNOSIS:  Cerebellum, cortex:  Hypoplasia, diffuse, severe, with multifocal Purkinje cell ectopia, degeneration, necrosis, and loss, breed unspecified, bovine.

 

ETIOLOGIC DIAGNOSIS:  Pestiviral cerebellar hypoplasia

 

CAUSE:  In utero infection with bovine pestivirus (bovine viral diarrhea virus - BVDV)

 

DISEASE:  Bovine viral diarrhea

 

GENERAL DISCUSSION: 

·       Worldwide, economically important disease caused by an enveloped RNA virus (family Flaviviridae, genus Pestivirus)

·       Two virus species have been recognized (BVDV type 1 and BVDV type 2), each of which contains distinct subtypes with genetic and antigenic variation; BVDV type 2 is more often isolated from severe cases

·       Further classified into cytopathic (cp) or noncytopathic (ncp) based on in vitro cell culture characteristics; cytopathogenicity in vitro is not directly related to virulence in vivo

·       Hobi-like virus or BVDV-3 is a recently discovered pestivirus species and causes similar disease; it has been identified in Brazil, Southeast Asia and Europe

·       A diverse and complex range of diseases occur depending on the age and immune status of the host and the strain and virulence of the virus

 

 

PATHOGENESIS: 

·       Key to the pathogenesis of BVDV is the development of persistently infected (PI) animals which serve as the farm reservoir and source of infection

o   PI animals are immunotolerant (seronegative) for the virus because they were infected as a fetus early in gestation (40-125 days) by a ncp strain before development of the humoral immune system

o   Essential to the establishment of PI’s is the viral interference of type I IFN signaling via:

§  Glycoprotein Erns expression with RNAse activity against viral RNA

§  Glycoprotein Npro which depletes IRF-3 of the IFN-regulatory cascade

·       Mucosal disease (MD) is the result of a PI calf infected with a cp strain

o   Cp strains induce apoptosis by the expression of viral protease NS3

o   Intrinsic pathway activation is a key element in MD development

·       Acute transient postnatal infections result from either cp or ncp strains; exposure often occurs from the viral shedding by PI’s

o   Involved pathogenesis may include the expression of Erns, NS3, apoptotic activating factor 1 and caspase 9; or reduction in TNF-α or Bcl-2

·       In utero infections can also cause abortion, fetal resorption or mummification when infection occurs before 100 days gestation; or cerebellar hypoplasia when infection occurs between 100-170 days gestation

o   The high mitotic activity of germinative cells of the external granular layer make them especially vulnerable to teratogenic agents

o   Cerebellar lesions compounded by necrosis of external granular and parenchymal destruction due to vasculitis-induced folial edema

 

TYPICAL CLINICAL FINDINGS:

·       For cerebellar hypoplasia (clinical signs usually present at birth):  Wide-based stance, ataxia, falling backward, opisthotonos, hypermetria, hyperreflexia

·       May appear blind:  No menace response, dilated pupils unresponsive to light

·       Acute infections:

o   Diarrhea, depression, oculonasal discharge, anorexia, decreased milk production, oral ulcerations, and pyrexia

o   Leukopenia characterized by lymphopenia and neutropenia

o   Hemorrhagic syndrome: Thrombocytopenia with bloody diarrhea, epistaxis, petechial hemorrhages, and bleeding from injection sites;  results from type 2 strains with increased virulence

 

TYPICAL GROSS FINDINGS: 

·       Wide spectrum of teratogenic lesions:

o   Folial atrophy and agenesis accompanied by cavitation

o   Folial edema and focal hemorrhage

o   Other CNS lesions include porencephaly, hydranencephaly, microencephaly, hydrocephalus, cystic septum pellucidum, dysmyelination

o   Ocular lesions:  Microphthalmia, retinal dysplasia and atrophy, corneal opacity, cataracts, optic neuritis and atrophy, and persistent pupillary membrane

o   Brachygnathism or brachycephaly

o   Failure of proper limb development (arthrogryposis) is an uncommon finding

·       Acute infections:

o   Ulceration of the alimentary tract, myocardial necrosis, cataracts, growth retardation lattices of long bones (sclerotic metaphyseal bone), retinitis/retinal atrophy

 

TYPICAL LIGHT MICROSCOPIC FINDINGS: 

·       Early lesions include necrosis of the external granular layer and vasculitis causing focal hemorrhages, and folial edema

·       Features of atrophy:  Depletion of granular cells, ectopic Purkinje cells, swollen Purkinje cell axons (torpedoes)

·       Hypomyelination

 

ADDITIONAL DIAGNOSTIC TESTS: 

·       Reverse transcription polymerase chain reaction (RT-PCR)

·       Virus isolation or antigen capture ELISA (ACE)

·       Immunoperoxidase or immunofluorescence

·       Immunohistochemistry

 

DIFFERENTIAL DIAGNOSIS (Gross): 

Cerebellar hypoplasia in cattle:

·       Akabane virus (Bunyaviridae)

·       Bluetongue virus (orbivirus)

·       Wesselsbron virus (Flaviviridae)

·       Genetically linked cerebellar lesions in Hereford, Angus, shorthorn

·       Dandy-Walker syndrome:  Atrophy or absence of cerebellar vermis

·       Schmallenberg virus

 

COMPARATIVE PATHOLOGY: 

Cerebellar atrophy/abiotrophy:

·       Dogs:  Cerebellar abiotrophy in Kerry blue terrier, Gordon setter, & rough-coated collie among other breeds

·       Horses:  Abiotrophy in Arab, Arab-cross foals, and Gotland ponies

 

Cerebellar hypoplasia:

·       Cats:  Feline panleukopenia virus (feline parvovirus) destroys the actively proliferating cells in the cerebellar external germinal layer

·       Dogs:  Cerebellar hypoplasia in Chow Chows

·       Dogs: Canine parvovirus DNA has been found in lesions of cerebellar hypoplasia, but there is no definitive proof that parvovirus is causative

·       Sheep:  Border disease virus (ovine pestivirus)

·       Swine:  Classical swine fever virus (porcine pestivirus)

·       Rat Parvovirus (Kilham’s rat virus) – although cerebellar hypoplasia may be seen in neonatal or infant rats, the most notable lesion is peritesticular hemorrhage and fibrosis in adults

·       Mice:  Minute virus of mice (MVM) – experimental exposure of infant mice

 

BVDV infection:

·       BVDV infection has been demonstrated in numerous species and PI BVDV infection has been documented in alpacas, mouse deer, mountain goats, white-tailed deer, sheep and goats

·       Virus distribution among tissues in PI sheep, WTD and mountain goats is similar to that seen in cattle

·       Swine: Increased incidence of natural infection; may complicate the diagnosis of classical swine fever; animals are usually asymptomatic but may have anemia, tremors, or diarrhea

 

References: 

1.      Bauermann, FV, Ridpath JF, Weiblen R, et. al. Hobi-like viruses: an emerging group of pestiviruses. J Vet Diagn Invest. 2013;25(1):6-15.

2.      Bianchi MV, Konradt G, de Souza SO, et al. Natural outbreak of BVDV-1d-induced mucosal disease lacking intestinal lesions.Vet Pathol. 2017 Mar;54(2):242-248.

3.      Blanchard PC, Ridpath JF, Walker JB, et. al. An outbreak of late-term abortions, premature births, and congenital deformities associated with a bovine viral diarrhea virus 1 subtype b that induces thrombocytopenia. J Vet Diagn Invest. 2010;22(1):128-131.

4.      Boes KM, Durham AC. Bone marrow, blood cells, and the lymphoid/lymphatic system. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Mosby Elsevier; 2017:758-759.

5.      Brodersen, BW. Bovine viral diarrhea virus infections: manifestations of infection and recent advances in understanding pathogenesis and control.  Vet Pathol. 2014;51(2):453-464.

6.      Cantile C, Youssef S. Nervous system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. Philadelphia, PA: Elsevier; 2016:104-105, 281-282.

7.      Constable PD, Hinchcliff KW, Done SH, et al. Veterinary Medicine: A Textbook of the Diseases of Cattle, Horses, Sheep, Pigs and Goats. 11th ed. Philadelphia, PA: Elsevier; 2017:577-599. 

8.      Gelberg HB. Alimentary system. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Mosby Elsevier; 2017:395.

9.      Herder V, Wohlsein P, Peters M, et. al. Salient lesions in domestic ruminants infected with the emerging so-called Schmallenberg virus in Germany. Vet Pathol. 2012;49(4):588-591.

10.   Hilbe M, Girao V, Bachofen C, et. al. Apoptosis in bovine viral diarrhea virus (BVDV)-induced mucosal disease lesions: A histological, immunohistological, and virological investigation. Vet Pathol. 2012;50(1):46-55. 

11.   Jarvinen JA, O'Connor AM. Seroprevalence of bovine viral diarrhea virus in alpacas in the United States and assessment of risk factors for exposure, 2006-2007. J Am Vet Med Assoc. 2014 Sep 15;245(6):696-703.

12.   Schlafer DH, Foster RA. Female genital system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. Philadelphia, PA: Elsevier; 2016:425-426.

13.   Topliff CL, Alkheraif AA, Kuszynski CA, et al.  Experimental acute infection of alpacas with Bovine viral diarrhea virus 1 subgenotype b alters peripheral blood and GALT leukocyte subsets.  J Vet Diagn Invest. 2017 Mar;29(2):186-192.

14.   Uzai FA, Plattner BL, Hostetter JM. Alimentary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. Philadelphia, PA: Elsevier; 2016:122-128.

15.   Workman AM, Heaton MP, Harhay GP, et al.  Resolving Bovine viral diarrhea virus subtypes from persistently infected U.S. beef calves with complete genome sequence. J Vet Diagn Invest. 2016 Sep;28(5):519-28.

16.   Zachary JF. Mechanisms of microbial infections. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Mosby Elsevier; 2017:200-201.


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