Bovine malignant catarrhal fever: Malignant catarrhal fever is usually a sporadic highly fatal disease of cattle and other ruminants, including deer, buffalo, and antelope, and can involve several animals in a herd. The disease has a worldwide distribution, and the clinicopathologic features do not differ significantly from one part of the world to another. The primary target tissues are the vasculature and lymphoid organs and epithelial tissue (particularly the respiratory and gastrointestinal tracts), but the kidneys, liver, eyes, joints, and CNS are also affected in some cattle. The virus appears to be transferred between lymphoid tissue/cells and endothelial cells via leukocytic trafficking in T lymphocytes. Two general types of the disease occur, the sheep-associated and wildebeest-derived forms. The causative agents involved belong to the herpesvirus subfamily Gammaherpesvirinae. The disease occurring outside Africa, caused by ovine herpesvirus 2 (OHV-2), often involves close contact of presumed “carrier” sheep with susceptible ruminants. The disease has recently been reported in muskox (Ovibos moschatus), Nubian ibex (Capra nubiana), and gemsbok (Oryx gazella). In Africa and occasionally in wildlife facilities outside the continent, the source of the infection (designated Alcelaphine herpesvirus 1 [AHV-1]) is the wildebeest. Two other antigenically related viruses, which apparently do not cause natural disease, include Alcelaphine herpesvirus 2 (AHV-2) and Hippotragine herpesvirus 1 (HiHV-1), which have been isolated from African hartebeest and roan antelope, respectively. It is generally accepted that cattle and other susceptible ruminants contract the disease in nature after respiratory or oral infection during association with carrier sheep (presumed) and wildebeest, particularly at the time of parturition. A cell-mediated and cytotoxic lymphocytic process has been proposed as involved in the development of the necrotizing vasculitis.

Gross lesions of the CNS include active hyperemia and cloudiness of the leptomeninges caused by nonsuppurative meningoencephalomyelitis and vasculitis. Lymphocytic perivascular cuffing and varying degrees of necrotizing vasculitis occur in the leptomeninges and in all parts of the brain and occasionally in the spinal cord, with the white matter most consistently involved. Other lesions in the affected CNS include variable neuronal degeneration, microgliosis, choroiditis, necrosis of ependymal cells, and ganglioneuritis. Clinical signs referable to CNS infection may include trembling, shivering, ataxia, and nystagmus.

Infectious bovine rhinotracheitis: Although bovine herpesvirus 1 (BoHV-1) occasionally causes a nonsuppurative meningoencephalitis, primarily in young cattle, two variants of BoHV-1 isolated in Argentina and Australia (referred to as BoHV-1, subtypes 3a and 3b, respectively) and recently BoHV-5 (isolated in South America, mainly Argentina and Brazil) have a particular tropism for the CNS. Recent evidence suggests that BoHV-5 uses an intranasal route to infect and replicate in the nasal mucosa and then enters the CNS by retrograde axonal transport using the trigeminal and olfactory nerves.

Gross lesions are nonspecific and include meningeal congestion and petechiation in ventral areas of the brain. Microscopic lesions consist of lymphomonocytic meningoencephalitis (nonsuppurative) with the occasional presence of neutrophils. Other changes include neuronal degeneration, vasculitis, focal malacia, and presence of intranuclear acidophilic inclusions in neurons and astrocytes.

Clinically, outbreaks of disease occur in young cattle ranging in age from 5 to 18 months. Lesions can also involve the eyes (conjunctivitis) and tissues of the reproductive, alimentary, and integumentary systems in addition to the nervous system.

Visna: Visna, which means wasting, is a slowly progressive, transmissible disease of sheep. The disease is caused by a strain of the ovine maedi-visna virus (MVV) complex, one of the eight basic “lenti” (slow) viruses (family Retroviridae). A different strain of the same virus causes a lymphocytic interstitial pneumonia referred to as maedi.

In recent years, the understanding of the factors associated with infection, including the mechanism of lesion development, has improved. Visna is a persistent viral disease that probably results from the ability of the virus to form provirus and integrate into the host genome. The virus can also change its antigenic characteristics (antigenic drift), which enables it to escape the effects of the host’s immune response. Although the visna virus and other lentiviruses can infect promonocytes and monocytes in the bone marrow and blood, viral replication is restricted in these cells, where it remains as provirus DNA until maturation and differentiation to macrophages. Primary viral replication occurs in cells of monocyte-macrophage-microglial lineage. Thus visna virus enters the CNS by way of leukocytic trafficking of virus-infected macrophages. Visna virus can also be present in oligodendrocytes and astrocytes located in foci of demyelination. It has been suggested that the virus gains access to these cells via close contact with infected monocytes. Recent studies suggest the virus can also infect and productively replicate in endothelial cells. This mechanism may provide an additional route for viral entry into the CNS and the potential for alterations of the blood-brain barrier.

Although gross lesions are not frequently observed, they may occur in areas of prominent inflammation where they appear as yellow-tan areas. Early microscopic lesions primarily affect the gray and white matter subjacent to the ependyma of the ventricular system of the brain and central canal of the spinal cord. These lesions are characterized by a nonsuppurative encephalomyelitis accompanied by pleocytosis, variable edema, CNS necrosis, astrocytosis, choroiditis, and nonsuppurative leptomeningitis. The inflammatory response is thought to be caused by the upregulation of expression of major histocompatibility complex class II genes that occurs in virus-infected macrophages. Degeneration of myelin sheaths also occurs at this time but is often accompanied by axonal degeneration, suggesting that it could be a secondary lesion, such as in Wallerian degeneration. Oligodendroglial and neuron injury and necrotic cell death are attributable to cytokines and other toxic factors secreted by inflammatory cells and glial cells. Recent in vitro studies suggest that caspase activation leading to apoptotic cell death may play a role in visna.

Neuronal cell bodies and oligodendroglia are normal (except in areas of necrosis) during this stage of the disease. The latter cells can become infected, however, which leads to later development of demyelination. Primary demyelination, particularly in the spinal cord, has been described in animals infected for prolonged periods (months to years). Such animals also have periventricular inflammation.

The primary demyelination that occurs during the late stages of the disease process (6 months to 8 years after infection) has been proposed to result from oligodendroglial cell infection. The main sources of excreted virus are the udder and lungs (as mainly cell-associated virus), and transmission occurs most readily between the dam and lamb via the milk and between confined individuals, probably via respiratory secretions. The MVV has also been detected in semen of infected rams. It is important to emphasize that no profound immune deficiency occurs with MVV infections, as is the case for immunodeficiency lentiviral infections that infect CD4⁺ T lymphocytes. Nonetheless, secondary infections can still significantly accompany MVV infection.

In addition to pneumonia, MVVs can also cause mastitis, arthritis (uncommonly of the carpus or hind limb joints), and a mesangial glomerulitis. Irrespective of the target organ, the lesions are to be regarded as chronic and lymphoproliferative, in contrast to the well-known immunodeficiency infections caused by human immunodeficiency virus 1 (HIV-1), simian immunodeficiency virus (SIV), and FIV.

Viral strain differences and breed of sheep can influence the lesions that develop. For example, the visna form of the disease does not commonly occur in ovine breeds of North America, although some degree of visna-like lesions can be seen with maedi. Visna originally was described in Iceland, but sheep with similar lesions of the CNS have been detected in The Netherlands, Kenya, the US, and Canada. CNS signs include an abnormal hindlimb gait that progresses to incoordination and rear limb paresis over a period of weeks or months.

Caprine leukoencephalomyelitis arthritis: Caprine leukoencephalomyelitis arthritis was first described in the US and has since been recognized in other parts of the world. The infection can be readily transmitted by colostrum and milk after birth, or by direct contact. A close relationship exists between the MVVs of sheep and the caprine arthritis encephalitis (CAE) virus, but genomic differences between them can be demonstrated. As with MVV infection of sheep, CAE viral infection is also a lymphoproliferative disease with a tropism for the macrophage, which acts as a carrier for the virus.

Gross lesions in the nervous system include tan- to salmon-colored foci of necrosis and inflammation that can occasionally be detected in the brain (Fig. 14-90) and most prominently in the spinal cord. Microscopic lesions of the nervous system are similar to those of visna (nonsuppurative encephalomyelitis) but can be more severe with CAE. Nonneural lesions include interstitial pneumonia of moderate severity in some affected kids. Such lungs fail to collapse completely and are mottled red or blue. As discussed under visna, the mechanism of infection and cell death appear similar.

The pattern of disease in CAE is age dependent. Neurologic manifestations are usually seen in young kids 2 to 4 months of age, but unlike visna in sheep, there is a more rapid progression and signs progressing to quadriplegia develop within weeks to months. As with visna, affected goats have pleocytosis. In adult goats, the primary target tissue is the synovium of the joints, and animals that survive the initial infection have lymphoproliferative synovitis and arthritis develop. Pneumonia, lymphocytic mastitis, and encephalomyelitis also occur in adult animals.

Primary cerebellar neuronal degeneration: Primary cerebellar neuronal degeneration has also been reported to occur in Yorkshire piglets, Merino and Charolais lambs, Holstein Friesian calves, Angus calves, and a moose. An autosomal recessive mode of inheritance is suspected or documented in several of the diseases, but the mechanism of injury is unclear. Grossly, the cerebellum can be normal or reduced in size and atrophic. Microscopically, lesions may include loss of Purkinje cells, variable neuronal depletion in the granular layer, fusiform swellings of proximal Purkinje cell axons, and astrogliosis in the molecular layer.

Animals with postnatal primary cerebellar neuronal degeneration are normal at birth or at the time of ambulation. Onset of ataxia with various other clinical signs referable to cerebellar disease begins weeks or months after a period of apparently normal development. Initial clinical signs are often subtle. Progression of the signs can be slow or rapid, relentless, or with static periods. Some individuals reach a stage without further progression of signs, but this is not typical of the syndrome in most animals.

Thiamine deficiency in ruminants: Thiamine deficiency in cattle, sheep, and less commonly, goats, has been termed polioencephalomalacia or cerebrocortical necrosis. Rumen microbes are able to synthesize thiamine. Conclusive evidence of an absolute thiamine deficiency as the sole cause of polioencephalomalacia in ruminants has been elusive. Evidence or theories linking thiamine with the ruminant disorder include the following:

Gross lesions, if present, are limited primarily to the cerebral cortex. Initially, 2 days after onset, the surface of the brain can be swollen (cerebral edema) as indicated by flattening of cerebrocortical gyri and narrow sulci. In rare cases with more severe brain swelling, brain displacement with herniation of the parahippocampal gyri beneath the tentorium cerebelli and the vermis of the cerebellum into the foramen magnum can occur. By 4 days after onset, yellow discoloration of the cerebrocortical gray matter occurs (Fig. 14-91), and it is at this time that autofluorescence (see later for more detail) is seen when the brain is examined under 375 nm ultraviolet light (Fig. 14-92). Eight to 10 days after onset, edematous separation and necrosis involving the middle to deeper lamina or gray-white matter interface may be appreciable (Fig. 14-93). In advanced cases with prolonged survival, areas of marked atrophy of cerebral gyri with an attenuated or absent gray matter zone are covered by meninges (Fig. 14-94).

Microscopically, the earliest lesions are laminar cortical necrosis and astrocytic swelling. Laminar cortical necrosis is characterized by neuronal necrosis (ischemic change), with a laminar pattern of edema in the cerebral cortex. Neurons in the middle to deep lamina of the parietooccipital lobes of the cerebral cortex are preferentially affected (Fig. 14-95, A). In the early stages or in mild cases, lesions can be limited to the depths of cerebrocortical sulci, but generally there is involvement of entire gyri that may be confluent over extensive areas of the cortex. After 4 to 5 days, neuronal necrosis and edema are more severe, and there is an early influx of blood monocytes that mature into tissue macrophages and become gitter cells as they phagocytose necrotic debris. Macrophages and gitter cells are observed most commonly in perivascular and perineuronal spaces and in the pia arachnoid (see Fig. 14-23, A). After 8 to 10 days, necrosis and edema have resulted in laminar separation (at the gray matter–white matter interface) in which there are prominent accumulations of macrophages (Fig. 14-95, B). Lesions that accompany the necrosis include vascular prominence caused by endothelial cell and perithelial cell hypertrophy and hyperplasia, congestion, and a minimal, if any, influx of neutrophils. Bilaterally symmetric focal lesions, similar to those seen in carnivores, occur in the thalamus and midbrain or colliculi and rarely in other brainstem structures. Animals that survive can have cerebral atrophy and develop hydrocephalus ex vacuo and have been known to live 1 to 2 years. It should be noted that laminar cortical necrosis can be caused by a variety of metabolic abnormalities. In ruminants, in addition to thiamine deficiency, water deprivation–sodium ion toxicosis, lead poisoning, and high sulfur intake can cause polioencephalomalacia and laminar cortical necrosis. Although autofluorescence at 365 nm ultraviolet light has been historically attributed to the accumulation of ceroid-lipofuscin in lipophages resulting from lipid degeneration in injured neuronal cell membranes, this supposition has recently been questioned. A recent study of cerebrocortical necrosis reported that autofluorescent substances in degenerating neurons occurred in structures resembling mitochondria and that ceroid-lipofuscin pigments were not demonstrated microscopically in damaged CNS. An association between mitochondria and autofluorescence has also been shown in the neuronal ceroid lipofuscinoses (Batten disease, ceroid-lipofuscin storage diseases). These diseases are characterized by the accumulation of an autofluorescent (365 nm ultraviolet light), intracytoplasmic storage material in CNS neurons composed mostly of subunit c of mitochondrial ATP synthase.

Clinically, the disease is seen most commonly in cattle 6 to 18 months of age fed concentrated rations. In sheep, most cases occur in younger age groups (2 to 7 months). Clinical signs in cattle and small ruminants may include depression, stupor, ataxia, head pressing, apparent cortical blindness, opisthotonos, convulsions, and recumbency with paddling and then death. If animals survive or respond to therapy, clinical signs can persist.

Polioencephalomalacia commonly occurs in cattle fed rations rich in carbohydrates with little roughage and is also associated with clinical or subclinical acidosis that may precipitate changes in rumen microflora. The disorder also occurs in association with other dietary factors, including cobalt deficiency, molasses- and urea-based diets, and diets high in elemental sulfur and sulfates and sulfides, some of which are not specifically associated with thiamine deficiency.

Recently, there has been considerable interest in the relationship of high dietary sulfur to polioencephalomalacia. All sources of sulfur, including formulated rations, plants rich in sulfur (Kochia scoparia), and high concentrations of sulfur in the drinking water, are additive. Total dietary intake should not exceed 0.3% to 0.4%. The exact mechanism to explain sulfur-induced polioencephalomalacia in ruminants has not been proved. Although deficiency or disordered metabolism of thiamine can be involved, it would seem not to be the sole cause or, in some instances, even a major factor in the disorder. Alternatively, polioencephalomalacia could represent a multifactorial metabolic disorder with multiple causes, all culminating in cerebrocortical necrosis. Any unifying hypothesis concerning the mechanism(s) of brain damage would have to reconcile all these variables.

Clostridium perfringens type D encephalopathy (pulpy kidney disease, overeating disease): Clostridium perfringens type D enterotoxemia, associated with epsilon toxin production, is a disease of sheep, goats, and cattle, but only sheep commonly exhibit the neurologic manifestations of the disease. Brain damage is due to vascular injury and breakdown of the blood-brain barrier. Binding of epsilon toxin to endothelial cell surface receptors results in opening of tight junctions, disturbed transport processes, increased vascular permeability that results in vasogenic edema, swelling of astrocytic foot processes, and ultimately necrosis caused by hypoxic-ischemic mechanisms. Some of the effects of epsilon toxin can be mediated by an adenyl cyclase–cAMP system.

Gross lesions are absent in some peracute cases but when present, consist initially of bilaterally symmetric foci of malacia, leading to yellow-gray to red foci with malacia and cavitation (Fig. 14-96, A). Lesions can be found in the internal capsule, basal nuclei, thalamus, hippocampus, rostral colliculus and substantia nigra, pons, corona radiata of frontal cortex, and cerebellar peduncles, especially the middle peduncle. Lesions in other tissue consist of pulmonary congestion and edema, serous pericardial effusion, petechiation, and soft (pulpy) kidneys (see Fig. 11-49).

Microscopically, the CNS lesion in acute cases is vasogenic edema secondary to vascular injury. The fluid in perivascular spaces is frequently protein rich and eosinophilic. Walls of arterioles can be hyalinized, and endothelial cell nuclei swollen and vesicular (Fig. 14-96, B). Vasogenic edema, which is interstitial in location, gives a light or pink-staining, spongy appearance to the CNS parenchyma. Both gray matter and white matter are affected. Pericapillary hemorrhage and acute necrosis of neurons and macroglia occur. Other changes occur with longer survival and include axonal swelling, accumulation of neutrophils and foamy macrophages (Fig. 14-96, B and C), vascular prominence caused by perithelial-endothelial nuclear enlargement or swelling, lymphocytic perivascular cuffing, and liquefactive necrosis.

Sheep of all ages, except newborns, are susceptible; incidence peaks between 3 and 10 weeks of age and in feeder lambs shortly after arrival at a feedlot. Resistance of newborns can be related to lack in the gut of pancreatic proteolytic enzymes necessary for activation of the epsilon toxin, and to trypsin inhibitors in colostrum. Lambs are typically in good condition and are found dead.

Enterovirus-induced porcine polioencephalomyelitis: See Web Appendix 14-1.

Hemagglutinating encephalomyelitis: See Web Appendix 14-1.

Pseudorabies: Pseudorabies virus (porcine herpesvirus 1), an alphaherpesvirus, causes encephalitis primarily in pigs; several species of domestic and wild animals are also susceptible. The disease is also known as Aujeszky’s disease and “mad itch.” Pseudorabies is not related to rabies but was named because its clinical signs sometimes resemble those seen with rabies.

The route of natural infection in pigs is intranasal, pharyngeal, tonsillar, or pulmonary by direct contact or aerosolization, followed by reproduction of virus in epithelial cells of the upper respiratory tract. The virus then travels to the tonsil and local lymph nodes by way of the lymph vessels. After replication in the nasopharynx, virus invades sensory nerve endings and is then transported in axoplasm via the trigeminal ganglion and olfactory bulb to the brain. The virus has also been reported to be capable of spreading transsynaptically. Recent studies have additionally shown that some strains produce lesions in the gastrointestinal tract and myenteric plexuses, suggesting that infection might spread from the intestinal mucosa to the CNS via autonomic nerves. In latently infected pigs, the oronasal epithelium can be recurrently infected by virus spreading from the nervous system, followed by its excretion in oronasal fluid. The mechanisms that allow for latency and recrudescence are unclear, but neuronal apoptosis may play a role. The virus can also spread hematogenously, although in low titer, to other tissues of the body. Cellular attachment, entry, and cell-to-cell spread of the virus are mediated by glycoprotein projections that extend from the surface of the viral particle.

Gross lesions in pigs occur in several nonneural tissues, including organs of the respiratory system, lymphoid system, digestive tract, and reproductive tract. Focal tissue necrosis also occurs in the liver, spleen, and adrenal glands, particularly in young suckling pigs, and mortality can be high. The CNS is free of gross lesions except for leptomeningeal congestion. Microscopic lesions in pigs are characterized by a nonsuppurative meningoencephalomyelitis with trigeminal ganglioneuritis. Injury to CNS tissue can be marked, with neuronal degeneration and necrosis. Intranuclear eosinophilic inclusion bodies are not commonly detected in pigs but can be present in neurons, astrocytes, oligodendroglia, and endothelial cells. In cattle, sheep, dogs, and cats, the pathogenesis involving axonal spread to the CNS is comparable to that of pigs, with lesions that include nonsuppurative encephalomyelitis accompanied by ganglioneuritis. Intranuclear inclusion bodies, either eosinophilic or basophilic in their staining characteristics, have been described in neurons of the brain.

The disease in susceptible species other than pigs is generally fatal. Although pigs—particularly young, suckling piglets—can die from infection, most mature pigs remain persistently infected and act as latent carriers. Infection of secondary hosts, such as cattle, sheep, dogs, and cats, regularly involves direct or indirect contact with pigs. Secondary hosts acquire the virus through ingestion, inhalation, and wound infection. Dogs and cats often acquire the virus by ingesting organs from pigs that contain the pseudorabies virus.

Classic swine fever (hog cholera): See Web Appendix 14-1 and Chapters 4 and 10.

Edema disease (enterotoxemic colibacillosis): Edema disease is a disorder of rapidly growing, healthy feeder pigs being fed a high-energy ration. The disease is caused by strains of Escherichia coli producing a Shiga-like toxin, which is similar to toxins produced by Shigella dysenteriae and is designated Shiga-like toxin type IIe (SLT-IIe). This toxin causes necrosis of smooth muscle cells in small arteries and arterioles and a reduction focally in the degree of circulation to the CNS parenchyma, leading to infarction manifested grossly as malacia in the CNS. Glycolipid cell surface receptors on endothelial cells, globotriaosylceramide or globotetraosylceramide, are binding sites for the toxin, and their presence confers susceptibility to the disease. Binding of the toxin to these receptors can initiate a chain of inflammatory and immunologic reactions that lead to vascular damage.

The basic lesion is an angiopathy that leads to edematous and hypoxic-ischemic injury in a variety of tissue, including the brain. Grossly, edema is present in the subcutis often prominent in the palpebrae, cardiac region of the gastric submucosa, gallbladder, colonic mesentery, mesenteric lymph nodes, larynx, and lungs, and serous effusions occur in the thoracic cavity and pericardial sac (see Figs. 7-126 and 7-127). Congestion and sometimes hemorrhage also occur. The characteristic gross lesions in the brain are usually bilaterally symmetric foci of necrosis in the caudal medulla, but they can extend rostrally as far as the basal nuclei. The lesions are yellow-gray, soft, and slightly depressed.

The primary microscopic lesion, a degenerative angiopathy/vasculitis, is noted most frequently and is most severe in the caudal medulla to the diencephalon and in cerebral and cerebellar meninges (see Fig. 10-42). Cerebral, cerebellar, and spinal blood vessels are also affected. Initially, perivascular edema results from early vascular injury. Edema is followed by necrosis of medial smooth muscle cells, deposition of fibrinoid material, and accumulation of macrophages and lymphocytes in the adventitia. Although endothelial cells and their nuclei become swollen and vesicular, this layer generally remains intact, and consequently thrombosis is not a feature. Lesions associated with the angiopathy include pallor and spongiosis of the CNS parenchyma caused by vasogenic edema and necrosis of neurons and glia. An influx of macrophages into the necrotic lesions can be observed with longer survival times.

Pigs are usually 4 to 8 weeks of age, but younger and older pigs can be affected. Clinically, affected animals are initially ataxic and then become laterally recumbent with rhythmic paddling of the limbs. As the disease progresses, they may become comatose and die. Most pigs die within 24 hours; however, pigs that survive for several days typically develop CNS lesions (see Table 14-1).

Canine distemper: Canine distemper is one of the most important diseases of the canine species. It is caused by a Morbillivirus (family Paramyxoviridae) and has a worldwide distribution. Morbilliviruses other than CDV include measles virus, rinderpest virus, peste des petits ruminants virus, phocine distemper virus of seals, equine Morbillivirus, and dolphin and porpoise Morbilliviruses. The virus is pantropic and has a particular affinity for lymphoid and epithelial tissues (lung, gastrointestinal tract, urinary tract, skin) and the CNS (including the optic nerve) and eye. In the CNS, there is demyelination without any substantial amount of inflammation.

Dr. Brian Summers (Cornell University, College of Veterinary Medicine) has commented on the sequence of events in CDV infection based on his studies of its pathogenesis. CDV is spread between dogs by aerosol transmission. The virus is trapped in the mucosa of the nasal turbinates (centrifugal turbulence), infects local macrophages, and is spread by macrophages (leukocytic trafficking) to regional lymph nodes (retropharyngeal). CDV replicates in these regional lymph nodes and replication is followed by a primary viremia that infects systemic lymph nodes, spleen, and the thymus approximately 48 hours after exposure. With infection of the lymphoid system, immunosuppression can occur, resulting in secondary bacterial infections, such as conjunctivitis, rhinitis, and bronchopneumonia, which are commonly seen in CDV infections.

Four to 6 days after the primary viremia, a secondary viremia occurs largely via leukocytic trafficking. CDV spreads from cells of the lymphoid system to infect the CNS and epithelial cells of the respiratory mucosa, urinary bladder mucosa, and gastrointestinal tract. In the CNS, trafficking leukocytes form perivascular cuffs, and from these cells CDV is disseminated throughout the CNS. It should be noted that the degree of inflammation in the CNS at this stage is minimal.

Under laboratory conditions, the severity of the disease and the cell populations and areas infected in the CNS depend on the (1) age of the dog, (2) strain of CDV, and (3) kinetics of the antiviral immune response. Virtually all cells of the CNS, including the meninges, choroid plexus, neurons, and glia, are susceptible to infection, but oligodendrocytes are novel in that the infection in these cells is usually defective (incomplete). In dogs infected experimentally with the A75-17 strain of CDV, isolated from a dog with CDV in 1975, approximately one-third of the dogs died from encephalomyelitis and the effects attributable to severe immunosuppression. One-third of infected dogs developed a timely systemic immune response, and the CNS disease was quickly resolved and they recovered. Finally, one-third of the dogs infected with CDV developed a subacute to chronic inflammatory/demyelinating disease of the white matter with some gray matter involvement because of a delayed and deficient immune response.

The encephalomyelitis of canine distemper is initiated after viral entry into the CNS, perhaps 1 week after exposure to CDV. Leukocytic trafficking spreads CDV to the gray and white matter of the CNS and to epithelial cells and macrophages of the choroid plexuses. The virus is shed from choroid plexus epithelial and ependymal cells into the CSF in infected macrophages. It is disseminated throughout the ventricular system, infects ependymal cells lining the ventricular system, and then spreads locally to infect astrocytes and microglia. Periventricular white matter lesions, especially those surrounding the fourth ventricle, are the result of this sequence of events.

By 25 days after exposure, CDV-infected leukocytes in the perivascular cuffs have disappeared; however, lesions in the white matter consist of periventricular foci of myelin degeneration and swollen astrocytes. CDV infects astrocytes, microglia, and other cells. Microglia and recruited blood monocytes phagocytose myelin fragments.

Inflammatory mediators released from lymphocytes, microglial cells, and trafficking macrophages result in expansion of the initial lesions. These inflammatory mediators may cause necrosis of cells and cell processes in the focus but do not result in a “selective” demyelinating process affecting axons. The characteristic white matter vacuolation (intramyelinic edema) seen in H&E stained sections of CDV-infected CNS is apparently caused by a direct effect of the virus on oligodendrocytes, as it appears in the earliest white matter lesions before they have acquired an “inflammatory” character—a dense infiltrate of lymphocytes, monocytes, and plasma cells.

Gross lesions characteristically occur in the cerebellum (medullary area, folial white matter, and subpial white matter) and cerebellar peduncles (with both white matter and sometimes gray matter involvement of the pons). Lesions also occur in medulla oblongata (particularly in the subependymal area of the fourth ventricle), rostral medullary vellum, cerebrum (both white matter and gray matter), optic nerves, optic tracts, spinal cord, and meninges.

Microscopically, in addition to demyelination there is status spongiosus, astrocytic hypertrophy and hyperplasia with focal and variable syncytial cell formation, reduced numbers of oligodendroglia, and variable neuronal degeneration (Fig. 14-97, A). Inclusion bodies (cytoplasmic, nuclear, or both) are detectable, particularly in astrocytes, which are important target cells for the distemper virus, but also in ependymal cells and occasionally in neurons (Fig. 14-97, B). The earliest evidence of myelin injury is a ballooning change resulting from a split in the myelin sheath, or more degenerative changes including axonal swelling. This lesion is also variably associated with astroglial and microglial proliferation. This initial injury of the myelin sheath, which has been suggested to be a result of perturbed astrocytic function after viral infection, is followed by a progressive removal of compact myelin sheaths by phagocytic microglial cells that infiltrate the myelin lamellae and variable axonal necrosis.

A late stage of demyelination, which is a reflection of an affected animal’s improved immune status, is more pronounced and is characterized by nonsuppurative inflammation (perivascular cuffing, leptomeningitis, and choroiditis) and also can be accompanied by tissue degeneration and accumulation of gitter cells.

In addition to the dog, animals of the families Ailuridae (red panda), Canidae (fox, wolf), Hyaenidae (hyena), Mustelidae (ferret, mink), Procyonidae (raccoon, panda), Ursidae (bear), Viverridae (civet, mongoose), and Felidae (exotic felids including lions, tigers, and leopards) are also reported to be susceptible to canine distemper viral infection. Additionally, canine distemper has recently been reported in javelinas (collared peccaries) of the family Tayassuidae in the US.

Neurologic signs in all affected species include convulsions, myoclonus, tremor, disturbances in voluntary movement, circling, hyperesthesia, paralysis, and blindness.

Old-dog encephalitis: Old-dog encephalitis is thought to arise from long-term persistent infection of the CNS with a defective form of CDV. This pathogenesis has been demonstrated in experimental infections with the CDV. Although the virus has the same general polypeptide composition and contains all of the major viral proteins as the one causing conventional distemper, some differences among peptides have been reported. The mechanisms involved in development of lesions are not known; however, they result in a proliferation of nonsuppurative inflammatory cells.

Lesions are primarily in the cerebral hemispheres and brainstem. Microscopic lesions are characterized primarily by demyelination with a disseminated, nonsuppurative encephalitis with variable, sometimes prominent, lymphoplasmacytic perivascular cuffing, microgliosis, astrogliosis, and variable leptomeningitis and neuronal degeneration. Nuclear and cytoplasmic inclusions, positive for distemper viral antigen, have been detected in neurons and astrocytes in the cerebral cortex, thalamus, and brainstem but in contrast to distemper, not in the cerebellum.

Old-dog encephalitis is a rare condition occurring in mature adult dogs. Clinical signs include depression, circling, head pressing, visual deficits, seizures, and muscle fasciculations.

Multisystem neuronal degeneration:

Primary cerebellar neuronal degeneration: Primary cerebellar neuronal degenerations, as described previously, have been reported to occur in many breeds of dogs and cats such as American Staffordshire terriers, Australian kelpie dogs, Italian hounds, border collies, Brittany dogs, beagle dogs, Portuguese podengo dogs, Scottish terriers, and domestic shorthair cats. This list is not inclusive and serves only to provide a few common examples. Although most common in young animals of the breeds listed, cerebellar degeneration in Brittany dogs occurs between 7 and 14 years of age. An autosomal recessive mode of inheritance is suspected or documented in several of the diseases. Grossly, the cerebellum can be normal or reduced in size and atrophic. Microscopically, the distribution and characteristics of lesions vary, depending on the breed and species of animal affected. A detailed discussion of the microscopic lesions for each breed and species is outside the scope of this chapter; however, lesions may include a combination of the following changes: loss of Purkinje cells and neurons of the granular layer, astrogliosis, fusiform swelling of proximal Purkinje cell axons, and axonal degeneration in the cerebellum, brainstem, and spinal cord.

Recently, neuronal vacuolation and spinocerebellar degeneration has been reported in young Rottweiler dogs. This breed variant of primary cerebellar neuronal degeneration raised biomedical concerns because of the similarities between the vacuolar lesions in neurons of this disease and those of the TSEs (scrapie, BSE). Analyses for protease-resistant scrapie prion protein were performed and were negative. The cause of this disease has not been determined but appears to have a hereditary basis. Apoptotic cell death is apparently not involved in neuronal degeneration. No gross lesions are observed in the brain, but atrophy of the dorsal cricoarytenoid muscles of the larynx has been reported. Microscopic lesions are characterized by spongiform change affecting neuron cell bodies and the neuropil. The cytoplasm of neurons of the cerebellar roof nuclei and nuclei of the extrapyramidal system contain one or more clear vacuoles (1 to 45 mm in diameter). Similar vacuoles are found in neurons in both dorsal nerve root ganglia, myenteric plexus, and other ganglia of the autonomic nervous system. Purkinje cells are also vacuolated, and in terminal stages of the disease there is degeneration with segmental Purkinje cell loss.

Clinical signs, seen as early as 6 weeks (commonly between 3 and 8 months of age in both sexes), include generalized weakness, ataxia, proprioceptive deficits, and paresis that progress in severity over the course of the disease.

Thiamine deficiency in carnivores: In monogastric carnivores and humans, the relationship between neurologic disease and thiamine deficiency per se is firmly established, and lesions in these species are similar. In carnivores (dog, cat, mink, and fox), there is an absolute dietary requirement for vitamin B₁. Dietary factors, such as the ingestion of fish containing thiaminase, deficient diets, or diets in which the vitamin has been destroyed by other means such as heating, can all lead to thiamine deficiency.

Gross and microscopic lesions are bilaterally symmetric and commonly involve brainstem nuclei, especially caudal colliculi and periventricular nuclei, but the cerebral cortex and cerebellum have also been affected (Fig. 14-100). Lesions consist of neuronal degeneration, neuronal necrosis, status spongiosus, myelin degeneration, and a secondary vascular endothelial and perithelial cell hypertrophy and hyperplasia. Necrotic neurons are those in the caudal colliculi (auditory nerves) that project via axons to the medial geniculate nucleus and those whose cell bodies are located in the periventricular nuclei of the hypothalamus that regulate the release of endocrine hormones from the anterior pituitary. Hemorrhage and an influx of macrophages also occurs in some cases.

Clinical signs in carnivores may include a combination of the following: anorexia, vomiting, depression, wide-based stance, ataxia, spastic paresis, circling, seizures, muscle weakness, recumbency, opisthotonus, coma, or death.

Feline infectious peritonitis: Feline infectious peritonitis (FIP), which is caused by a coronavirus and has a worldwide distribution, is mainly a disease of domestic cats, although wild Felidae can be affected. There are two recognized feline coronaviruses (FCoV): feline enteric coronavirus (FECV) and feline infectious peritonitis virus (FIPV), which cause FECV and FIP infections, respectively. The viruses for each infection are antigenically and morphologically indistinguishable and are currently considered to represent avirulent (FECV) and virulent (FIPV) strains of the same basic FCoV virus. After ingestion, FECV infects and replicates in epithelial cells of the intestine and usually is an insignificant infection, although severe intestinal disease can occur. It has been proposed that when FECV gains the ability (by mutation) to replicate in macrophages, then FIP can occur.

The FIP virus (FIPV) enters the susceptible cat primarily by ingestion of contaminated saliva or feces, although transmission by direct inoculation (e.g., cat bites, licking open wounds) and in utero (rarely) have been reported. After infection, the virus replicates in macrophages that spread the virus to the liver, visceral peritoneum and pleura, uvea, and the meninges and ependyma of the brain and spinal cord.

After dissemination of the virus in the body, the development of disease depends on the type and degree of immunity that develops. Virus containment with resistance to disease occurs following development of a strong cell-mediated immunity. Humoral immunity by itself is not protective and can actually enhance development of the effusive form of FIP (wet form) by two proposed mechanisms. The first involves the development of virus-antibody-complement complexes that particularly accumulate in the same areas as infected macrophages around small blood vessels, resulting in inflammation and subsequent vascular injury (type III hypersensitivity) accompanied by effusion of large amounts of fluid. The second mechanism involves a process referred to as antibody-dependent enhancement (demonstrated to occur experimentally), which involves uptake of virus-antibody-complement complexes by macrophages followed by significant viral replication. The heavily infected macrophages, frequently perivascularly oriented, release cytokines that result in alteration of endothelial junctional complexes that leads to leakage of substantial amounts of fluid.

Noneffusive FIP (i.e., dry form), in comparison, is thought to occur when partial cell-mediated immunity (type IV hypersensitivity) develops and represents an intermediate stage between nonprotective humoral immunity alone and protective cellular immunity. Support for this mechanism is the fact that cats that develop the noneffusive form of FIP after experimental infection usually have a preceding and transient bout of effusive-type disease. In addition, there is evidence to support the theory that cats recovered from FIP are immune by a process of “infection immunity” or “premunition.” Once these cats no longer retain such infections, they seem to also lose protective (cell-mediated) immunity and are, in fact, more sensitive to a subsequent challenge exposure because of the presence of humoral antibody.

The basic lesion in effusive and noneffusive FIP is a pyogranulomatous inflammation, leading to vasculitis followed by an inconsistent vascular necrosis resulting in infarction. The effusive form is typified by serositis, accumulation of fluid in the abdominal and thoracic cavities, with varying degrees of severity of inflammation. Lesions of the noneffusive form more frequently result in leptomeningitis, chorioependymitis, focal encephalomyelitis, and ophthalmitis, although involvement of the kidneys, hepatic and mesenteric lymph nodes, and less frequently, serosa and other abdominal viscera can occur. In the CNS, pyogranulomatous vasculitis tends to affect blood vessels of (1) the leptomeninges, especially in sulci and near their entrance into subjacent CNS tissue and around the circle of Willis (Fig. 14-105) and (2) the periventricular white matter, especially around the fourth ventricle (Fig. 14-106). The uvea, retina, and optic nerve sheath are also commonly involved in FIP.

FIP generally occurs sporadically in cats of all ages, but it is most common in younger cats between the ages of 3 months and 3 years and can be clinically significant because it can result in death. The disease manifests itself in effusive (wet) or noneffusive (dry) forms. Clinical signs caused by involvement of blood vessels in the CNS can include behavioral changes, dullness, coma, paresis, ataxia, paralysis, and seizures.

Primary Sensory Neuropathies: Primary sensory neuropathies included here are the hereditary, familial, and breed- or species-associated syndromes reported in a variety of domestic animals that result in degeneration of PNS sensory neurons (dorsal root ganglion) or axons innervating the limbs. Two examples of primary sensory neuropathies have been described in English pointers and long-haired dachshunds. In pointer dogs, the onset is 2 to 12 months of age with signs of self-mutilation and insensitivity to pain resulting in neuropododermatitis or acral mutilation syndrome (Fig. 14-110). Additional signs can include ataxia, loss of conscious proprioception, and patellar hyporeflexia. In dachshunds, a sensory neuropathy is manifested shortly after birth by ataxia and alterations in the function of the autonomic division of the PNS, such as urinary incontinence and digestive disturbances. Lesions in pointer dogs consist of small dorsal root ganglia with neuronal loss and replacement by satellite cells (nodules of Nageotte) and mild reduction in size of dorsal nerve rootlets because of degeneration and loss of myelinated and nonmyelinated axons with the presence of cell bands of Büngner (indicative of attempts at remyelination). In dachshunds, lesions are a distal axonopathy with loss of large myelinated and unmyelinated axons. Lesions can occur in the vagus nerve.

Other degenerative distal axonopathies of the PNS have also been reported in Birman cats and in dog breeds, including Bouvier des Flandres, Siberian huskies and crossbreeds, Boxer dogs (sensory axonopathy), Rottweilers (sensory axonopathy), dachshunds (sensory axonopathy), Dobermans (dancing Doberman disease is thought to be a primary myopathy), German shepherds (giant axonal neuropathy), and Dalmatians. They may have a genetic basis and be inherited.

Gross lesions in the PNS are inapparent; however, microscopically, depending on the breed involved, spheroids can be found in cranial and spinal nerves and brainstem nuclei. Affected animals are usually young (birth to 15 months of age) and show signs of ataxia, muscle weakness (paresis and tetraparesis) followed by muscle atrophy, proprioceptive deficits, urinary incontinence, and digestive disturbances (enteric division involvement).

Dysautonomias:

Hypomyelination/Dysmyelination Diseases: In contrast to the CNS, congenital and postnatal disorders of myelin formation are rare in the PNS but have been described in dogs, calves, and a cat. These disorders are thought to have a genetic predisposition and to be inherited. In dogs, hypomyelination has been described in golden retrievers with onset at approximately 7 weeks of age. Clinical signs include a peculiar hopping gait, depressed spinal reflexes, and circumduction of the limbs while walking. Lesions in peripheral nerves include thin myelin sheaths, increased numbers of Schwann cells, neurolemma cells with abnormally increased cytoplasmic volume, and no evidence of active demyelination or effective remyelination. The lesions are believed to involve a defect in Schwann cells or an abnormal axon–Schwann cell interaction.

In calves, a myelinopathic peripheral neuropathy has been described in Santa Gertrudis–Brahman cross-breeds. Microscopically, lesions were present in the vagus nerves, somatic peripheral nerves of the brachial plexuses, and the sciatic nerves. Dorsal and ventral spinal nerve roots also had similar lesions. There was “sausage-shaped” thickening of the myelin sheaths as a result of excess myelin arranged about the axons or as irregularly folded myelin sheaths not surrounding axons. Onset of clinical signs was at 6 to 10 months of age. Clinical signs were dysphagia, abnormal rumination with bloat, and a weak shuffling gait. Congenital hypomyelination has also been described in a 2-month-old Dorsett lamb with tremors and incoordination.

Coyotillosis: Another cause of primary demyelination is the shrub coyotillo (Karwinskia humboldtiana) affecting mainly small ruminants in the semidesert areas of the southwestern US. Seeds in the fruit contain polyphenolic compounds that are toxic when ingested. Four toxic compounds have been isolated, including a substance called karwinol A that induces primary demyelination of peripheral nerves.

Vitamin A, Vitamin D, and Riboflavin Deficiencies: Nutritional axonopathies are relatively uncommon and are chiefly caused by vitamin A and some of the B vitamin deficiencies. Vitamin A deficiency results indirectly in peripheral neuropathy by affecting bone growth and remodeling. In neonatal calves, the neuropathy is due to narrowing of the optic foramina caused by continued bone deposition with decreased resorption resulting in compression of the optic nerves, Wallerian degeneration, and blindness. B vitamin deficiencies are primarily diseases of pigs and poultry. In pigs, deficiency of pantothenic acid (B-complex vitamin, vitamin B₅) causes a sensory neuropathy with axonal degeneration, demyelination, and chromatolysis and neuron loss in the dorsal root ganglia, resulting in proprioceptive deficits, goose stepping, and dysmetria. The exact sequence of events in pantothenic acid–deficiency neuropathy is controversial because one study in pigs described initial lesions in the axon, whereas a second study described initial lesions in the cell body. Riboflavin deficiency in poultry, named curly toe paralysis, is primarily a demyelinating neuropathy. Peripheral nerves are swollen because of endoneurial edema, and there is subsequent demyelination with mild axonal degeneration.

Vitamin E Deficiency:

Chemicals: Toxic diseases resulting from chemicals are discussed in greater detail in the section on the CNS. Examples of chemical toxins causing distal axonal degeneration are the vinca alkaloids, vincristine and colchicine, both causing disassembly of microtubules and inhibiting axoplasmic flow. Taxol, an alkaloid from the western yew (Taxus brevifolia), promotes the assembly of and stabilizes microtubules but also causes an axonopathy. An outbreak of distal polyneuropathy has been reported in cats fed commercial diets contaminated with the ionophore salinomycin, which is used as a coccidiostatic drug in poultry and growth promoter in cows. There was acute onset of lameness and paralysis affecting the hindlimbs that progressed to the forelimbs. Demyelination of peripheral nerves followed the axonal degeneration. Some toxins seem to cause different patterns of injury in the CNS and PNS. For example, in the CNS, lead is noted to cause neuronal necrosis, whereas in the PNS, demyelination, preferentially affecting Schwann cells, is prominent in some species.

Other Toxic Neuropathies: A number of toxins can affect the PNS, with or without damage in the CNS. The initial toxic effects can be at the level of the neuron cell body, the axon, or the myelin sheaths. Examples of toxins targeting neuronal cell bodies are organomercurial compounds such as methylmercury and the cancer chemotherapeutic agent doxorubicin. Methylmercury is particularly toxic because it directly alters biochemical reactions. Although methylmercury poisoning can result from ingestion of water or forage contaminated with industrial discharge, in animals the consumption of fish containing excessive concentrations of methylmercury is the most likely source of the toxin. Fish accumulate methylmercury in their muscle as a result of a “normal” environmental process called biomethylation. Biomethylation converts elemental mercury to methylmercury, which is ingested in the diet of fish. In mercury poisoning, sensory neuron cell bodies of the dorsal root ganglion are preferentially involved and the motor neurons are spared; whereas with doxorubicin, both dorsal root ganglion and autonomic cell bodies are affected. Experimental studies suggest that neuronal cell death is caused by apoptosis of neuronal cell bodies resulting in axonal and Wallerian degeneration.

Neuromuscular Junction Diseases:

Botulism: Botulism is characterized by a flaccid paralysis caused by the neurotoxin of Clostridium botulinum type A, B, or C in North America and type D in South Africa. The bacterium is a ubiquitous Gram-positive spore-forming anaerobe commonly found in soil. This disease most commonly occurs in horses in North America and cows in South Africa. Different forms of botulism affect foals and adult horses. Toxicoinfectious botulism occurs in foals. Foals contract the disease by ingesting soil contaminated with clostridial spores. In past years, spores were thought to vegetate, replicate, and produce toxin in gastric or duodenal ulcers induced by stress or steroids and nonsteroidal antiinflammatory drugs (NSAIDs) passed in mares’ milk. However, recent retrospective studies suggest that gastric or duodenal ulcers are not involved in the pathogenesis of toxicoinfectious botulism in foals. Currently, the site of bacterial colonization and toxicoinfection in foals is unknown. In human infants, the large intestine is thought to be the site of colonization and toxicoinfection.

In adult horses, poisoning after ingestion of toxin-contaminated forage and less commonly wound botulism occur. Adult horses contract the disease principally through the ingestion of preformed toxin in contaminated feeds, usually haylage that is prepared and stored improperly. Less commonly, adult horses contract the disease through tissue injury and an anaerobic environment, such as hoof abscesses and skin wounds. Spores of Clostridium botulinum are either carried into wounds by nails or other contaminated foreign objects or into gastric ulcers by ingestion of contaminated soil. In either case, the spores germinate only in necrotic tissue that has an anaerobic environment. The bacteria replicate and produce exotoxin, which is absorbed through the capillary endothelium and enters the bloodstream. In adult horses that ingest contaminated feeds, the toxin is absorbed from the alimentary system and enters the bloodstream.

Other than the wound where the bacteria replicates, the toxin of Clostridium botulinum causes no macroscopic and microscopic tissue lesions. Once botulinum toxin is in the bloodstream, it enters myoneural junctions and binds to receptors on presynaptic terminals of peripheral cholinergic synapses (see Fig. 4-27). The toxin is then internalized into vesicles, translocated to the cytosol, and then mediates the proteolysis of components of the calcium-induced exocytosis apparatus, thus interfering with acetylcholine release. Inhibition (blockage) of the release of acetylcholine results in flaccid paralysis of muscles innervated by cholinergic cranial and spinal nerves, but there is no impairment of adrenergic or sensory nerves.

Clinically, affected horses have progressive paralysis of the muscles of the limbs, mandible, larynx/pharynx, upper eyelid, tongue, and tail. Death is usually caused by flaccid paralysis of the diaphragm resulting in respiratory failure. Blockage of acetylcholine release at presynaptic cholinergic terminals is permanent. Improvement occurs only when axons develop (sprout) new terminals to replace those damaged by botulinum toxin.

Colonic Agangliosis: Colonic agangliosis (lethal white foal syndrome) is a disorder involving development of the enteric division of the PNS and is analogous to Hirschsprung’s disease in infants. This disease occurs most commonly in foals of American Paint Horses with Overo markings. Affected foals have white or nearly white skin color. Specific information on these skin marking patterns can be obtained from the American Paint Horse Association. The gene, which results in the “colonic agangliosis” phenotype being expressed, is inherited as a homozygous dominant.

Recently, mutations in the endothelin-B receptor gene have been detected in affected horses and in some patients with Hirschsprung’s disease. Both glial-derived neurotrophic factor (GDNF) and endothelin-3 (ET-3) are required for normal development of the enteric nervous system and enteric ganglia. It is proposed that GDNF is required for proliferation and differentiation of neuronal precursor cells destined to populate the gut. ET-3 might modulate these effects by inhibiting differentiation, thus allowing sufficient time for precursor cells to migrate and populate the intestinal wall in a cranial to caudal progression before they differentiate to form enteric ganglia.

There are no gross lesions in the intestine related to the enteric division of the PNS. Microscopically, the myenteric and submucosal enteric ganglia are absent and the areas affected vary but can extend anywhere between the ileum and distal large colon. Affected foals die soon after birth from functional blockage of the ileum and/or colon because of the lack of innervation and thus normal gut motility.

Acquired Dysautonomias:

Deficiencies:

Dysautonomias: A discussion on hereditary dysautonomias can be found in the section on Disorders of Domestic Animals.

Dysautonomias:

Acute Idiopathic Polyneuritis: Acute idiopathic polyneuritis (coonhound paralysis) is an acute, fulminating polyradiculoneuritis with ascending paralysis that occurs in dogs after the bite or scratch of a raccoon. By definition, polyradiculitis refers to disease or injury involving multiple cranial or spinal nerve roots, whereas polyradiculoneuritis refers to disease or injury involving multiple cranial or spinal nerve roots and their corresponding peripheral nerves.

Coonhound paralysis has been compared with Guillain-Barré syndrome. This human syndrome typically follows a viral illness, vaccination, or some other antecedent disease that results in an autoimmune response resulting in primary demyelination of cranial and spinal rootlets and nerves and delayed conduction of action potentials down the axon. Humoral and cell-mediated components are suspected to be involved in the autoimmune response.

Coonhound paralysis, like Guillain-Barré syndrome, is believed to represent an autoimmune primary demyelination. Despite the lack of close association of macrophages with the degenerating myelin and axons early in the development of the lesions, secretion of TNF-α by these cells could explain both the demyelination and axonal degeneration.

Acute idiopathic polyneuritis has been reported in dogs without an association with raccoons and also occurs rarely in cats, suggesting multiple factors might be involved in this type of nerve damage. Lesions in coonhound paralysis are most severe in ventral spinal nerve rootlets and progressively diminish distally in the peripheral nerve. Involvement of dorsal spinal nerve rootlets and ganglia is not constant and relatively minor. Lesions in the ventral nerve rootlets consist of segmental demyelination with a variable influx of neutrophils, depending on the acuteness and severity of clinical signs, along with lymphocytes, plasma cells, and macrophages (Fig. 14-116). Axonal degeneration is a common sequela. Evidence of remyelination with cell bands of Büngner and axonal sprouting occur during the recovery phase, but the effectiveness of the latter to establish continuity of the nerve rootlet and thus reinnervation of muscle is limited.

A chronic polyradiculoneuritis with infiltrations of lymphocytes, plasma cells, or macrophages; demyelination; and variable axonal degeneration in cranial and spinal nerve rootlets and cranial nerves is also reported in dogs and cats. With repeated episodes of demyelination, onion bulbs can be apparent. Both sensory and motor nerves can be involved with sensory disturbances and muscle atrophy.

Clinically, affected dogs have signs of coonhound paralysis that develop 1 to 2 weeks after exposure to raccoon saliva. Initial signs of hyperesthesia, weakness, and ataxia are replaced in 1 to 2 days by tetraparesis and/or tetraparalysis that may last from weeks to months. Dogs can die from respiratory paralysis. Recovery is common, but the paralysis can be prolonged in dogs with extensive muscular atrophy.

Astrocytosis: Increased numbers of astrocytes.

Astrogliosis: Reactive astrocytic response with increased number (variable), length, and complexity of cell processes. In the CNS, reparative processes after injury, such as inflammation and necrosis, are facilitated by astrogliosis.

Axonopathy, distal, of the PNS: A neuropathy with degeneration of the terminal and preterminal axon of peripheral nerves.

Axonopathy, distal of the CNS and PNS: Degeneration of axons involving distal portions of peripheral nerves, and distal portions of long axons in the CNS (spinal cord).

Axonotmesis: Axonal injury of a peripheral nerve in which there is degeneration of the part distal to the site of trauma, leaving the supporting framework intact and allowing for improved potential for regeneration and effective reinnervation.

Blood-brain barrier of the CNS: A barrier to free movement of certain substances from cerebral capillaries into CNS tissue. Relies on tight junctions between capillary endothelial cells and selective transport systems in these cells. Endothelial cell basement membrane and foot processes of astrocytes abutting the basement membrane may play role in barrier function.

Blood-CSF barrier of the CNS: A barrier that consists of tight junctions located between epithelial cells of the choroid plexus and the cells of the arachnoid membrane that respectively separate fenestrated blood vessels of the choroid plexus stroma and dura mater from the CSF.

Blood-nerve barrier: A barrier to free movement of certain substances from the blood to the endoneurium of peripheral nerves. Barrier properties are conferred by tight junctions between capillary endothelial cells of the endoneurium and between perineurial cells and selective transport systems in the endothelial cells.

Brain edema: Increase in tissue water within the brain that results in an increase in brain volume. The fluid may be present in the intracellular or extracellular compartments or both. The term also is used to include the accumulation of plasma, especially in association with severe injury to the vasculature.

Brain swelling: Marked, rapidly developing, sometimes unexplained, increase in cerebral blood volume and brain volume because of relaxation (dilation) of the arterioles that occurs after brain injury.

Büngner, cell bands of: A column of proliferating Schwann cells that forms within the space previously occupied by an axon following wallerian degeneration. The proliferating column of cells is surrounded by the persisting basement membrane of the original Schwann cells.

Central chromatolysis: Dissolution of cytoplasmic Nissl substance (arrays of rough endoplasmic reticulum and polysomes) in the central part of the neuronal cell body that results from injury to the neuron (often involving the axon). The cell body is swollen, and the nucleus frequently is displaced peripherally to the cell membrane. These structural changes functionally represent a response to injury that can be found (if the cell survives) by axonal regeneration with protein synthesis to produce components of the axon required for fast and slow axonal transport.

Cranium bifidum: A dorsal midline cranial defect through which meninges alone or meninges and brain tissue may protrude into a sac (-cele), covered by skin.

Demyelination: A disease process in which demyelination (destruction of the myelin sheath) is the primary lesion, although some degree of axonal injury may occur. Primary demyelination is caused by injury to myelin sheaths and/or myelinating cells and their cell processes. Secondary demyelination occurs with axonal injury, as in wallerian degeneration.

Dysraphism: Dysraphia, which literally means an abnormal seam, refers to a defective closure of the neural tube during development. This defect, which may occur at any point along the neural tube, is exemplified by anencephaly, prosencephalic hypoplasia, cranium bifidum, spina bifida, and myeloschisis.

Encephalitis: Inflammation of the brain.

Encephalo-: A combining form that refers to the brain.

Encephalopathy: A degenerative disease process of the brain.

Ganglionitis: Inflammation of peripheral (sensory or autonomic or both) ganglia.

Gemistocyte: Reactive, hypertrophied astrocyte that develops in response to injury of the CNS. The cell body and processes of gemistocytes become visible with conventional staining (e.g., H&E stain). The cell bodies and processes of normal astrocytes are not visible with H&E staining.

Gitter cell: Macrophage that accumulates in areas of necrosis of CNS tissue. The cytoplasm is typically distended, with abundant lipid-containing material derived from the lipid-rich nervous tissue. Gitter cell nuclei are often displaced peripherally to the cell membrane. These cells are often referred to as “foamy” macrophages.

Hydranencephaly: A large, fluid-filled cavity in the area normally occupied by CNS tissue of the cerebral hemispheres resulting from abnormal development. The nervous tissue may be so reduced in thickness that the meninges form the outer part of a thin-walled sac. The lateral ventricles are variably enlarged because of their expansion into the area normally occupied by tissue.

Hydrocephalus: Accumulation of excess CSF resulting from obstruction within the ventricular system (noncommunicating form) associated with enlargement of any or all of the following: lateral ventricles, third ventricle, mesencephalic aqueduct, and fourth ventricle. Hydrocephalus can also occur with communication of the CSF between the ventricular system and the subarachnoid space (communicating form). Hydrocephalus ex vacuo (compensatory hydrocephalus) is characterized by an expansion of the lateral ventricle (or ventricles) that follows loss of brain tissue.

Leuko-: Combining form referring to white matter of the brain or spinal cord.

Leukoencephalitis: Inflammation of the white matter of the brain.

Macroglia: A collective term referring to astrocytes and oligodendrocytes. Has also been variously used to refer solely to astrocytes or to astrocytes, oligodendrocytes, and ependymal cells of the CNS, and Müller cells of the retina.

Malacia: Grossly detectable (macroscopic lesion) softening of CNS tissue, usually the result of necrosis.

Meningo-: Combining form referring to meninges.

Meningomyelocele: A form of spina bifida in which meninges and spinal cord herniate through a defect in the vertebral column into a sac (-cele) covered by skin.

Microglia: Resident cells of the CNS believed to arise from monocytes that populate the brain during embryonic development.

Motor neuron, lower: Large multipolar neurons in the brainstem and ventral horns of the spinal cord with axons extending into the PNS.

Motor neuron, upper: Motor neurons with axons residing solely in the CNS that control lower motor neurons.

Myelitis: Inflammation of the spinal cord.

Myelo-: Combining form referring to spinal cord.

Myelopathy: A degenerative disease process of the spinal cord.

Myeloschisis: Similar to spina bifida, except in its severe form is characterized by complete failure of the spinal neural tube to close, therefore a lack of development of the entire dorsal vertebral column.

Neuroglial cells: Astrocytes, oligodendroglia, ependymal cells, and microglia of the CNS.

Neuronophagia: Accumulation of microglial cells around a dead neuron.

Neuropil: The gray matter feltwork that consists of intermingled and interconnected processes of neurons (axons and dendrites) and their synaptic junctions, plus processes of oligodendroglia, astrocytes, and microglia.

Neurapraxia: Traumatic injury to a peripheral nerve with temporary conduction block but with no permanent axonal damage.

Neurotmesis: Complete transection of a nerve and supporting framework with little potential for normal reinnervation.

Onion bulb: Concentric arrays of Schwann cell cytoplasm around an axon signifying multiple episodes of demyelination and remyelination.

Polio-: Combining form referring to gray matter of the CNS.

Polioencephalomalacia: Softening (usually the result of necrosis) of the gray matter of the brain.

Polioencephalomyelitis: Inflammation of the gray matter of the brain and spinal cord.

Poliomyelomalacia: Softening (usually the result of necrosis) of the gray matter of the spinal cord.

Porencephaly: A cleft or cystic defect in the cerebral hemisphere that communicates with the subarachnoid space and also may communicate with the ventricular system. The defect may contain CSF.

Radiculoneuritis (polyradiculoneuritis): Inflammation of a spinal nerve rootlet (or rootlets).

Rarefaction: Reduction in density of CNS tissue that may result from edema, necrosis, and the like. This lesion is usually observed microscopically.

Satellitosis: An accumulation of oligodendroglia around neuronal cell bodies. Although this feature can be seen in normal brains, some consider that it may also be associated with neuronal injury.

Sclerosis: Literally means induration or hardening and, when used in describing lesions of the CNS, often refers to induration or hardening of the brain or spinal cord resulting from astrogliosis (astrocytic scar formation).

Spina bifida: A dorsal midline defect involving one to several vertebrae of the spinal column caused by failure of the neural tube to close, permitting exposure of the underlying meninges and spinal cord. The lesion may be associated with herniation of meninges alone or meninges and spinal cord tissue into a sac (-cele) covered by skin, or there may be no herniation (spina bifida occulta).

Status spongiosus: An encompassing term meaning the presence of small focal, ovoid to round “clear (unstained or poorly stained [H&E stain])” spaces in the CNS. The lesion can result from several different tissue alterations, which include splitting of the myelin sheath, accumulation of extracellular fluid, swelling of cellular (e.g., astrocytic and neuronal) processes, and axonal injury (wallerian degeneration) when swollen axons are no longer detectable within distended spaces.

Syringomyelia: A tubular cavitation (syrinx) in the spinal cord that is not lined by ependyma and may extend over several segments.

Wallerian degeneration: Degeneration of the distal component of an injured (compressed or severed) axon. Although the term originally referred to injury of axons in the PNS, current usage also includes the CNS. This process also results in functional and structural alterations in the cell body (central chromatolysis) and proximal internode segment of the axon, and in secondary demyelination.