Bovine herpesviral meningoencephalitis: large case study and literature review

Abstract

Bovine herpesviral meningoencephalitis (BHM) is an infectious disease of cattle caused by bovine alphaherpesvirus 1 (BoAHV1; Orthoherpesviridae, Varicellovirus bovinealpha1) or 5 (BoAHV5; Orthoherpesviridae, Varicellovirus bovinealpha5). Cases are frequent in South America, but the disease is sporadic in other countries. Infection typically leads to fatal necrotizing meningoencephalitis that most often affects calves <1-y-old and yearlings under stressful situations, including weaning, large concentrations of animals, transport, and introduction of cattle from other locations into a herd. Clinical disease lasts from 1–10 d and often leads to typical gross and histologic lesions that are more prominent in the frontal lobes of the brain. This particular neuroanatomic distribution of lesions results from retrograde viral infection from the nasal mucosa along the olfactory nerves and bulbs with subsequent spread to the rostral cerebrum. Because of its particular geographic distribution, many aspects of BHM are still poorly documented in the English language veterinary literature, and thus a comprehensive review of the disease is warranted. Here we review the main aspects of BHM, including its historical timeline, etiology, pathogenesis, epidemiology, clinical and pathologic findings, diagnosis, and control and prophylaxis.

Keywords

bovine herpesvirus central nervous system diseases of cattle meningoencephalitis viral diseases

Bovine herpesviral meningoencephalitis (BHM) is an infectious disease of cattle that typically causes neurologic signs in young calves and, less frequently, adult cattle.^65,70,72 The disease is caused most often by bovine alphaherpesvirus 5 (BoAHV5; Orthoherpesviridae, Varicellovirus bovinealpha5; bovine encephalitis herpesvirus), but bovine alphaherpesvirus 1 (BoAHV1; Orthoherpesviridae, Varicellovirus bovinealpha1; infectious bovine rhinotracheitis virus) can also be involved.^65,68 BoAHV1 and BoAHV5 are closely associated genetically and antigenically, and thus cannot be differentiated using conventional laboratory testing.⁷⁴ BHM has an uneven geographic distribution worldwide, with most cases reported in South America.⁶⁷ Because of this particular distribution, many aspects of BHM are poorly documented in the English veterinary literature, resulting in descriptions that may be imprecise and limited to sporadic single case reports. Here we review the main aspects of BHM, including its historical timeline, etiology, pathogenesis, epidemiology, clinical and pathologic findings, diagnosis, and control and prophylaxis.

A brief history of BHM

The first suspicion of a herpesvirus as a cause of neurologic disease in cattle arose from an experimental intranasal infection of calves with a New Zealand strain of infectious bovine rhinotracheitis virus (IBRV) in 1959. Although 2 inoculated calves developed neurologic signs, gross and histologic lesions were absent in the CNS of those individuals.⁸⁶ At approximately the same time, 16 natural cases of “nonsuppurative encephalomyelitis” of unknown etiology were reported in calves in Australia.^40,44 Histologic changes were suggestive of a viral infection but attempts to transmit the disease to other calves failed on that occasion.⁴¹ The same authors subsequently studied an outbreak of meningoencephalitis with high morbidity and fatality in calves from 2-wk to 6-mo-old.⁴¹ Meningoencephalitis was characterized by perivascular lymphocytic inflammation, swollen endothelial cells, microgliosis, and marked dilation of the perineuronal and perivascular spaces in the cerebral hemispheres and midbrain. Myelitis, consisting of lymphocytic perivascular inflammation and microgliosis, was also reported. Neurologic disease and meningoencephalitis were reproduced by intracerebral inoculation of brain suspension from affected calves into susceptible calves.⁴¹ A virus isolate from these cases (N569) was subsequently identified as IBRV.^33,34 Similar reports were also documented in the United States, where IBRV was isolated from Holstein-Friesian dairy calves that died of meningoencephalitis in Los Angeles County,³ and again in Australian freshly weaned 4–8-wk-old calves,³⁷ cementing a possible role of IBRV in cases of neurologic disease in cattle.

In the early 1980s, the disease was documented in South America, affecting freshly weaned calves suffering from respiratory and neurologic disease in Uruguay and soon after in Argentina.^16,17 Histologic and ultrastructural investigation of the brain from those cases revealed lymphoplasmacytic and necrotizing meningoencephalitis with intranuclear viral inclusion bodies (INIBs) in neurons and astrocytes; viral particles typical of herpesvirus were observed within affected cells using transmission electron microscopy.^16,17 The virus was isolated from brain tissue and characterized as IBRV. In the 1980s and 1990s, several authors reviewing cases of neurologic disease assumed to be thiamine-responsive polioencephalomalacia (PEM) of cattle in Brazil^63,87 and Uruguay⁷¹ confirmed those cases to be in fact associated with a herpesviral infection using cell culture or cell culture and in situ hybridization.^63,71,87

Until the 1980s, BHM was considered a clinical and pathologic manifestation of IBRV.³⁸ However, molecular evidence indicated that viral isolates from respiratory (IBR) and genital disease (infectious pustular vulvovaginitis [IPV], infectious pustular balanoposthitis [IPB]) were distinct from those associated with neurologic disease.^10,47,48 Because of these differences, the virus was reclassified into 3 subtypes, namely BoHV-1.1 (associated with IBR), BoHV-1.2 (associated with IPV or IPB), and BoHV-1.3 (associated with neurologic disease). Subsequently, The Herpesvirus Study Group of the International Committee on Taxonomy of Viruses reclassified the neurotropic strains of the virus as BoAHV5.⁷³ For many years, BHM was attributed to BoAHV5 infection,^22,67 but neurologic disease was still occasionally associated with BoAHV1.^{21,22,28,35,57} Today, data from endemic areas indicate that the epidemiology, clinical signs, and pathologic features of BHM caused by BoAHV1 and BoAHV5 are identical, and the viruses cannot be differentiated without specific molecular testing.⁶⁸

The agent

Herpesviral infections occur in many animal species, including insects, mollusks, amphibians, reptiles, birds, and mammals.⁵⁵ Infection is typically more severe in newborns and when the virus adapts and infects a different animal species than its original host-adapted species.⁵⁵ Herpesviruses belong to the order Herpesvirales,^24,55 which is composed of 3 families, namely Alloherpesviridae (herpesviruses of frogs and fishes), Malacoherpesviridae (herpesviruses of oysters), and Orthoherpesviridae (herpesviruses of mammals, reptiles, and birds). Here we will focus on the family Orthoherpesviridae and its 3 subfamilies, Alphaherpesvirinae, Betaherpesvirinae, and Gammaherpesvirinae. All ruminant herpesviruses are in the subfamilies Alphaherpesvirinae or Gammaherpesvirinae (Table 1).⁷⁹ BoAHV1 and BoAHV5 are in the subfamily Alphaherpesvirinae, genus Varicellovirus. BoAHV1 causes IBR, IPV, and IPB, but there is evidence that BoAHV1 is also responsible for cases of BHM.⁶⁹ BoAHV5 is the main cause of BHM in endemic areas.⁷⁴

Table 1.

Herpesviruses (Herpesvirales, Orthoherpesviridae) affecting cattle.

Taxonomic identification	Common name	Abbreviation	Disease manifestations
Subfamily Alphaherpesvirinae
Genus Varicellovirus
Bovine herpesvirus 1	Infectious bovine rhinotracheitis, infectious pustular vulvovaginitis virus	BoAHV1	Rhinotracheitis (IBR), pustular vulvovaginitis (IPV) and balanoposthitis (IPB), abortion, meningoencephalitis
Bovine herpesvirus 5	Bovine meningoencephalitis herpesvirus	BoAHV5	Meningoencephalitis
Genus Simplexvirus
Bovine herpesvirus 2	Bovine mammillitis virus	BoAHV2	Generalized benign skin infection and ulcerative mammillitis
Subfamily Gammaherpesvirinae
Genus Macavirus
Ovine herpesvirus 2	Sheep-associated malignant catarrhal fever virus	OvGHV2	Sheep-associated malignant catarrhal fever
Alcelaphine herpesvirus 1	Wildebeest-associated malignant catarrhal fever virus	AlGHV1	Gnu-associated malignant catarrhal fever
Bovine herpesvirus 6	Bovine lymphotropic herpesvirus	BoGHV6	Suspected cause of abortion
Genus Rhadinovirus
Bovine herpesvirus 4	Movar virus	BoGHV4	Conjunctivitis, respiratory disease, endometritis, vaginitis, mastitis, nodular dermatitis, lymphoma (no proven causal association)

Herpesviruses are large, 120–250-nm diameter, double-stranded, linear DNA viruses. The viral DNA encodes nearly 200 genes and is surrounded by an icosahedral protein capsid composed of 162 capsomeres. The nucleocapsid (capsid and genome) is embedded in an amorphous protein tegument that is surrounded by an envelope formed by a double-lipid layer that originates from the host cell and is covered with viral glycoproteins.^45,79 Herpesviruses (particularly those from the family Alphaherpesvirinae) may undergo productive infection and cell lysis or latent infection.^2,32

Viral infection begins with the recognition of viral glycoproteins by host cell surface receptors (adsorption). Adsorption is mediated by at least 5 viral glycoproteins (gB, gD, gH, gL, gK) and is followed by fusion and entry of the virus into the cell.⁴⁵ Once in the cytoplasm, the viral genome is transported to the nucleus of the host cell via microtubules.⁴⁶ In the nucleus, viral replication starts and the viral DNA is transcribed into α (immediate early), β (early), and γ (late) genes.³² Proteins from α genes (immediate early proteins) are involved in the initial functions of viral infection, including regulating the expression of other viral genes. Proteins from β genes (early proteins) are involved mainly in viral replication. Finally, γ genes are expressed only after viral DNA replication and generate structural proteins (late proteins) of the nucleus, capsid, and envelope.³² After late proteins are synthesized, nucleocapsid assembly begins, with the viral genome packaged in the nucleus. The primary viral envelope is formed by the budding of the nucleocapsid through the inner nuclear membrane. This envelope is lost upon viral fusion with the outer nuclear membrane. The capsid accumulates in the cytoplasm, is re-enveloped by the dictyosomatic (Golgi) complex membranes, and finally transported in vesicles to the extracellular environment to infect new cells.^45,46

Viral transmission occurs by direct contact between animals or indirectly between animals and fomites. Primary viral replication occurs in epithelial cells of the oral, nasal, oropharyngeal, and ocular mucosae from which the virus spreads by local invasion of nerve endings and/or viremia.²⁹ BoAHV1 and BoAHV5 entry into the CNS takes place ~7 d post-infection via retrograde axonal transport along cranial nerves, mainly the olfactory but also the trigeminal nerves.²⁶ In the CNS, a new cycle of viral replication leads to either meningoencephalitis (the primary manifestation of the disease) or life-long latent infection.^66,75

Episodes of viral reactivation from latency typically result from stressful conditions and allow for the virus to be shed and transmitted to other individuals.^55,58,84 During latency, viral particles produce a latency-related gene but there is no production of viral proteins or infectious viral particles.⁵⁵ However, viral DNA can be detected by PCR or in situ hybridization in the nucleus of neurons at sites harboring latent infection.²⁹ In cattle, these sites include the trigeminal nerve or sensory root ganglia, olfactory bulbs, telencephalic cortex, midbrain, pons, cerebellum, and medulla oblongata.⁸³

Epidemiology

The disease affects mainly calves <1-y-old and yearlings but can occasionally occur in older cattle.⁶⁹ Epidemiologic factors that may favor viral dissemination in a herd include weaning of calves at an age that coincides with the decline in passive immunity, large concentrations of animals, transport, introduction of cattle from other locations, change of feed, change of paddocks, vaccination, marking (branding, ear tags, etc.), and castration.^20,27,38 Early weaning of calves was documented in 75% of the farms in which cases of BHM caused by BoAHV5 occurred; however, a possible failure in the passive transfer of immunity was not confirmed.⁶⁶ Experimental studies confirmed the role of passive immunity by demonstrating that groups of calves deprived of colostrum developed meningoencephalitis and respiratory disease after inoculation with BoAHV5 and BoAHV1, respectively.⁸ Calves fed colostrum and inoculated with BoAHV5 did not develop any neurologic or respiratory signs during primary infection. However, when dexamethasone was administered on day 60 post-infection, inoculated calves developed respiratory signs, lethargy, and fever. In addition, viral shedding was confirmed from nasal discharge, confirming viral reactivation similar to the process that occurs during natural stressful situations.⁸

Viral reactivation may occur subclinically or associated with neurologic disease that is identical to that observed in acute infection.^15,83 Experimental evidence suggests that lesions caused by PEM may reactivate latent BoAHV5 infections in cattle.²³ Similarly, bovine viral diarrhea virus (BVDV) may have exacerbated the neurologic signs of cattle experimentally infected with BoAHV5, increasing the amount of virus excreted via the nasal route.⁷⁸ These authors suggest that PEM and BVDV may be associated with cases of BoAHV5 meningoencephalitis in natural situations, but more data are needed to confirm or refute these assertions.

BHM occurs in several countries but with a higher frequency in Brazil and Argentina. There is a strong association between BoAHV1 infection and the bovine respiratory disease complex (BRDC), which causes losses of nearly US$1 billion per y worldwide.²⁵ These economic losses have led to the adoption of widespread vaccination against BoAHV1. One explanation for the lower prevalence of BHM cases in Europe and North America is that the natural or vaccine-induced immunity against BoAHV1 in these countries protects animals against BoAHV1 and also BoAHV5.⁸² Therefore, outbreaks of neurologic disease would be more frequent in regions where vaccination against BoAHV1 occur less frequently, which is the case in some parts of Brazil (Ricardo A. A. Lemos, Claudio S. L. Barros, pers. comm., 2024 Feb 21).

Clinical signs

As part of the MS dissertation of one of the authors (D.R. Rissi under the supervision of C.S.L. Barros at the Laboratory of Veterinary Pathology, Federal University of Santa Maria, Brazil), we investigated 7 outbreaks of BHM in recently weaned calves in a population at risk of 1,359 cattle in southern Brazil.⁶⁶ A total of 54 individuals were affected, 50 died spontaneously or were euthanized, and 4 recovered. The overall morbidity, mortality, and case fatality rates were 4%, 4%, and 93%, respectively. The clinical course was 3–10 d. These features were typical of cases of BHM in our routine caseload in southern Brazil, where the disease was the third most prevalent neurologic disorder of cattle, following rabies and hepatic encephalopathy secondary to hepatic fibrosis caused by Senecio spp. (ragwort) poisoning.⁶⁹

The typical clinical signs of BHM, somnolence and obliviousness, are key indicators of the disease in endemic areas.⁶⁹ Affected cattle move away from the herd and remain still, with low head carriage (Fig. 1). Another finding includes serous nasal and ocular discharge that, as the disease progresses, becomes mucoid and mucopurulent (Figs. 2, 3). Cerebrocortical signs, such as grinding of the teeth, muscle tremors, circling, blindness, incoordination, pressing of the head against objects, nystagmus, and seizures, usually follow (Fig. 4).^20,27,66,75 Some cattle may fall and remain recumbent or develop paddling movements (Fig. 5).⁶⁹ Rare clinical signs include aggressiveness and mania.^7,39 Nonspecific signs, such as dehydration, weight loss, rough hair coats, fever, abdominal pain, anorexia, tachycardia, and tachypnea, are also described.^{20,37,40,42,62
–64,75,87} Some affected individuals may develop complications from recumbency, such as bacterial bronchopneumonia.⁸

Figures 1–5.

Herpesviral meningoencephalitis in cattle. Figure 1. A 7-mo-old male calf was separated from the herd, was somnolent, and stood still for long periods with a low head carriage. Figure 2. Affected 6-mo-old female calf with serous ocular discharge and drooling. Figure 3. Same calf in Fig. 1 with yellow, mucopurulent nasal discharge. (Image from Pesq Vet Bras 26:123–132, 2006; with permission). Figure 4. A 7-mo-old female calf from the same outbreak in Figs. 1 and 3 was ataxic and had a wide-based stance. Figure 5. Same calf in Figs. 1 and 3 with recumbency.

Pathology

The diagnostic autopsy findings are restricted to the brain. Gross lesions vary among affected cattle, and are clearly more intense in the rostral portions of the brain, particularly the frontal and olfactory lobes.^{8,20,27,37,65,66,75} Mild-to-moderate lesions are observed early in the disease course (Figs. 6–8) and consist of hyperemia of the leptomeningeal vessels throughout the brain.^17,37,66 In some affected individuals, hyperemia is accompanied by edema and hemorrhage of the rostral cerebral cortex.^20,27 Edematous areas have evident narrowing of sulci and flattening of gyri.^20,27,66 The cut surface of the cerebral cortex may be slightly red or yellow and soft.⁶⁶ As the disease progresses, more pronounced swelling of the frontal lobes can be observed (Figs. 9–11), with yellowing and softening of the convolutions, characteristic of malacia.⁶⁶ Cross-sections of the brain reveal a red-to-brown and soft cerebral cortex. These areas subsequently become markedly depressed, gelatinous, and yellow-to-brown (Figs. 12, 13), with a granular appearance on cut surface.^20,66 Areas of malacia can also be observed in the parietal lobes and less often the basal and thalamic nuclei.⁶⁶ In more advanced cases, a residual lesion may develop, consisting of segmental collapse of the frontal cerebral cortex (Fig. 14), which is replaced by gelatinous, brown, necrotic debris located between the leptomeninges and the subcortical white matter.⁶⁶ Other findings may include mucus in the nasal cavity, hyperemia of the nasal mucosa, retropharyngeal and mediastinal lymphadenomegaly, and laryngeal and pharyngeal hemorrhage.^16,67

Figures 6–14.

Herpesviral meningoencephalitis in cattle. Figure 6. Acute lesions consist of leptomeningeal hyperemia and mild hemorrhage and swelling of the frontal lobes. Figure 7. Frontal view of the brain in Fig. 8 highlights the hemorrhage and swelling of the frontal lobes. Figure 8. In acute cases, the gray matter of the frontal and parietal lobes is yellow and granular, evidencing early necrosis. Figure 9. Subacute lesions consist of extensive hemorrhage and swelling of the frontal lobes. Figure 10. Frontal view of the same brain in Fig. 11 highlights the extensive hemorrhage and swelling of the frontal lobes. Figure 11. In subacute cases, the gray matter of the frontal and parietal lobes is friable, granular, and dark-yellow to brown. Figure 12. Chronic lesions consist of depression and hemorrhage of the frontal lobes. (Image from Pesq Vet Bras 26:123–132, 2006; with permission). Figure 13. Frontal view of the brain in Fig. 14 with depressed and hemorrhagic frontal lobes. Figure 14. In a chronic case, the frontal cortex is collapsed and largely replaced by red-brown gelatinous material. There are 2 soft, gelatinous, yellow areas of necrosis in the rostral portion of the right subcortical white matter (arrowhead).

Because BHM is rare in many parts of the world, the gross lesions associated with BHM are not described in detail in the main veterinary pathology textbooks,⁵⁰ with some sources stating that gross lesions are typically absent¹⁴ or completely absent.⁸⁰ However, our experience with cases in Brazil and other countries in South America supports the assertion that gross lesions (particularly malacia) in the brain of cattle with BHM caused by BoAHV1 or BoAHV5 are common and specific enough for a presumptive gross diagnosis of the disease in endemic areas.^66,67,69 To assess the frequency of malacia in published cases, we reviewed 31 reports of spontaneous outbreaks of BHM in which a gross description was available. For our search, we defined malacia as a gross lesion perceptible as a softening of the CNS tissue.⁵⁰ Malacia was described in 18 (58%) published and unpublished cases (Sharon Yang, Vanderbilt University Medical Center, pers. comm., 2018 Nov 04) of BHM.^{9,20,27,35,36,43,53,59,61,64
–66,68,75,77,81,90} Of these, 16 (89%) were from South America (Argentina, Brazil) and only 2 (11%) were from other countries, namely USA (S. Yang, pers. comm., 2018 Nov 04) and Japan.³⁵ Thirteen publications did not mention malacia.^{3,5
–7,16,37,40,41,51,54,62,71,85} These findings corroborate the fact that necrotic gross lesions are common in cases of BHM. In addition, the severe histologic changes associated with necrosis in many published cases may suggest that malacia was present but, for some reason, it was not defined as such.

Histologic lesions are observed primarily in the gray matter and parallel the neuroanatomic distribution and intensity of the gross lesions (Fig. 15).⁶⁶ Lesions can be classified in a chronologic sequence as acute, subacute, and chronic.^20,27,66,75 Acute lesions consist of segmental, randomly distributed, cerebrocortical necrosis and edema with neutrophilic infiltration, astrocytosis, and microgliosis (Figs. 16, 17). Affected neurons have a bright-red, shrunken, angular cytoplasm (red neurons), and pyknotic or absent nuclei. The cerebrocortical necrosis is not laminar. Areas of neuronophagia and astrocytosis are scattered throughout the affected cortex (Fig. 18). Clusters of neutrophils and fewer macrophages are present within areas with more prominent neuronal necrosis. Areas of white matter edema are often present in the junction between the gray and white matter. Edema and neutrophilic inflammation can extend deep into the subcortical white matter. Subpial and cortical hemorrhages are common. A few lymphocytes and plasma cells surround leptomeningeal vessels. Eosinophilic INIBs may be present in neurons and astrocytes (Fig. 19), but their frequency varies among cases.^27,38,66 Ultrastructural findings reveal that these inclusions contain assembling herpesviral particles.^16,17

Figures 15–22.

Herpesviral meningoencephalitis in cattle. H&E. Figure 15. The gray matter of the frontal lobe is effaced by extensive hemorrhage and loss of the neuroparenchyma (asterisk), with cleavage of the cortex from the underlying white matter and areas of inflammation (arrowhead). Figure 16. Necrotic neurons in the frontal cortex have intensely eosinophilic and angular cytoplasm (red neurons) with pyknotic or absent nuclei. Figure 17. Necrotic neurons in the frontal cortex are surrounded by clusters of neutrophils. Figure 18. A necrotic cortical neuron in the frontal lobe is surrounded by neutrophils and microglia (neuronophagia). Figure 19. Astrocytes in the frontal lobe have eosinophilic viral INIBs (arrowheads) that displace the chromatin to the periphery of the nucleus. Figure 20. Perivascular lymphoplasmacytic inflammation in the frontal lobe. The neuroparenchyma is hypercellular (astrocytosis and microgliosis). Figure 21. The neuroparenchyma is almost completely replaced by sheets of foamy macrophages. Figure 22. A residual lesion in the frontal lobe consisting of scattered foamy macrophages and blood vessels (Image from Pesq Vet Bras 26:123–132, 2006; with permission).

As the lesions become subacute, perivascular lymphoplasmacytic inflammation becomes apparent within the affected neuroparenchyma (Fig. 20). Foamy macrophages (gitter cells) are scattered throughout the necrotic gray matter (Fig. 21). Rare ferruginated neurons (partially necrotic neurons with cytoplasmic mineral) can be observed interspersed within the necrotic cortex, but necrotic neurons and viral INIBs become less frequent. Dense lymphoplasmacytic and histiocytic perivascular inflammation is present in the leptomeninges.^20,27,66,75

Chronic lesions are less commonly observed because affected individuals typically die before the lesions become apparent. These changes consist of partial or complete collapse and hemorrhage of the gray matter (decortication), which is replaced by sheets of foamy macrophages or apparently empty spaces consisting of blood vessels surrounded by foamy macrophages (residual lesion, Fig. 22).⁶⁶

We systematically assessed the distribution of the histologic changes in the brain of 19 yearling calves affected by BHM (Fig. 23).⁶⁶ Histologic changes are more prominent in the frontal lobes, followed by basal nuclei, thalamus, parietal lobe, midbrain, pons, occipital lobe, medulla oblongata, cerebellum, and hippocampus. However, from a diagnostic standpoint, when considering tissues for diagnostic confirmation of BHM, it is important to remember that the most pronounced lesions (and viral load) are concentrated in the frontal lobes, basal nuclei, and thalamus.^66,69

Figure 23.

Distribution of the inflammatory and necrotizing lesions caused by herpesviral meningoencephalitis in cattle. Black lines represent areas from which standard tissue sections were collected for histology: 1 = frontal lobe; 2 = basal nuclei; 3 = parietal lobe; 4 = hippocampus; 5 = thalamus; 6 = occipital lobe; 7 = midbrain; 8 = cerebellum; 9 = pons; 10 = medulla oblongata. Black dots correspond to the intensity of inflammation and necrosis. Lesions were predominantly inflammatory in sections 7–10. (Image by Dr. Mario A. Neto, Balneário Camboriú, SC, Brazil).

Spinal cord lesions are rarely described,⁹⁰ but their true frequency is unknown because of the infrequent examination of the spinal cord during large animal autopsy. Because the virus can also reach the CNS via retrograde transport along the trigeminal nerve,^15,49 a few reports mention trigeminal ganglionitis in cattle with BHM.^49,58 To assess these findings, we examined the trigeminal ganglion of all BHM cases in our routine caseload and found no evidence of inflammation.^60,66 Our findings support the hypothesis that the olfactory nerve pathway is more rapid and efficient for the virus to reach the CNS and that affected cattle likely die before inflammation is established in the trigeminal nerve and ganglia.²⁶

Diagnosis

In endemic areas, the typical gross and histologic lesions are highly suggestive of BHM.^32,66,68,69 Although INIBs in neurons and astrocytes can be used as further evidence of infection, they may be rare or occasionally absent, and confirmation should be performed using more specific laboratory tests such as PCR testing, immunohistochemistry (IHC), and viral isolation.^{1,12,13,18,19,30,67,82} Brain samples submitted for ancillary testing should include the frontal portions of the cerebral cortex, and laboratory results should be interpreted in the context of the epidemiology, clinical features, and lesions suggestive of BHM.

PCR testing can be performed on refrigerated, frozen, or formalin-fixed specimens and is a rapid method for diagnostic confirmation and/or typing of the virus.^56,74 Although PCR detection of BoAHV gB confirms herpesviral infection, it does not discriminate between BoAHV1 and BoAHV5,⁷⁴ which is achieved by the use of a PCR test able to amplify a region of the herpesviral gC that is specific for either BoAHV1 or BoAHV5.^67,74 IHC is available for routine diagnostic confirmation of BoAHV infection.¹¹ However, data are still scarce, and immunolabeling is often inconsistent in diagnostic cases, suggesting that IHC may not be a reliable tool for diagnostic confirmation (Daniel R. Rissi, pers. comm., 2024 Sep 1). Viral isolation needs to be performed on refrigerated samples that must be shipped to the laboratory in a timely manner. This may be problematic when the disease is suspected or diagnosed in remote areas.⁷⁰ Serology is of little use in cases of neurologic disease because affected cattle usually die or are euthanized during the sample collection period.³²

The differential diagnoses for BHM should include cases of neurologic disease leading to inflammation and/or necrosis in the rostral portions of the brain. As part of the National Surveillance Program for Transmissible Spongiform Encephalopathies in Southern Brazil (2000–2007), we diagnosed 501 cases of neurologic disease in cattle at the Laboratory of Veterinary Pathology (Federal University of Santa Maria, Santa Maria, Brazil).⁶⁹ The neurologic disease of cattle that resembles BHM most closely is PEM.^4,76 Gross lesions of PEM also consist of cerebrocortical swelling, softening, and yellow areas of necrosis in the cortex, but these are more prominent in the parietal cortex.⁴ In addition, lesions of PEM are typically restricted to the cerebral cortex, whereas lesions of BHM also extend more deeply into the subcortical white matter.^4,52,68 Histologic findings associated with PEM are typically bilateral and symmetrical and predominantly necrotic (laminar cortical neuronal necrosis and edema), with a mild-to-moderate inflammatory component composed of foamy macrophages and other inflammatory cells, but not neutrophils.^52,69 Finally, contrary to BHM, PEM does not have a clear age predilection for young calves.⁴ Hemorrhagic and necrotic gross lesions caused by Histophilus somni may resemble those of BHM but are distributed throughout the brain and/or spinal cord.¹⁴ Further, the presence of vasculitis and thrombosis with bacterial organisms in the CNS and extraneural tissues should be consistent with H. somni infection.¹⁴

Control and prophylaxis

There is no specific or effective treatment for affected cattle.⁷⁰ In endemic areas, control and prophylactic measures aim to lower the economic losses caused by respiratory, reproductive, and neurologic disease.³² These include disease surveillance using serology to determine whether the infection is present in the herd or in individuals that will be introduced into the herd, minimization of potentially stressful situations, and isolation of affected individuals in cases of clinical disease.³² In addition, vaccination is strongly recommended to prevent and reduce economic losses caused by BoAHV infection,⁷⁰ particularly in herds with a history of clinical disease or high cattle turnover. In endemically infected herds, high immunity levels also provide effective protection against the disease. Research has shown that vaccination does not impact the reproductive performance of beef cows compared to unvaccinated cattle.³¹ Notably, genetically engineered vaccines produce antibodies that can be distinguished from those generated by natural infection, giving them an edge over traditional vaccines.^32,88,89

Footnotes

Acknowledgements

This review was written as part of the first author’s Doctorate Dissertation. We thank Dr. Mario A. Neto for providing the image for the distribution of the lesions (Fig. 23). We also thank Pesquisa Veterinária Brasileira (Brazilian Journal of Veterinary Research) for allowing us to reuse Figs. 3, 12, and .

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

Dr. B.S. Santos’ Doctorate was partially funded by CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Finance Code 001) and Fundação Universidade Federal de Mato Grosso do Sul (UFMS/MEC).

ORCID iD

Daniel R. Rissi

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