JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

April 2026

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 grey matter 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), and are often either swollen with vacuolated cytoplasm (degenerate), angular with deeply eosinophilic cytoplasm and nuclear 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 ectopic Purkinje cells, and Purkinje cell 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 of cattle caused by an enveloped ssRNA virus (family Flaviviridae, genus Pestivirus)
• Important viral pathogen of bovine fetus
• Common in cattle 8 months to 2 year of age
• Cattle can serve as virus reservoir to non-domestic ruminants
• 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 two forms; cytopathic (Cp) or noncytopathic (Ncp) is based on in vitro cell culture characteristics
    • Ncp can be introduced into a herd through commingling of infected cattle, semen, fomites, or through other contact exposure to carrier animals.
      • Become immunotolerant to Cp (does not mount an immune response); predispose to disease
    • Cp arises through mutation (antigenic shift or drift) of Ncp viral strain
      • Naïve cattle to Ncp strain can prevent or limit Cp viral disease
  • Hobi-like virus or BVDV-3 is a recently discovered pestivirus species and causes similar disease; it has been identified in South America, Asia and Europe. Co infection with BVDV1 recently found in Argentina (Margineda 2022).
• Causes 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
  • Gastrointestinal disease: Mucosal disease (MD, see D-V09). See digestive systemic document for pathogenesis, gross lesions, clinical pathology and histology information for this disease
• The US cattle have serologic evidence of exposure to nonvaccine BVDV
• Similar with Border Disease Virus and Classical Swine Fever. These three viruses cross-infect naturally between species (swine, goat, sheep, cattle).

PATHOGENESIS:

• Inhalation or ingestion via direct contact or fomite exposure 🡪 replication in MALT monocytic cells (e.g., tonsils) 🡪 Leukocyte trafficking and/or viremia
  • Ncp tropism likely monocytes
  • Cp form tropism follicular dendritic cells and MALT B lymphocytes
  • Proliferation of lymphoid cells in Peyer’s patch and then lymphocytolysis
  • Apoptosis induced in bystander lymphocytes and monocytes
• Outcome viremia determined by viral genotype and virulence, host immune status, and host pregnancy status and stage of gestation (see below)
• Viral attachment:
  • Virus outer membrane proteins E1 and E2 may act as attachment proteins
  • CD46 is a likely cellular receptor required for attachment to host cells, and clathrin-mediated endocytosis is required for internalization
• As an RNA virus, BVDV is highly mutable
  • Recombination of Ncp to Cp results from splitting of the nonstructural protein NS2-3 protein to NS3, a viral protease which is used by Cp strains to induce host apoptosis; NS3 is a marker for Cp BVDV
• In utero infections may cause, according to gestation day:
  • Prior to day 100: Abortion, fetal resorption, or mummification
    • BVDV may cause immunosuppression leading to concomitant infections causing abortion; BVDD can be the primary cause
  • 100-170 gestation, developmental defects:
    • Cerebellar hypoplasia (and other teratogenic lesions)
      • Local vasculitis and ischemia -> Cerebellar folial edema -> Depending on severity, folial edema may result in focal lesions, cavitation, or total folial destruction
      • The high mitotic activity of germinative cells of the external granular layer make them especially vulnerable to teratogenic agents
        • Edema in the folia leads to further necrosis of external granular layer
    • Hypomyelination due to BVDV-2 strain
    • Retinal dysplasia (secondary to retinal and choroid necrosis and mild lymphocytic endophthalmitis); commonly within peripheral retina especially in infected in later stages; retinal lesions can be as early as 79 days in gestation (JKP)
  • <125-150 days gestation (Ncp strain): Possible persistent infection (PI)
  • After 170 days: Unlikely to be teratogenic/abortogenic, but can cause intrauterine growth retardation and atrophy of the thymus and lymphoid tissues
    • At 170 days, fetuses can develop neutralizing viral antibodies
  • Calves go through myelination between gestational week 20 and post natal week 8
• A key to the pathogenesis of BVDV is persistently infected (PI) animals which serve as the farm reservoir and source of infection
  • Naïve pregnant heifers infected with Ncp strain at 40-120 days of gestation, clinically asymptomatic, and passes infection in utero
  • If fetus survives infection by Ncp strain prior to 125 days gestation, it may develop immunotolerance and persistent infection (PI) (bovine fetuses become immunocompetent at 150-200 days of gestation)
  • PI animals are immunotolerant (seronegative) for the virus because they were infected as a fetus early in gestation by a Ncp strain before development of the humoral immune system
  • PI calves usually die before a year of age; if they survive they can pass infection to fetus in gestation
• Acute transient postnatal infections result from either Cp or Ncp strains; exposure often occurs from viral shedding of PI animals
• Mucosal disease (MD, see D-V09) is the result of a PI calf infected with a Cp strain..
• Nasopharynx associated lymphoid tissues (NALT) is another location site for viral replication and induces localized immunosuppression allowing for secondary infections part of the Bovine Respiratory Disease Complex (Hegazy, 2025)

TYPICAL CLINICAL FINDINGS:

• Calf with 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
• Reproductive disease: fertilization failure, embryonic death, birth of small calves or with congenital defects, abortion, adsorption, mummification, stillbirth
• Acute infections:
  • Diarrhea, depression, oculonasal discharge, anorexia, decreased milk production, oral ulceration, respiratory disease, and pyrexia
  • Leukopenia characterized by lymphopenia and neutropenia
    • Thrombocytopenic syndrome: Thrombocytopenia with bloody diarrhea, epistaxis, multisystemic petechial hemorrhages, and bleeding from injection sites; results from type 2 strains with increased virulence
    • Bovine neonatal pancytopenia Syndrome resulting from immune mediated disorder from commercial BVDV vaccine; Alloimmunization against polymorphic bovine leukocyte antigen (BOLA) 1 was incorporated into the vaccine calf < 1 year of age, peripheral thrombocytopenia and neutropenia; death secondary to hemorrhages or secondary infections
  • Infertility

TYPICAL GROSS FINDINGS:

• Fetal (teratogenic) lesions:
  • CNS lesions: Cerebellar hypoplasia (folial atrophy and agenesis accompanied by cavitation, folial edema, and focal hemorrhage); flattened and narrowed frontal part of cranium, thicker cranial bones, porencephaly, hydranencephaly, microencephaly with normal gyri size but simplified pattern, hydrocephalus, hypomyelinogenesis, myelination defects, cystic septum pellucidum
  • Ocular lesions: Microphthalmia, retinal dysplasia and atrophy, retinal scarring, cataracts, optic neuritis and atrophy, and persistent pupillary membrane
    • All calves with retinal dysplasia also have cerebellar atrophy and some have hydrocephalus/hydranencephaly
  • Musculoskeletal lesions: Brachygnathism or brachycephaly; arthrogryposis (failure of proper limb development) is uncommon
    • Segmental enamel hypoplasia due to enamel formation during the period of virus infection
    • Similarly, growth retardation with growth-arrest lines in long bones
  • Other lesions: Thymic aplasia; enlargement, nodularity, and mottling of the liver with 1-2 mm white areas; splenomegaly or lymphadenomegaly; peribronchiolar lymphoid hyperplasia; pulmonary hypoplasia; hypotrichosis with partial alopecia that spares the tail, the lower portion of the limbs, and the head (points of initial hair growth during fetal development); multifocal perivascular dermatitis
• Adult lesions:
  • GI: Ulceration of the alimentary tract especially lineal ulcers within the esophageal mucosa, fibrinonecrotic membrane overlying Peyer’s patches and/or typhlocolitis
  • Respiratory: +/- ulceration on muzzle and nares as well as tracheitis, bronchitis, and bronchiolitis
    • May progress to secondary bacterial pneumonia (BDV is part of the Bovine Respiratory Disease Complex)
    • BVD infection can play an important role in pathogenesis of respiratory disease (Ridpath, 2020)
  • Musculoskeletal: Growth retardation lattices of long bones (sclerotic metaphyseal bone), bone marrow necrosis; myocarditis
  • Reproductive: Edematous placenta, altered testicular development
  • Other: Cataracts, retinitis, multifocal dermatitis, coronary band ulceration, germinal center lymphoid atrophy, thymus atrophy (only epithelial stroma and macrophages persisting in cortex), oophoritis,

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Fetal (teratogenic) lesions:
  • Cerebellar hypoplasia: Most characteristic defect; necrosis and loss of the external granular layer, degeneration and loss of immature postmitotic Purkinje cells, disorganized cortex
  • Vasculitis, especially of the white matter (characterized by endothelial proliferation and perivascular leukocytic infiltration) with resulting focal cortical hemorrhages that may accompany folial edema
  • Features of cerebellar atrophy: folial atrophy secondary to ischemia, Depletion of granular cells, ectopic Purkinje cells (located in molecular layer), swollen Purkinje cell axons (torpedoes)
  • Cerebrum hypoplasia of gray and white matter
  • Hypomyelination-dysmyelination: white and grey matter appear blended, no necrosis
  • Lymphoplasmacytic leptomeningitis, occasionally with fibroplasia
    • can cause adhesions between adjacent cerebellar folia and focal obliteration of the subarachnoid space
  • Ocular: nonsuppurative retinitis +/- retinal dysplasia, microphthalmia and optic neuritis
    • The most significant clue suggesting viral than genetic cause is the presence of residual inflammation and post necrotic scarring in the retina, optic nerve, and perhaps subtly, in choroid.
    • Patchy alteration of abortive retinal regeneration, hyperplastic pigment epithelium, and post necrotic glial scarring; lesion more severe in non-tapetal retinal and are bilateral but not symmetrical
  • Other fetal lesions: Mononuclear, predominantly macrophage, infiltration of hepatic portal areas, myocardium, spleen, and lymph nodes; osteopetrosis, necrotizing dermatitis, hypoplasia of hair follicles, cystic distention of adnexal glands
• Acute infection:
  • Multifocal epithelial necrosis especially enterocytes; intestinal erosions, crypt proliferation with microabscesses, hyaline degeneration and fibrinoid necrosis of submucosal and mesenteric arterioles; lymphoid (especially GALT) necrosis/depletion, spermatozoa defects; multifocal vasculitis

ADDITIONAL DIAGNOSTIC TESTS:

• Reverse transcription polymerase chain reaction (RT-PCR)
  • Ear notch samples were used with very high specificity and sensitivity at different days to identify PI calves (compared ELISA to RT-PCR) (McDougal, 2021)
  • Pan-bovine pestivirus primers recently developed (Monteiro, 2021)
• Virus isolation or antigen capture ELISA (ACE)
  • Ear notch samples were used with very high specificity and sensitivity at different days to identify PI calves (compared ELISA to RT-PCR) (McDougal, 2021)
• Immunoperoxidase or immunofluorescence
• Immunohistochemistry (skin biopsies in PI animals)
• Titers of fetal antibody
• Clinical pathology: thrombocytopenia, neutropenia

DIFFERENTIAL DIAGNOSIS:

• Cerebellar hypoplasia in cattle (other arboviruses or pestiviuses:
  • Akabane virus (Bunyaviridae): Can lead to porencephaly, hydranencephaly, ventral horn neuronal degeneration in spinal cord of ruminants; Japan, Australia, and Israel
  • Bluetongue virus (Orbivirus, N-V02): With in utero infection (at time of development) can lead to hydranencephaly and retinal dysplasia in calves, but more common in lambs
  • Cache valley fever (Bunyaviridae)
  • Wesselsbron virus (Flaviviridae) and Rift Valley Fever (Phlebovirus): Hydranencephaly of lambs in Africa
  • Genetically linked cerebellar lesions in Hereford, Angus, shorthorn
  • Dandy-Walker syndrome: Atrophy or absence of cerebellar vermis seen in numerous species
  • Schmallenberg virus: Neurologic signs and/or head, spine, or limb malformations in lambs, kids, and calves ; hydranencephaly.
• Hereditary neuraxial edema (N-M05): Autosomal recessive branched-chain α-ketoacid decarboxylase deficiency (BCKD) in neonatal Hereford or cross calves; results in dull or recumbent calves -> death; cerebrum may be swollen with flattened cerebral gyri with status spongiosus

COMPARATIVE PATHOLOGY:

• Cerebellar atrophy/abiotrophy: (N-M01)
  • Dogs: Cerebellar abiotrophy in, Kerry blue terrier, Gordon setter, & rough-coated collie among other breeds;
  • Horses: Abiotrophy in Arabian, 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, Beagle, Silky terrier, Airedale terrier, Irish setter, Boston terrier, Bull terrier, wire fox terrier
    • Cerebellar hypoplasia with intraneuronal inclusions reported from New Zealand in Cocker Spaniel dogs.
    • Cerebellar cortical dysplasia in St. Bernard puppies
    • Standard Poodle puppies have a genetic form with dysplastic foci consisting of clusters of intermixed granule and Purkinje neurons
    • Canine parvovirus DNA has been found in lesions of cerebellar hypoplasia, but there is no definitive proof that parvovirus is causative
    • Canine herpes virus can lead to segmental cerebellar dysplasia secondary to necrosis
  • Sheep:
    • Bluetongue virus (Orbivirus, N-V02):
    • Border disease virus (ovine pestivirus): selective necrosis of external granular layer cells
    • Cache valley fever (Bunyaviridae): selective necrosis of external granular layer cells
  • Swine:
    • Classical swine fever virus (porcine pestivirus): potentially acts through inhibition of cell division and maturation
    • Sows treated with OP trichlorfon
  • Cattle: A condition commonly referred as CT leads to an autosomal recessive hereditary cerebellar ataxis with nonsymmetrical hypomyelination in Jersey cattle. Similar syndromes reported in Angus, Shorthorn, Hereford, Shorthorn cross breeds. Holstein-Friesian calves reported with white matter degenerative lesion of CNS.
  • Rat: Rat virus (RV) or Kilham’s rat virus (Parvoviridae): Cerebellar hypoplasia may uncommonly be seen in neonatal or infant rats; the most notable lesion is peri-testicular hemorrhage and fibrosis in adults; intranuclear inclusions may be present; infertility, fetal resorption, and abortion may occur in pregnant females
  • Mice: Minute virus of mice (MVM) (Parvoviridae): Experimental exposure of infant mice may target the cerebellar outer granular layer, leading to cytolosysis, resulting in cerebellar hypoplasia; intranuclear inclusions may be present.
  • Goat and Sheep: hypocuprosis (copper deficiency)
• Porencephaly/microencephaly
  • Border disease virus (Pestivirus): lamb disease; hydranencephaly, subventricular zones of necrosis
  • Copper deficiency (Swayback) in lambs.
• BVDV infection in other species:
  • BVDV can infect most even-toed ungulates: demonstrated in numerous species, including various farmed and free-range wildlife (e.g., different species of deer, camelids, alpacas)
    • Reproductive failure and PI BVDV infection documented in camelids (alpacas and crias), mouse deer, white-tailed deer, mountain goats, sheep and goats
    • Virus distribution among tissues in PI sheep, white-tailed deer, and mountain goats similar to cattle
    • In a Switzerland study, where BVDV was eradicated in 2013, water buffalo on 3 farms had evidence of being transiently infected with BVDV, opening up the possibility of being a sourse of epidemiology in domestic ruminants (Lechmann, 2023)
  • Camelids: A new substrain of BVDV (BVDV-1q) was first identified in Bactrian camels in China and later identified in dairy cattle and swine
  • Swine: Hog cholera (Classical swine fever) is antigenically closely related to BVDV; may complicate the diagnosis of CSF due to cross reaction; can be infected through contact with infected cattle; increased incidence of natural BVDV infection; animals are usually asymptomatic but may have anemia, tremors, or diarrhea
  • Swine and goats: stillbirth and neonatal death reported

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