Congenital Hydrocephalus: CSF can accumulate in the ventricular system, the subarachnoid space, or both. The type of hydrocephalus that develops depends on the site of blockage that disrupts normal flow of CSF.

Exactly which portions of the ventricular system will be dilatated in hydrocephalus depends on the site of the blockage:

As an example, following blockage of the interventricular foramina, the pressure in the lateral ventricles increases; the ventricles dilate; the ependyma becomes atrophied and focally discontinuous; and because of the pressure gradient, CSF is forced into the periventricular white matter leading to hydrostatic edema. Hydrostatic edema results in degeneration and atrophy of myelin and axons, and this loss of tissue results in further expansion of the ventricles.

The forms of hydrocephalus are communicating and noncommunicating hydrocephalus. Communicating hydrocephalus, the least common of the two forms, occurs when there is communication of ventricular CSF with the subarachnoid space where the CSF can be in excess. Noncommunicating hydrocephalus results from obstruction within the ventricular system at, or rostral to, the lateral apertures of the fourth ventricle. An area of great vulnerability for obstruction is the mesencephalic aqueduct. Noncommunicating hydrocephalus can also occur without any evidence of obstruction to CSF flow as a result of failure of the reabsorption of CSF.

A recent hypothesis proposes that communicating hydrocephalus is caused by a decreased expansion of intracranial arteries during systole as a result of reduced compliance involving the arterial walls, or the subarachnoid space, and is referred to as restricted arterial pulsation hydrocephalus. Because the intracranial arteries cannot fully expand, a pressure gradient develops in which there is greater pressure within the brain tissue and the ventricles than outside the brain. Several causes have been advanced, including arteritis, subarachnoid hemorrhage, and meningitis.

A third type of hydrocephalus, referred to as hydrocephalus ex vacuo (or compensating hydrocephalus), is not usually a congenital abnormality but occurs secondary to absence or loss of cerebral tissue. This type of hydrocephalus can occur in utero from destruction and loss of cerebral tissue surrounding the lateral ventricles (e.g., in hydranencephaly). Hydrocephalus ex vacuo is discussed further in the next section on Acquired Hydrocephalus.

In domestic animals, congenital hydrocephalus can be caused by in utero viral infections leading to aqueductal stenosis (incomplete closure) in the dog that results in the development of noncommunicating hydrocephalus; however, a genetically programmed predisposition may occur in very small and brachycephalic breeds of dogs.

Gross lesions associated with communicating and noncommunicating congenital hydrocephalus include enlargement (doming) of the cranium if obstruction occurs before the sutures have fused (Fig. 14-37). The bones of the calvarium are extremely thin and the fontanelles are prominent (Fig. 14-38). In the brain there is prominent enlargement of the ventricular system proximal to the point of obstruction (Fig. 14-39). White matter adjacent to the dilated lateral ventricles is reduced in thickness, although the gray matter can retain a relatively normal appearance. As the hydrocephalus progresses, atrophy with fenestration of the interventricular septum (septum pellucidum), atrophy of the hippocampus in the floor of the lateral ventricles, and flattening of cortical gyri can occur. If the obstruction is abrupt and pressure builds rapidly, the cerebral hemispheres can be displaced caudally, causing herniation of the parahippocampal gyri under the tentorium cerebelli and of the vermis of the cerebellum through the foramen magnum. The resulting coning of the cerebellum can be accompanied by necrosis of cells in the cerebellar folia as a result of ischemia and infarction. Microscopically the ependyma can become atrophied and focally discontinuous, and there is loss of cells and cell processes in adjacent white matter and variably in the gray matter.

Clinically, congenital hydrocephalus occurs most frequently in brachycephalic or toy breeds such as the Chihuahua, Lhasa apso, and toy poodle. Clinical signs occur within the first year of life, often before 3 months of age. Behavioral changes are the most common and include poor motor skill development; delay in learned behavior, such as house training; somnolence; dullness; episodic confusion; circling; periodic aggression; and seizures.

Acquired Hydrocephalus: Noncommunicating acquired hydrocephalus has been associated with injury of the ependyma, resulting in obstruction of any of the following: the lateral apertures of the fourth ventricle, the cerebral aqueduct, or the interventricular foramen. Causes of obstruction include compression by cerebral abscesses and neoplasms, and blockages by infectious/inflammatory disease resulting in a ventriculitis and, uncommonly, by cholesteatomas in the choroid plexus of the lateral ventricles of the horse. Because the calvarium has now ceased to grow, unlike congenital hydrocephalus, it is of normal size and shape, and its bone is of normal thickness.

A second type of acquired hydrocephalus, referred to as hydrocephalus ex vacuo (or compensating hydrocephalus), usually occurs in the cerebral hemispheres secondary to loss of neural tissue. If there is loss of neurons in the cerebral cortex, as in bovine polioencephalomalacia or other types of laminar cortical necrosis, the axons of these neurons, which normally traverse the white matter of the cerebral hemispheres, will disappear by Wallerian degeneration, and there will be atrophy of the cortex from the loss of neuronal cell bodies and of the white matter from the loss of axons. The lateral ventricles will expand into the space once occupied by white matter. This dilatation of the lateral ventricles may be bilateral when there has been a loss of white and gray matter from both cerebral hemispheres, or it may be unilateral. If the loss of cortex is localized, as in an infarct, then dilatation of the lateral ventricle will not uniformly involve the whole lateral ventricle. Examples of disorders in which hydrocephalus ex vacuo occur include some storage diseases (ceroid-lipofuscinosis in sheep), aging, and postradiation exposure, all of which are associated with cerebral atrophy. There is no evidence of obstruction of the normal flow of CSF in this type of hydrocephalus.

Brain Abscesses: Cerebral abscesses in animals are relatively uncommon but arise after entry of bacteria into the CNS. This may occur either from direct extension or hematogenously. With direct extension, abscesses occur following penetrating wounds, such as calvarial fractures, or from spread of infection from adjacent tissues, such as the leptomeninges, paranasal sinuses, and internal ear, and through the cribriform plate of the ethmoid (see Fig. 14-29). Diseases that cause bacteremia or septicemia result in infectious agents being trapped in vascular beds within the CNS and meninges. Abscesses usually arise within gray matter because it receives a disproportionate share of blood flow in the CNS, usually at the gray-white (cortex-subcortical white matter) junction. They exert effects in the CNS by disruption and destruction of tissue and by displacement as space-occupying lesions. If the abscess grows quickly, tissue is more likely to be disrupted and destroyed and in the worst case penetrate the wall of the lateral ventricle and cause a ventriculitis. Bacteria in the CSF may be carried into the subarachnoid space and cause a leptomeningitis. On the other hand, if growth is slow, tissue is more likely to be displaced. Chronic abscesses become encapsulated by either fibrous tissue if they are close to the leptomeninges or by astrocytes away from the meninges. The mechanism of tissue injury is likely a secondary bystander effect related to the actions of the mediators of inflammation and the toxins and other products elaborated from bacteria. Bacteria appear to localize in specific areas of the CNS based on receptor-mediated attachment or because of vascular flow patterns unique to the gray matter–white matter interface of the CNS that allows bacteria to attach to and move through the blood-brain barrier. This latter flow mechanism likely occurs because small blood vessels supplying the cerebrum fail to continue into the white matter and end with their horizontal branches running parallel to the surface of the gyrus within the gray matter at the interface with the white matter. Once within the CNS or meninges, bacteria replicate and elicit an inflammatory response. Lytic enzymes released from lysosomes of neutrophils and other inflammatory cytokines secreted by lymphocytes and macrophages destroy neurons and their processes and disrupt synapses, thus affecting neurotransmission.

Grossly, brain abscesses can be single or multiple, be discrete or coalescing, and have varied sizes (Fig. 14-40). Early in the process, abscesses consist of a white to gray to yellow, thick to granular exudate. The color of the exudate can be influenced by the exuberance of the pyogenic response elicited by the inciting bacteria and by any pigments produced by the bacteria. Streptococcus spp., Staphylococcus spp., and Corynebacterium spp. may produce a pale-yellow to yellow, watery-to-creamy exudate. Coliforms, such as Escherichia coli and Klebsiella spp., may produce a white to gray, watery to creamy exudate. Pseudomonas spp. may produce a green to bluish-green exudate. The borders of abscesses are often surrounded by a red zone of active hyperemia induced by inflammatory mediators acting on capillary beds. With chronicity, abscesses may be walled off by processes of astrocytes and fibrous connective tissue from the pia mater, especially when the abscess results from a penetrating wound.

Brain abscesses can arise in some food animal species from an extension of otitis interna (see Fig. 14-29). These animals often display evidence of facial nerve paralysis, such as a drooping ear. The cerebellopontine angle and adjacent structures are the common locations for such abscesses. In horses, Streptococcus equi (strangles) can cause brain abscesses via hematogenous spread from lymphoid tissues (Fig. 14-41). Direct penetration may also occur in small ruminants that lack frontal sinuses because of improper dehorning procedures. Brain abscesses are space-occupying lesions and as such can have a devastating effect on brain function. Depending on size and location, compression via mass effect (increased intracranial pressure) of vital structures (nuclei that regulate cardiac and respiratory rhythms) and brain displacements (cerebellar vermis, parahippocampal gyri) are two common sequelae to acute abscesses. Abscesses can occur in the spinal cord as a result of direct extension of bacterial vertebral osteomyelitis through the dura (Fig. 14-42), after tail docking in lambs, and occasionally from hematogenous spread.

Clinically, animals with brain abscesses can show abnormal mental behaviors, ataxia, head tilt, circling, and loss of vision.

Diffuse Encephalitis: Common bacteria have the potential to produce disease in the CNS by hematogenous spread and vasculitis (see the section on Neonatal Septicemia).

Ependymitis and Choroid Plexitis: Infectious agents, especially pus-forming bacteria, such as the coliform and Streptococcus spp., can enter the CNS hematogenously or via direct extension, invade the choroid plexuses, and be released into the CSF, gaining access to ependymal cells lining the ventricular system. Inflammation of the ependyma is called ependymitis, whereas inflammation of the choroid plexus is called choroid plexitis. Gross lesions usually consist of gray-white to yellow-green thick to gelatinous CSF within the ventricular system and choroid plexuses that are granular and gray-white, with areas of active hyperemia and hemorrhage. If the bacteria traverses through the lateral apertures of the fourth ventricle, they can enter and spread throughout the subarachnoid space, possibly inducing suppurative bacterial leptomeningitis. The exudate can also obstruct CSF flow, leading to noncommunicating hydrocephalus. Microscopically, inflammatory cells, especially neutrophils, mixed with fibrin, hemorrhage, and bacteria, can be seen in the exudate.

Meningitis: Meningitis refers to inflammation of the meninges (Fig. 14-43). In animals, meningitis is most commonly caused by bacteria such as Escherichia coli and Streptococcus spp. that traverse to the leptomeninges and subarachnoid space hematogenously. Bacteria can also spread to the meninges by direct extension and leukocytic trafficking. In common usage, the term meningitis generally refers to inflammation of the leptomeninges (the pia mater, subarachnoid space, and adjacent arachnoid mater) in contrast to inflammation of the dura mater, which is referred to as pachymeningitis. Leptomeningitis can be acute, subacute, or chronic and, depending on the cause, suppurative, eosinophilic, nonsuppurative, or granulomatous. Inflammation of specific parts of the dura mater of the cranial cavity can occur in the external periosteal dura after osteomyelitis, formation of extradural abscesses and pituitary abscesses, and skull fracture and involve the inner dura in association with leptomeningitis. Abscesses of the pituitary fossa occur with some frequency in cattle. Bacteria isolated from the cases include Pasteurella multocida and Actinomyces pyogenes. The abscess can result from spread of infection arising in the caudal nasal cavity or sinuses, possibly through direct extension or through the venous circulation. Incision of the pituitary fossa releases a thick viscous opaque tan to yellow exudate, which can elevate the dura mater surrounding the fossa. Infection can extend via the infundibular recess of the third ventricle into the ventricular system, resulting in ventriculitis, ependymitis, and empyema. Systemic bacterial infections in neonates are a common cause of acute meningitis (leptomeningitis), which are suppurative and fibrinous. In animals, leptomeningitis secondary to a selective viral infection only of the leptomeninges is very rare and is usually seen in combination with viral-induced encephalitides.

Neonatal Septicemia: Neonatal septicemia typically involves Escherichia coli, Streptococcus spp., Salmonella spp., Pasteurella spp., and Haemophilus spp. The release of endotoxins and bacterial cell wall components, such as lipopolysaccharide (LPS), teichoic acid, and proteoglycans, in the CNS vasculature leads to the secretion of cytokines (tumor necrosis factor [TNF], interleukin [IL], platelet-activating factor [PAF], prostaglandins, thromboxane, and leukotrienes) from the endothelium and trafficking CNS macrophages, followed by adhesion of neutrophils, injury to the endothelium and blood-brain barrier, and vasculitis resulting initially in brain swelling and brain edema and increased intracranial pressure.

Although there are differences in the diseases caused by these organisms, they tend to produce fibrinopurulent inflammation of membranous tissues (serosal surfaces) of the body. Leptomeninges, choroid plexus, and ependyma of the CNS—sites often preferentially involved in hematogenous spread of bacteria, synovium, uvea, and the serosal lining of body cavities—can be affected in various combinations. Infections are often acquired perinatally, and onset is usually within a few days of birth up to 2 weeks (Box 14-7). The initial portal of entry can be oral; intrauterine; umbilical; or surgical, via postsurgical procedures such as castration and ear notching; or via the respiratory system, but the bacteria eventually spread to the CNS hematogenously.

Gross CNS lesions are commonly present and include congestion, hemorrhage, and diffuse to focal cloudiness or opacity in the leptomeninges, resulting in a leptomeningitis caused by accumulation of exudates (see Fig. 14-43). The ventricles contain fibrin, usually as a thin layer on the ependymal surface or as a pale coagulum in the CSF of the ventricular lumen, secondary to a choroid plexitis and/or ependymitis.

Microscopic lesions vary according to the organism. With the exception of Salmonella spp., the lesions consist of deposits of fibrin and an infiltration of mainly neutrophils in and around the blood vessels and capillaries of the leptomeninges, choroid plexus, and ependymal or subependymal areas of the brain. The epithelium of the choroid plexus and ependymal lining of the ventricles can be disrupted by cellular degeneration, disorganization, and necrosis, and this inflammation can extend into the adjacent CNS. A vasculitis with thrombosis and hemorrhage can be associated with lesions caused by Escherichia coli. Lesions caused by Salmonella spp. are not limited to the perinatal period. CNS involvement in salmonellosis is generally limited to foals and pigs and in contrast to the above infections, the leukocytic response tends to have a greater proportion of macrophages and lymphocytes, often to the extent that the inflammation is designated histiocytic or granulomatous. This difference presumably reflects the fact that Salmonella spp. can be facultative pathogens of the monocyte-macrophage system. As is true in other tissues, vasculitis, thrombosis, necrosis, and hemorrhage often accompany Salmonella infections of the CNS. Haemophilus parasuis, which causes Glasser’s disease, is also a frequent cause of leptomeningitis, polyserositis, and polyarthritis in 8- to 16-week-old pigs. Again, lesions are as previously noted with fibrinopurulent inflammation involving the leptomeninges, serosal linings of body cavities, and joints.

Bacterial infection with CNS and visceral involvement occurs in neonatal pigs and through the weaning period. These diseases are deserving of special mention because of the incidence and stereotyped nature of the infections. Several strains of Streptococcus suis are capable of causing disease. Type 1 strains generally cause disease in suckling pigs ranging in age from 1 to 6 weeks, whereas type 2 strains affect older pigs 6 to 14 weeks old. Type 2 strains are recognized as one of the more important serotypes, causing meningitis not only in pigs but also in humans, particularly those working with pigs or handling porcine tissues. Other serotypes and untypable strains can also cause systemic disease that results in leptomeningitis, choroid plexitis, and ependymitis. Extension to involve cranial nerve roots or the central canal of the cervical spinal cord also occurs. The character of the inflammation is fibrinopurulent, and necrotic foci can be found in brainstem, cerebellum, and anterior spinal cord.

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.

Arboviruses:

Herpesviruses: Encephalitic herpes viruses, members of the subfamily Alphaherpesvirinae, cause cell injury through (1) necrosis of infected neurons and glial cells, (2) necrosis of infected endothelial cells, and (3) secondary effects of inflammation, cytokines, and chemokines. Although necrosis appears to be the principal mechanism for cell injury, recent studies indicate that bovine herpesvirus–induced apoptotic cell death can occur.

Neurotropic herpes viruses enter the CNS principally by retrograde axonal transport; however, entry by hematogenous spread via viremia and leukocytic trafficking may occur. These viruses also have a unique survival mechanism that allows them to hide in a latent form in nervous tissue, for example, in trigeminal ganglion of pigs infected with pseudorabies virus. Stress or other factors can activate latent virus resulting in encephalitis.

Rhabdoviruses:

Bornaviruses:

Cryptococcus Neoformans: Cryptococcosis, most commonly occurring in cats, dogs, and horses, is caused by Cryptococcus neoformans. This pathogen enters the leptomeninges and subarachnoid space by direct extension through the cribriform plate after a nasal or sinus infection or hematogenously by leukocytic trafficking usually from a pulmonary infection. Leptomeningeal inflammation can also extend along the roots of cranial nerves. Cryptococcus neoformans secretes a thick mucopolysaccharide capsule that protects the organism from host defenses. The accumulation of the organism and its mucopolysaccharide capsule gives the leptomeninges a cloudy-to-viscous appearance. The leukocytic response can vary from sparse to granulomatous. In some infected cats, Cryptococcus neoformans may be present in large numbers without an inflammatory response. It is unclear whether this absence of inflammation is to the result of suppression of the immune response by the organism or a defect in the cat’s immune and/or inflammatory responses to the pathogen.

Two virulence factors have been documented. First, a thick mucopolysaccharide capsule protects the organism from host defenses. Second, virulent organisms possess a biochemical pathway that can use catecholamines and that consists of a specific transport pathway and the enzyme phenoloxidase with production of a melanin or melanin-like compound through a series of oxidation-reduction reactions. This pathway can help protect the organism from oxidative damage in the brain. Both virulence factors are important for survival of the organism in the host. In addition, CSF lacks alternative pathway complement components that bind to the organism’s carbohydrate capsule and facilitate phagocytosis and killing by neutrophils.

Grossly in CNS tissue and the leptomeninges, multiple small “cysts” with a viscous, gelatinous appearance can be seen (Fig. 14-49). Microscopically, leptomeningeal lesions have a loosely organized, lacy appearance with often myriad cryptococcal organisms and little or no inflammation. The leptomeningeal reaction can extend along the roots of cranial nerves. Spread of the CNS infection results in ventriculitis and choroiditis. In CNS tissue, in addition to the presence of the organism and its capsule, the response can vary from being sparse to a granulomatous inflammation.

The leukocytic response consists of neutrophils, eosinophils, macrophages, giant cells, and small mononuclear cells, depending on the immune status of the host. Animals with normal immune responses usually clear the infection from nasal cavities, sinuses, and the pulmonary system before its spreads systemically. Resistance to infection is provided by cell-mediated immunity. Immunosuppression of cell-mediated immunity caused by feline immunodeficiency virus (FIV) and feline leukemia virus (FeLV) in cats and by Ehrlichia canis or long-term glucocorticoid therapy in dogs appear to increase susceptibility to cryptococcosis.

The yeast is spherical (2 to 10 mm in diameter), crescentic, or “cup shaped,” usually surrounded by a thick nonstaining (H&E stain) capsule (1 to 30 mm in diameter), and reproduces by narrow-based buds (Fig. 14-50, A). Special stains, such as periodic acid–Schiff (PAS) and Gomori’s methenamine silver, demonstrate the organisms readily, and the capsule can be stained with mucicarmine and Alcian blue (Fig. 14-50, B).

Clinically, cryptococcosis with CNS infection occurs in cats, dogs, horses, and cattle. The character of neurologic signs varies with the location of the lesions but can include depression, ataxia, seizures, paresis, and blindness.

Opportunistic Fungi: Opportunistic fungi, including those fungi in the Zygomycetes group, such as Absidia corymbifera, Rhizomucor pusillus, and Rhizopus arrhizus, and those fungi in the genus Aspergillus, such as Aspergillus niger, can invade blood vessels (angiotropic) and cause vascular thrombosis and infarcts in the CNS (Fig. 14-51). It must be noted that the term opportunistic implies that some form of tissue damage precedes fungal invasion. As an example, necrotizing enterocolitis caused by Salmonella spp. in the horse can provide an “open” vascular bed in the lamina propria of the intestinal mucosa that may be invaded by such fungi. Affected animals are often immunocompromised.

Neosporosis: Neosporosis, a naturally occurring or experimental disease caused by Neospora caninum or a Neospora-like coccidian, has been recognized in a variety of animals, including dogs, cats, cattle, sheep, and horses (Neospora hughesi), as well as laboratory rodents. First described in 1988 as a multisystemic infection in the dog, the organism has an affinity for the nervous system. The dog has recently been identified as the definitive host for the organism, but other hosts may exist. Some of the features of the organism are similar to those of Toxoplasma gondii, including division of tachyzoites by endodyogeny and having both proliferative (tachyzoites) and tissue cyst phases. However, Neospora caninum does not develop within a parasitophorous vacuole of a host cell, as does Toxoplasma gondii. This latter feature is evident only with the use of transmission electron microscopy.

Although there are morphologic differences between the organisms (Neospora caninum has a thicker cyst wall), differentiation by light microscopy is unreliable, and electron microscopic examination or immunohistochemistry is required. Apart from transplacental transmission proposed for a variety of species, the mechanism of infection is unknown. Neospora caninum can infect a variety of cell types, but outside of the CNS, it appears to have an affinity for cells of the monocyte-macrophage system. The most likely method of spread to the CNS is via leukocytic trafficking.

In the CNS, neurons and ependymal cells; mononuclear cells in the CSF; and cells of blood vessels, including endothelium, intimal connective tissue, and tunica media smooth muscle cells; can harbor organisms. Organisms have also been detected in spinal nerves. In all animals studied to date, the cyst form of Neospora caninum has been seen only in the CNS, whereas tachyzoites have been found in a variety of other tissue. Overall the morphologic pattern and character of lesions caused by Neospora spp. in the CNS are most consistent with endothelial tropism, vascular swelling and injury, tissue ischemia, and multifocal infarction.

Neurologic disease can be divided into two categories: that occurring during postnatal life and that associated with midterm to late-term abortions, the latter a notable problem in dairy cattle. Postnatal syndromes have been observed mainly in young and adult dogs, but horses are also affected. In young dogs, clinical signs are due to an ascending polyradiculoneuritis and polymyositis. In adult dogs, clinical signs are more referable to CNS lesions complicated by polymyositis, myocarditis, and dermatitis.

In horses, the pathogen causing neosporosis is Neospora hughesi. Clinical signs resemble those of protozoal myeloencephalitis caused by Sarcocystis neurona. Lesions in horses include meningoencephalomyelitis; variable vasculitis and necrosis with microgliosis; and perivascular cuffing by macrophages, multinucleated giant cells, lymphocytes, plasma cells, or neutrophils, most commonly in the gray and white matter of the spinal cord but also in the pons and medulla.

Gross lesions can involve the white and/or gray matter. Peracute gross lesions may include foci of hemorrhage and necrosis distributed in a vascular pattern. Acute lesions have the same pattern of distribution but are on cut surface granular in texture and yellow-brown to gray. In some cases the periventricular white matter may be more affected. Chronic lesions have larger areas of granular yellow-brown to gray discoloration, which often makes white matter indistinguishable from gray matter. Microscopically the lesions and their temporal occurrence are similar to those described for Toxoplasma gondii, including brain lesions that occur in aborted animals. Neospora caninum or Neospora-like organisms in lesions can be identified in tissue sections by H&E stain and immunohistochemical staining methods. Clinical signs are similar to those described for encephalitides induced by Toxoplasma gondii.

Toxoplasmosis: Toxoplasmosis is a disease in cats and other mammalian species caused by the obligate intracellular protozoan, Toxoplasma gondii. Domestic, feral, and wild cats are the definitive hosts of Toxoplasma gondii. Cats acquire Toxoplasma gondii by ingesting infective cysts, oocysts, or tachyzoites when eating infected prey, such as rodents or birds. Ingestion of one of these stages initiates the intraintestinal life cycle, which occurs only in members of the cat family. Toxoplasma gondii replicates and multiplies within epithelial cells of the small intestine and produces oocysts. Oocysts are released into the feces in large numbers for 2 to 3 weeks following initial ingestion of cysts, oocysts, or tachyzoites. When oocysts sporulate, usually within 5 days after passage in the feces, they become infectious for intermediate hosts. Sporulated oocysts are highly resistant and can survive in moist shaded soil or sand for months. Cats are unique in the biology of the organism, serving as both definitive (intraintestinal life cycle) and intermediate (extraintestinal life cycle) hosts.

Toxoplasma gondii can infect a wide variety of animals as intermediate hosts (extraintestinal life cycle), including fish, amphibians, reptiles, birds, humans, and many other mammals. New World monkeys and Australian marsupials are the most susceptible, whereas Old World monkeys, rats, cattle, and horses seem highly resistant.

Toxoplasma gondii can also parasitize a wide variety of cell types in the intermediate host and can cause lesions in such tissues as the lungs, lymphoid system, liver, heart, skeletal muscle, pancreas, intestine, eyes, and nervous system. After ingestion, bradyzoites from tissue cysts or sporozoites from oocysts enter intestinal epithelia and multiply. Evidence suggests active penetration of plasma membranes by organism-secreted lytic products, allowing a portal of entry rather than by uptake via phagocytosis. Toxoplasma gondii can then spread locally, free in lymph or intracellularly in lymphocytes, macrophages, or granulocytes to Peyer’s patches and regional lymph nodes. Intracellularly, organisms multiply as tachyzoites within a parasitophorous vacuole by repeated cycles of endodyogeny during the early acute stages of infection. Dissemination to distant organs is via lymph and blood, either as free organisms or intracellularly in lymphocytes, macrophages, or granulocytes via leukocytic trafficking.

With chronicity and an increasing antibody response by the host, tachyzoites of Toxoplasma gondii transform into slow-growing bradyzoites that replicate in cysts within muscle. Infection of the CNS occurs hematogenously; neurons and astrocytes are the eventual target cells. The typical sequence of events in the pathogenesis of the characteristic lesion is similar to that in Sarcocystis neurona infection. In utero infections in animals and humans can result in CNS infection. In fetal brains, foci of necrosis are most common in the brainstem and induce the formation of microglial nodules. Additionally, foci of necrosis and mineralization occur in the cerebrocortical white matter and are caused by fetal hypoxia and ischemia resulting from severe placentitis, fetal myocardial damage, or initiation of a systemic inflammatory reaction in the fetus. In older more mature individuals, Toxoplasma gondii infections have been associated with immunosuppression such as occurs in concurrent CDV infection and toxoplasmosis. In some cases, this could represent activation of latent inactive Toxoplasma gondii cysts [bradyzoites] in neural tissues.

Immune-mediated mechanisms have been proposed to explain the vascular injury (type III hypersensitivity) and cellular or tissue necrosis (type IV hypersensitivity). Lysis of infected cells by primed cytotoxic, CD8⁺ T lymphocytes also could potentially contribute to the tissue damage through the production of cytokines, such as interferon-γ (INF-γ), which can activate microglia and astrocytes to inhibit parasite replication and induce cytotoxic T lymphocytes to kill infected cells. This exuberant inflammatory response and the cytokine cascade that ensues to kill the organism also causes severe damage to cells in the area of inflammation, especially axons and neurons. Intracellular growth of tachyzoites also has been advanced as a cause of cellular necrosis. The organism does not produce a cytotoxin.

The blood-brain barrier of the CNS is breached when free organisms or those located intracellularly (leukocytic trafficking) infect endothelial cells of the CNS vasculature, especially capillaries. Gross lesions can involve any area of the CNS without predilection for gray or white matter, may also involve nerve rootlets, and may initially include foci of hemorrhage and necrosis and later, by granular, yellow-brown to gray foci. Peracute lesions initially include endothelial cell swelling as the result of infection by tachyzoites and vasculitis with hemorrhagic infarcts followed by vasogenic edema. If the edema is sufficiently severe to cause increased brain volume, the edema can lead to brain displacement and herniation.

Early microscopic lesions include infection of and proliferation within endothelial cells by Toxoplasma gondii tachyzoites. Endothelial injury results in endothelial cell swelling, endothelial cell degeneration, hemorrhage, capillary occlusion, ischemic necrosis, and edema of adjacent tissue. Subsequently, tachyzoites invade the CNS, inducing a prominent acute inflammatory response leading to necrosis and hemorrhage often striking in severity. With time, the inflammatory response consists of perivascular cuffing of blood vessels within the CNS and leptomeninges by lymphocytes and macrophages. CNS responses to injury consist of microgliosis and astrogliosis; however, these responses are often insufficient to replace the loss of tissue in the cerebral hemispheres, resulting in dilation of the lateral ventricles (hydrocephalus ex vacuo) and the formation of persistent cysts in the tissue. With chronicity and increasing inflammatory and immunologic responses by the host, tachyzoites change to slow-growing bradyzoites that replicate in and form tissue cysts. Organisms in lesions can often be identified with an H&E stain, but immunohistochemistry facilitates their detection and identification. As the infection is systemic, lesions can occur in several other tissues.

Occasionally, cysts (bradyzoites) can be observed in “normal” CNS tissue without an inflammatory or tissue lesion. These cysts are likely the result of a previous infection with Toxoplasma gondii that was successfully resolved. Experimental studies have confirmed that administration of corticosteroids and thus immunosuppression increases susceptibility or exacerbates the infection with Toxoplasma gondii or both or may contribute to the reactivation of tissue cysts.

Clinical signs can vary, depending on the age of the animal, species infected, and areas of the CNS involved and may include depression, weakness, incoordination, tremors, circling, paresis, and blindness.

Insect Larvae: Among the most common larvae are those of Oestrus ovis and Hypoderma bovis. The larvae of Oestrus ovis develop in the nasal cavity of sheep but can penetrate into the cranial vault through the ethmoid bone. Larvae of Hypoderma bovis can enter the spinal canal during their migration in the subcutis from the hoof to the dorsal midline in cattle and rarely as an aberrant parasite in the brain of horses. Damage in the CNS caused by Hypoderma bovis in cattle is typically the result of inflammation directed at the degenerating parasites after anthelmintic treatment. Larvae of Cuterebra spp., usually a parasite of rabbits and rodents, can invade the CNS of dogs and cats (see the section on Feline Ischemic Encephalopathy).

Cestodes: Coenurus cerebralis, the larval form of the dog tapeworm Multiceps multiceps, most commonly infests sheep and occasionally other ruminants. The larval forms presumably reach the CNS hematogenously and then cause damage during migration and encystation, forming space-occupying lesions. Another parasite for which humans are the definitive host is Taenia solium, with pigs being the intermediate host. The larval stage, Cysticercus cellulosae, generally develops in muscle of the pig but can also occur in the meninges and brain, resulting in a disease called “cysticercosis.” Involvement of the CNS has been termed “neurocysticercosis.”

Initially, viable cysticerci become “trapped” within capillaries of the CNS, but they do not apparently elicit an inflammatory response. At some point, the host responds immunologically and the cyst becomes denser, collapses inwardly, and disintegrates to eventually become calcified debris in a focus of inflammation. The inflammatory response has humoral and cellular components. Antibodies of the IgG family are directed against the cyst; however, cysts are likely killed by mediators released from eosinophils, which are attracted to the site by mediators released from lymphoid cells in the inflammatory exudate. For undetermined reasons, in “susceptible” animals viable cysts can become established and grow slowly for years. Viable cysticerci can cause asymptomatic infection by actively evading and suppressing the immune response of the host. These cysts cause vasogenic edema and increased intracranial pressure related to behavior as “space-occupying” masses.

Gross lesions are usually seen in the cerebral hemispheres, commonly at the interface of gray and white matter in a hematogenous pattern. Cysts can also be found in the cerebellum, medulla, ventricles, subarachnoid space, and the spinal cord. There are usually no gross changes in the CNS surrounding the cysts. Cysts are round to oval and of varied sizes and number, many of which can be large and visible up to centimeters in diameter. They have a translucent cyst wall and contain a thick, clear fluid. Within the fluid is a scolex, visible as a small 2- to 3-mm nodule. Microscopically, there is little or no inflammation or tissue injury surrounding the cysts, except for compression and edema.

Nematodes (Cerebrospinal Nematodiasis): Aberrant migration of larval stages of nematode parasites into and through the CNS is called cerebrospinal nematodiasis. They gain access to the CNS hematogenously and actively enter the CNS by crossing the blood vessel wall through their locomotive processes. Nematodes cause damage in the cerebromedullary area of the brain and/or spinal cord either from aberrant migration in the definitive host or migration in an aberrant host (Table 14-4; Fig. 14-52). Larval stages of Strongylus spp. and Baylisascaris procyonis, for example, are typically involved, the exception being Dirofilaria immitis, where the adult parasite is found. Greater CNS damage is often created by the migration of the parasites in an aberrant host.

Macroscopic lesions of nematode larval migration often appear as linear or serpentine tracts of necrosis and/or hemorrhage in the tissue. Migration results in endothelial injury, vasculitis, and thrombosis, which may result in vascular occlusion and infarction. Larvae can often be found in histologic sections, and they induce a mononuclear cell inflammatory exudate, including abundant eosinophils (Fig. 14-53).

Halicephalobus (Micronema) deletrix is a free-living rhabditiform nematode that can infest the nasal cavity, CNS, and kidneys of the horse. The life cycle, pathogenesis, and route of infection of Halicephalobus deletrix are poorly understood. It has been proposed that the CNS is infected hematogenously in a manner similar to that described for cerebrospinal nematodiasis and that larvae penetrate skin and mucous membranes in recumbent horses with subsequent invasion of sinuses and/or blood vessels. In the CNS, microscopic lesions are prominently associated with blood vessels along which the parasite apparently migrates.

Transmissible Spongiform Encephalopathies: Ovine spongiform encephalopathy (scrapie), bovine spongiform encephalopathy (BSE), and human spongiform encephalopathies are classified within a group of diseases called transmissible spongiform encephalopathies (TSEs). Table 14-5 lists the known TSEs in animals and humans. These diseases are caused by proteinaceous infectious particles (prions) that (1) are composed of an abnormal isoform of a normal cellular protein, the prion protein (PrP^c [a 27- to 30-kD polypeptide]), designated PrP^Sc and (2) resist inactivation by procedures that degrade nucleic acids and proteins (i.e., heat, ultraviolet irradiation, and strong enzymes). PrP^c is expressed throughout the body and is the product of a highly conserved gene found in organisms as diverse as fruit flies and humans. The “Sc” superscript is derived from the word “scrapie” because scrapie is the prototype prion disease.

Although the mechanism by which PrP^Sc forms has not been completely explained, a posttranslational modification of PrP^c has been proposed (Fig. 14-54). This mechanism proposes that PrP^Sc acts as a template on which PrP^c undergoes a conformational change (is refolded) by a process facilitated by another protein (referred to as protein X), whereby the α-helical content of PrP^c diminishes and the amount of β-sheet increases, resulting in the formation of PrP^Sc. The features of a specific PrP^Sc is determined by the animal in which it is formed. When PrP^Sc of one species is inoculated into a different species, the recipient is less readily infected and generally has a prolonged incubation period. This resistance to infection is referred to as the species barrier. A review of prion biology and diseases can be found in Prusiner (2004) in the Suggested Readings on the Evolve site. Dr. Prusiner was awarded the Nobel Prize in Medicine in 1997 for his work on prion diseases.

Spongiform encephalopathies occur through horizontal transmission (scrapie-infected sheep offal fed to cows [BSE] has been proposed) and through an inherited mutation of the normal human prion gene (parent to child), resulting in the spontaneous formation of PrP^Sc. In animals, the primary route of infection appears to be through horizontal transmission. It has been proposed that prions ingested in infective feedstuffs enter the body through the intestine. The role of the rendering process in the pathogenesis of prion infectivity is also unclear. Prions are thought to cross the intestinal wall at Peyer’s patches and are phagocytosed and transported to other lymph nodes by leukocytic trafficking. Prions replicate in lymphocytes and macrophages of the lymphoid system. Because these tissues are innervated, prions have been proposed to be transported by retrograde axonal transport to the brain; however, hematogenous spread via leukocytic trafficking may also be involved. In this example, scrapie infective ovine prions (OvPrP^Sc) accumulate in neurons and somehow result in the conversion of normal bovine prion proteins (BoPrP^c) in neurons to the disease-causing form, BoPrP^Sc, through a process in which a portion of the α-helical and coil structure of PrP^c is refolded into β-sheets (PrP^Sc). When neurons accumulate sufficient PrP^Sc to alter the normal function of neurons (it can take years), neurologic signs are observed.

Prion diseases are fatal. The adaptive immune system does not recognize prions as foreign; therefore no immunologic protection develops. How the accumulation of PrP^Sc causes neurodegeneration and neuron loss in prion diseases is not clear; however, astrocyte and microglial cell activation and apoptosis appear to be likely components of the pathway leading to neuronal injury.

No gross lesions of the nervous system are detectable in animals with spongiform encephalopathies. Microscopic lesions in scrapie-infected sheep and goats are limited to the CNS and are most commonly present in the diencephalon, brainstem, and cerebellum (cortex and deep nuclei), with variable lesions in the corpus striatum and spinal cord. Except for some minor changes, the cerebral cortex is essentially unaffected.

The type of neuronal degeneration can vary and commonly is characterized by shrinkage with increased basophilia and cytoplasmic vacuolation (Fig. 14-55, A), although other changes, such as central chromatolysis and ischemic cell change, variably occur. Astrocytosis in affected areas of the brain, including the cerebellar cortex, can be severe (Fig. 14-55, B). There has been speculation whether the astrocytic reaction is a primary or a secondary response. An abnormal protein (prion amyloid protein) first accumulates in astroglial cells in the brain during scrapie infection, which could mean that this cell is the primary site of replication. The spongiform change tends to affect the gray matter, and greater severity of this lesion has been associated with long incubation periods. The lesion in the gray matter is the result of dilation of neuronal processes, but vacuolation of neuronal and astroglial perikarya, swelling of astrocytic processes, dilation of the periaxonal space, and splitting of myelin sheaths have also been reported. Finally, the disease is not accompanied by any notable inflammation within the CNS.

Aminoacidopathies: Two diseases characterized by errors of amino acid metabolism have been described in neonatal calves. One disease, maple syrup urine disease (MSUD), occurs in young polled Hereford and Hereford calves. The second disease, bovine citrullinemia, which was originally described in Australia, occurs in neonatal Friesian calves.

MSUD is caused by an inherited defect in branched chain keto-acid dehydrogenase enzyme complex necessary to metabolize the branched-chain amino acids leucine, isoleucine, and valine. These amino acids are essential and must be obtained from protein in the diet. After consumption, proteins are digested and the amino acids are released to be used to generate energy and for other metabolic processes. In MSUD there is a mutation in one or more of the genes that regulate this degradation process; therefore abnormal metabolites and ketoacids accumulate to toxic levels and cause disease. Urine has a sweet odor attributable to a derivative of isoleucine resembling maple syrup. In human infants, the disease is confirmed biochemically by finding elevated concentrations of leucine, isoleucine, and valine in the blood.

Gross lesions are not typically present. Microscopically, marked spongiosis, caused by vacuolation of myelin sheaths, is present throughout the neuraxis. The spongiosis affects both gray and white matter. Lesions are often most notable in areas, such as the brainstem, in which there is an intermingling of gray and white matter.

Affected calves may be normal at birth. Within a few days, depression, dullness, and weakness progress to recumbency and opisthotonus.

Bovine citrullinemia is a rare inborn error of metabolism of the urea cycle that results in a pronounced accumulation of citrulline and ammonia in the body fluids because of a failure of the normal synthesis of arginosuccinic acid by the enzyme arginosuccinate synthetase. In human infants, the disease is confirmed biochemically by finding elevated concentrations of citrulline in the blood. The cerebral lesions have also been suspected to result from the hyperammonemia or possibly some defect in excitatory neurotransmitter metabolism. However, the pathogenesis of the disease in calves remains unsettled.

Grossly, brains appear normal and have normal weights. Livers are pale yellow. Microscopically, there is fatty change in the liver. Lesions in the brain are characterized by mild-to-moderate diffuse astroglial swelling in the cerebral cortex.

Calves are normal at birth. Within a few days, a severe generalized CNS disorder develops characterized by apparent blindness, depression, and tremors that rapidly progress to seizures, coma, and death within a few hours.

Cerebral Cortical Atrophy: Brain atrophy caused by the loss of neurons in the cerebral cortex can occur in animal species but is observed most commonly in sheep with lipofuscinosis. Lipofuscin pigment, a “wear and tear” pigment associated with low-grade chronic membrane damage via lipid peroxidation, is often found in affected neurons. The cause of this lesion is unknown but thought to be related to long-term “wear and tear” on the CNS. Atrophy most frequently involves the cerebral hemispheres, especially the cortex. The cerebral hemispheres are increased in firmness and often have a tan color (lipofuscin), gyri are thinned, and the sulci widened. Microscopically, there is loss of neuron cell bodies in cortical laminae without inflammation. Astrogliosis in response to neuronal loss is also observed, as is an increased prominence of the adventitial layer of blood vessels.

Channelopathies: Channelopathies are a newly emerging group of inherited neuromuscular diseases of humans that affect the excitability of membranes of neurons and skeletal myocytes. These diseases result from mutations in genes encoding ion channel proteins that regulate calcium, sodium, and chloride channels and acetylcholine receptors. In humans, neurologic diseases, such as epilepsy and migraine headaches, have been attributed to channelopathies. In veterinary neurology, channelopathies will likely be shown in the future to be the underlying mechanism for epilepsy and other primary neuronal degenerations.

Degenerative Leukomyelopathies: Degenerative leukomyelopathies are a heterogeneous group of familial, likely inherited, and acquired diseases that have been described in dogs, cows, and horses. Although there is no universal agreement, the degenerative leukomyelopathies described here are best characterized as axonal degenerations with spheroid formation predominantly within spinal cord white matter and secondary changes in myelin sheaths and myelin loss. In dogs, familial or inherited diseases include degenerative axonopathy of Ibizan hounds, axonopathy in Labrador retrievers, and axonopathy in Jack Russell and smooth fox terriers. A disease in Rottweilers (see the section on Primary Cerebellar Neuronal Degenerations in Dogs and Cats) is another disorder with spinal cord white matter involvement that is familial and possibly inherited. An acquired disease, hound ataxia, has been described in the United Kingdom and Ireland in harrier, beagle, and foxhounds. Hound ataxia may represent a nutritional disorder in hunting dogs fed paunch (tripe). Degenerative leukomyelopathies in cattle can be inherited as an autosomal recessive trait or have a familial predisposition. Leukomyelopathies have been reported in Murray Grey, Holstein-Friesian, and in certain lines of Brown Swiss cattle. In horses, a degenerative leukomyelopathy is recognized that does not seem to have a well-defined familial or hereditary basis (see the section on Disorders of Horses).

Gross lesions are usually not observed. Microscopically, lesions in the white matter of the spinal cord are bilaterally symmetrical and consist of axonal degeneration with formation of spheroids, loss of axons, and secondary myelin degradation. Depending on the species or breed affected, lesions can involve any of the funiculi. Spinocerebellar tracts in the dorsolateral aspects of the lateral and septomarginal areas of ventral funiculi are commonly affected, as is the fasciculus gracilis in the dorsal funiculus. Severe involvement of the dorsal spinocerebellar tracts can extend into the caudal brainstem and via caudal cerebellar peduncles to the cerebellar cortex and Purkinje cells. In some species and breeds, there can also be involvement of additional specific brainstem structures.

Age of onset varies with the familial or inherited disorders. Paresis, ataxia, and dysmetria are the predominant clinical signs.

Epileptic Brain Damage: Brain damage caused by prolonged (usually >30 minutes) convulsive seizures (status epilepticus) is not widely recognized nor is its occurrence even accepted in domestic animals. In humans and experimental animals, brain damage resulting from status epilepticus is well documented. One study reported a relatively high incidence of brain lesions in dogs caused by status epilepticus. In this study, acute brain damage was widespread and corresponded well with areas of the brain prone to hypoxic-ischemic injury such as the cerebral cortex, pyriform cortex, basal nuclei, and hippocampus.

The cause of neuronal injury with prolonged convulsive seizures is debatable. It remains unclear if necrosis, apoptosis, or a combination of these two mechanisms causes neuronal injury in status epilepticus. During seizures, there is an increased metabolic demand for glucose and oxygen by neurons; however, cerebral blood flow increases during seizures so that the amount of glucose and oxygen available for neurons to generate energy remains adequate, at least during earlier stages. Acute neuronal necrosis still occurs even when cerebral blood flow, oxygenation, body temperature, and other metabolic parameters are maintained within normal limits in experimental animals with status epilepticus.

Excitotoxic injury caused by accumulation of neurotoxic amino acid neurotransmitters, such as glutamate during the extreme neuronal activity occurring in status epilepticus, is an attractive explanation for neuronal necrosis. Excitotoxicity would account for both the selective vulnerability of certain brain areas and the character of the lesions. Status epilepticus induced experimentally in rats with kainic acid, an excitatory amino acid receptor agonist, has been shown to cause primarily neuronal necrosis and some characteristics of apoptosis. Other experimental studies have suggested that astrocytes produce clusterin during status epilepticus. Clusterin (dimeric acidic glycoprotein), a sulfated glycoprotein, initiates apoptosis when expressed in cells in elevated concentrations. It is proposed that clusterin secreted by astrocytes during status epilepticus is actively endocytosed by hippocampal neurons, and these neurons die by an apoptotic mechanism. The exact mechanism of neuronal injury remains to be proved. There is some evidence that the mature brain is more prone to injury induced by status epilepticus than the immature brain.

Gross lesions, if present, usually consist of widened and flattened gyri and narrow indistinct sulci caused by cerebral edema. Acute neuronal ischemic cell change and astrocytic swelling are observed microscopically. In experimental animals with status epilepticus, neuronal degeneration is observed within 30 minutes and neuronal necrosis within 60 minutes.

Hepatic Encephalopathy: Acute and chronic liver failure, as well as hepatic atrophy associated with congenital or acquired vascular shunts, often results in hepatic encephalopathy and disordered neurotransmission because of the accumulation of toxic substances, principally ammonia, in the systemic circulation and thus the CNS. Ammonia is formed in the gastrointestinal tract by bacterial degradation of amines, amino acids, purines, and urea from proteins consumed in the diet. In healthy animals, ammonia is detoxified in the liver by conversion to urea by the ornithine citrulline arginine urea cycle. Urea is far less toxic than ammonia and is excreted in the urine. Ammonia has several neurotoxic effects such as (1) changing the transit of amino acids, water, and electrolytes across the neuronal cell membranes and (2) inhibiting the generation of both excitatory and inhibitory postsynaptic potentials in neurons. Ammonia and other toxic metabolites also appear to (1) cause increased permeability of the blood-brain barrier leading to vasogenic edema and (2) alter osmoregulation within the CNS. These mechanisms likely led to the spongy change (status spongiosus) characteristic of the disease microscopically. Because astrocytes play an important role in regulating fluid and electrolyte balances in the CNS and are the primary cell type having lesions (Alzheimer’s type II astrocytes) in hepatic encephalopathy, it is not surprising that alterations in osmoregulation are a component of the pathogenesis of the disease. Ammonia and other toxic metabolites likely also affect oligodendroglia. Finally, it has been proposed that alterations in the blood-brain barrier may facilitate passage of neurotoxins such as short-chain fatty acids, mercaptans, false (pseudo-) neurotransmitters (tyramine, octopamine, and β-phenylethanolamine), ammonia, and GABA into the CNS leading to neuronal dysfunction. A similar condition, termed renal encephalopathy, has been described in dogs, a horse, and a cow with renal failure. It is likely related to high concentrations of ammonia or ammonia-metabolites in the circulation because of inadequate renal clearance caused by severe glomerular or tubular injury.

In all species except the horse, lesions of hepatic encephalopathy are of two types: spongy change and formation of Alzheimer’s type II astrocytes (see Fig. 14-10, D). Spongy change can be present throughout the neuraxis but typically involves areas of confluence or intermingling of gray and white. These areas include the deep cerebrocortical gray-white matter interface, basal nuclei and adjacent internal capsule, reticular areas throughout the brainstem, and deep cerebellar nuclei. The spongy change is due to intramyelinic edema, causing splitting and vacuolation of myelin sheaths. Spongy change can be produced experimentally by ammonia infusion and is reversible. Alzheimer’s type II astrocytic change is a subtle alteration that has been reported in all domestic animals and is the only CNS change observed in horses with hepatic failure. Alzheimer’s type II astrocytes are found in gray matter and have enlarged vesicular nuclei with peripheral chromatin, glycogen deposits, and demonstrable nucleoli or nucleolar-type bodies. Immunocytochemical staining for GFAP is typically weak or absent, possibly indicating a toxic effect on astrocytes.

Clinically, affected animals show CNS signs such as seizures, ataxia, depressed mentation, walking aimlessly, and head pressing.

Mitochondrial Encephalopathies: In humans, various encephalopathic and myopathic syndromes caused by point mutations in mitochondrial DNA affecting tRNA genes are grouped under the acronyms MELAS (mitochondrial encephalopathy, lactic acidosis, strokelike episodes) and MERRF (myoclonus epilepsy, ragged red fibers). The various human syndromes include Leigh’s disease (subacute necrotizing encephalomyelopathy), Kearns-Sayre syndrome, and Leber’s hereditary optic atrophy.

Diseases that might be classified as mitochondrial encephalopathies are not well characterized in animals. Despite this caveat, the diseases reported in the Alaskan husky, Australian cattle dogs, English springer spaniel dogs, and a Jack Russell terrier, as well as in Limousin and Simmental cattle and New Zealand South Hampshire sheep, could represent mitochondrial disorders. Table 14-6 summarizes the salient features of the diseases. Characteristics of these diseases in both humans and animals are symmetric bilateral involvement of the neuraxis and lesions typified by status spongiosus (edema of cerebral white matter) with variable progression to cavitation or necrosis. The CNS is highly dependent on oxidative metabolism and is therefore the most severely affected organ in mitochondrial disorders. Mitochondria isolated from affected human patients have impaired oxygen consumption and reduced respiratory chain enzyme complex activity. Recently, although quite controversial, it has been suggested that alterations in the function of genes in endothelial cells cause dysfunction of the blood-brain and CSF-blood barriers, which may play an important role in the underlying pathogenesis of mitochondrial encephalopathies.

Primary Neuronal Degeneration: Primary neuronal degeneration that occurs in many or all animal species is discussed in this section. Disorders of individual animal species are discussed in sections covering disorders unique to that species.

The term primary neuronal degeneration encompasses three groups of diseases affecting specific regions of the CNS in a temporally and spatially stereotyped manner and are characterized by degeneration, necrosis, and loss of specific populations of functionally linked neurons. Box 14-8 gives an overview of these diseases. The first group includes the multisystem neuronal degenerations, which are diseases that affect populations of functionally related neurons in the basal ganglia, brainstem, and cerebellum. The second group includes the primary cerebellar neuronal degenerations, which are diseases that affect populations of neurons restricted to the cerebellum and cerebellar roof nuclei. The third group includes primary spinal cord degenerations, which are diseases associated with axonal swellings (axonal spheroids) in the neuraxis termed neuraxonal dystrophies. Another term used to denote some of these diseases in the biomedical literature and veterinary textbooks is abiotrophy; this term was introduced by Gowers in 1902. The term literally means lack of (“a”) a vital (“bios”) nutrition (“trophy”) required to sustain the life of a tissue. For discussion of the primary neuronal degeneration affecting individual animal species, see sections covering disorders specific for the species.

Multisystem Neuronal Degeneration: Multisystem neuronal degeneration is discussed in sections covering disorders unique to individual animal species.

Primary Cerebellar Neuronal Degeneration: Depending on the degree of maturation of the cerebellum and related systems at the time of birth in the various species, clinical signs in animals with the neonatal syndromes can be manifest in the immediate postnatal period (bovine, ovine) or can be delayed until the time of ambulation (canine). Hereditary transmission is known or suspected in some instances. Lesions vary among affected species and breeds but overall include degeneration or absence of Purkinje cells, proximal swelling of Purkinje cell axons, variable loss of granule cells, cortical astrogliosis, and degeneration of nuclei in the cerebellar medulla.

Animals with postnatal cerebellar syndromes 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.

Grossly, the cerebellum can be normal or reduced in size and atrophic. Microscopically, lesions are analogous to those that occur in the neonatal syndromes with loss of Purkinje cells, variable neuronal depletion in the granular layer, and astrogliosis in the molecular layer. Fusiform swellings of proximal Purkinje cell axons are found in the rough-coated collie and the Yorkshire pig. In the rough-coated collie and Merino sheep, lesions occur in other areas of the neuraxis. In these syndromes, degeneration and loss of neurons in the deep cerebellar and other nuclei are accompanied by axonal degeneration in the cerebellum, brainstem, and spinal cord. Loss of spinal ventral horn motor neurons has been noted in the rough-coated collie. An autosomal recessive mode of inheritance is suspected or documented in several of the diseases. For individual disorders, see sections covering disorders of individual animal species.

For discussion of the primary cerebellar neuronal degeneration affecting individual animal species, see sections covering disorders specific for the species.

Vitamin B₁ (Thiamine) Deficiency: Thiamine diphosphate is the active form of thiamine. It is a critical cofactor for several thiamine-dependent enzymes involved in carbohydrate metabolism, and brain damage is thought to be related to a decline in thiamine-dependent enzymes, energy deprivation, and oxidative stress with the abnormal metabolism of free radicals in neurons. These enzymes are also important in the synthesis of several cell constituents, including neurotransmitters. Thiamine deficiency has been associated with neurologic disease in carnivores (Chastek paralysis), humans (Wernicke’s encephalopathy), and ruminants. For discussion of nutritional diseases affecting individual animal species, see sections covering disorders specific for the species.

Vitamin A Deficiency: See the section on the PNS and Chapter 20.

Chemicals: Chemically induced distal axonopathies have been classified by functional alterations affecting motor or sensory neurons, location of injury within the nerve (distal, proximal), or by the type of nerve affected (cranial or spinal). Because of the large number and wide use of chemicals in commerce, there exists an extensive list of experimental studies describing toxic axonopathies and neuropathies. Their complete discussion is outside the scope of this chapter.

Chemicals used in agricultural, industrial, and pharmaceutical commerce can injure nerves by interfering with axoplasmic flow. Such chemicals include acrylamide (polymerizing agent to strengthen paper), carbon disulfide (fat solvent, used for extraction of oil from oil-bearing fruit such as olives), triorthocresyl phosphate (high-performance lubricants in airplane engines), halomethane (refrigerants), methylene chloride (extraction agents, paint solvents, and degreasing agents), carbon tetrachloride (solvents), and butane (fuel source).

Acrylamide causes a unique distal axonopathy (dying-back axonopathy) primarily affecting axons of the PNS (less commonly the CNS) in which there is accumulation of neurofilaments within affected axons. Axonal spheroids are thought to be related to alteration of axonal transport resulting from phosphorylation of neurofilaments and their abnormal rearrangement within the axon. This “dying-back” axonopathy is microscopically characterized by degeneration of axons starting at or near synapses and proceeding toward the neuronal cell body. The most distal axonal projections are furthest from the cell body and thus cannot be maintained. Thus they are most vulnerable to functional alterations; however, it is unclear whether this degeneration is caused by energy deficits, lack of antioxidants, or physical obstruction of axoplasmic flow. Axonal degeneration is followed by secondary demyelination.

Certain types of toxic and biochemical injury to axons result in a stereotypic pattern of morphologic change that affects either distal or proximal segments of the axon and results in the formation of segmental axonal spheroids. Based on the location of the spheroids, such diseases are divided into one of two groups, either diseases affecting axons a distance away from their cell bodies (distal axonopathies) or diseases affecting axons near their cell bodies (proximal axonopathies).

It is hypothesized that axonal spheroid formation and subsequent axonal degeneration are caused by alterations in axoplasmic flow and by alterations of anterograde or retrograde flow, depending on the nature of the injury resulting in the accumulation and/or rearrangement of cytoskeletal proteins. The histologic lesion common to these two types of axonopathies is the formation of axonal spheroids with subsequent degeneration of the axon and secondary demyelination, which is a process that in many ways resembles the lesions described for Wallerian degeneration. Axonal spheroids are common to a variety of neuronal derangements; therefore distal and proximal axonopathies must be differentiated from other diseases that cause spheroids such as the compressive axonopathies.

Distal and proximal axonopathies have been further subdivided by some scientific disciplines into groups based on whether initial axonal lesions progress in an anterograde or retrograde direction. The terminology and classification schemes, although useful to some, are outside the scope of this chapter and are often confusing. The occurrence of secondary anterograde or retrograde lesions is discussed in the context of some of the diseases presented next.

Metals:

Microbial Toxins:

Plant Toxins:

Meningeal Melanosis (Congenital): The leptomeninges of animals and humans with heavily pigmented skin, especially black-faced sheep and black-skinned pigs, can have melanin (Fig. 14-57). The extent and degree of pigment deposition varies dramatically from animal to animal. Similar pigment deposits can be found in other areas of the body, including the lung, uterine caruncles, liver, and respiratory and alimentary systems’ mucous membranes. Congenital meningeal melanosis produces no clinical impairment in affected animals.

Hypomyelinogenesis:

Globoid Cell Leukodystrophy: See the previous section on Lysosomal Storage Diseases.

Spongy Degeneration (Status Spongiosus): Spongy degeneration is a group of diseases of young animals characterized by a spongy lesion (referred to here as status spongiosus) that primarily occurs in the white matter of the CNS but also extends into the gray matter. Status spongiosus is a somewhat nonspecific term and can develop by several different mechanisms. It includes a variety of lesions, such as splitting of lamella forming myelin sheaths (characteristic of the diseases discussed here), accumulation of extracellular fluid (extracellular cerebral edema), swelling of cellular processes (astrocytic, neuronal), and Wallerian degeneration at a later stage when the necrotic myelin and axons have been phagocytosed and the spaces once occupied by these structures are empty.

Gross brain lesions reported for spongy degeneration range from no gross lesions to swelling, edema, and pallor of the white matter, and dilation of the ventricles. Microscopically, the lesion is characterized by variably sized empty spaces within the white matter. Ultrastructurally, with spongy degeneration and some other disease processes characterized by status spongiosus, there is splitting or separation of the myelin sheath at the intraperiod line with the formation of large intramyelinic spaces. In some cases, myelin formation is deficient.

Some species and breeds affected with spongy degeneration include the canine (Labrador retriever, Saluki, silky terrier, Samoyed), feline (Egyptian mau), and bovine (Jersey, shorthorn, Angus shorthorn, Hereford), and an autosomal recessive mode of transmission has been proposed for some forms of this disorder. A unique form of the spongy degeneration also occurs in a group of metabolic inherited diseases called aminoacidopathies.

The term spongiform change should not be confused with spongy degeneration. Spongiform change is characterized by small clear vacuoles of varied sizes that form in the cytoplasm of neuron cell bodies and proximal dendrites in diseases, such as the TSEs and rabies encephalitis, and in the processes of astrocytes that are spatially related to the affected neurons.

Metabolic Causes:

Circulatory and Physical Disturbances: Physical compression of CNS tissue that results from various causes, usually chronic, can also induce demyelination. Some possible mechanisms include compression of myelin sheaths and oligodendroglia, interference with circulation resulting in CNS ischemia, and disease processes resulting in the accumulation of extracellular fluid.

It is well known that vasogenic and hydrostatic edema caused by inflammation, neoplasms, trauma, and obstructive hydrocephalus can cause degeneration of myelin sheaths. The underlying mechanisms for this injury are multiple and include creation of a hypoxic-anoxic environment, degeneration of oligodendroglia, and alteration in stability of the myelin sheath, permitting entrance of injurious proteolytic enzymes from the surrounding environment.

Diseases Caused by Microbes:

Immune-Mediated Diseases: In veterinary medicine, naturally occurring immune-mediated demyelination in domestic animals is rare, and other than canine polyradiculoneuritis (coonhound paralysis), it is usually only suspected rather than proved. These diseases are mostly known to occur in humans as sequelae to postinfectious and postvaccinal events. They result in primary demyelination of the CNS. Autoimmune diseases of the CNS are mechanistically either a type II hypersensitivity (antibody-mediated) or a type IV (cell-mediated) hypersensitivity, and T lymphocytes and macrophage-derived cytokines play contributory roles.

Autoimmune injury to oligodendroglia in the CNS arising from aberrant cellular and/or humoral immune responses can result from one of the following four proposed mechanisms:

The mechanism of myelin breakdown in immune-mediated demyelination is not clearly understood. The initial step is thought to be exposure of antigens in myelin basic protein of the major dense line of myelin lamellae after injury. Myelin proteins are substrates for calpain, a calcium-activated neutral proteinase. Calpain has been implicated in several autoimmune diseases and may play an important role in CNS demyelination. Exposed antigens are then recognized by the immune system, and experimental studies suggest that lesions result from a complex interaction between inflammatory cells and their mediators and lamellae of myelinating cells. T lymphocytes, some B lymphocytes, and activated macrophages (recruited monocytes) and microglia cells, adhesion molecules, cytokines, chemokines, and their receptors have been demonstrated in the lesions. This interaction results in primary demyelination.

Gross lesions are usually not present but can include a gray-to-yellow discoloration of white matter. Microscopically, lesions are best observed in white matter and are characterized by vacuolation of myelin and the presence of lymphocytes, macrophages, and plasma cells. Myelin sheaths degenerate from injury caused by (1) inflammatory mediators and (2) direct actions of macrophages on lamellae. Myelin lamellae separate as a result of intramyelinic edema, fragment, and are phagocytosed by macrophages.

The best-known model of immune-mediated demyelination is an experimental model referred to as experimental allergic encephalomyelitis (EAE). EAE is produced by inducing a hypersensitivity to myelin or more specifically, to myelin basic protein. If appropriate laboratory animals are inoculated with white matter or myelin basic protein (suspended in complete Freund’s adjuvant), they become paralyzed after 2 to 3 weeks. Lesions are characterized by perivascular (perivenular) demyelination accompanied by accumulation of lymphocytes and macrophages.

A similar process, referred to as postvaccinal encephalomyelitis, occurred occasionally in humans when human rabies vaccine contained CNS tissue. The incidence decreased after 1957 when duck embryo rabies vaccine came into use. In some cases with mild clinical signs, recovery was complete and axons were remyelinated after immune-mediated demyelination.

A third situation in which this type of demyelination occurs follows infection with certain viruses in humans (rubeola virus) and animals (e.g., influenza virus). These diseases, which are rare and designated as postinfectious encephalomyelitis, are also characterized by development of lesions in the CNS comparable to those of EAE.

1. A blow to the stationary (but freely movable) head produces a cerebrocortical coup contusion beneath the point of cranial impact, but with rare exceptions causes no cerebrocortical contrecoup contusion opposite the point of cranial impact. This outcome is not always true of animals, in which a blow to the dorsum of the head from a flat object, such as a spade, causes marked subarachnoid hemorrhage on the ventral surface (contrecoup).

2. An impact of a moving head (moving before impact, as in a fall from a standing position) against a firm or unyielding surface causes a cerebrocortical contrecoup contusion opposite the point of cranial collision (often at the poles and inferior surfaces of the frontal and temporal lobes), but with rare exceptions there is no contusion beneath the point of impact. In contrast, horses that fall backward and land on their backs and strike the occiput often have subarachnoid hemorrhage over the occipital poles of the cerebral hemispheres.

3. Falls from great heights and crushing of the head between a strong external force and unyielding surface are generally not associated with the occurrence of contrecoup lesions.

Hematomyelia (Hemorrhagic Myelomalacia): Traumatic injury to the spinal cord can cause stretching and tearing of blood vessels, usually arterioles, within the gray matter, resulting in hematomyelia. Hematomyelia is also particularly associated with severe type I disk herniation. If larger vessels are torn, blood pressure can force blood into the gray matter. This outcome results in the formation of a dissecting blood-filled cavity ascending and/or descending initially within the gray matter of the spinal cord (Fig. 14-69). This lesion, which is characterized by a softening to semiliquefaction (myelomalacia) and hemorrhage of the tissue, can develop within 12 to 24 hours after injury and can progress both cranially and caudally from the original site of trauma. As the cavity extends cranially, the hemorrhage at the original site also extends into the white matter and can transect the spinal cord. If this lesion extends to the fifth cervical cord segment, the phrenic nerves to the diaphragm will be denervated and respiratory paralysis will result. Bleeding continues until pressure in the blood-filled cavity is equal to the vascular pressure or until bleeding ceases because of hemostasis in the vessel. Hemorrhage can also result from bleeding in arteriovenous malformations within the spinal cord. Hematomyelia is characterized by neurologic deficits consistent with a sudden onset of ascending or descending flaccid paralysis and sensory abnormalities.

Brain Displacements: See the discussion of cerebral edema (permeability changes) in the section on Circulatory Disturbances.

Cervical Stenotic Myelopathy: Cervical stenotic myelopathy, or wobbler syndrome, is characterized by stenosis of the cervical vertebral canal, which causes compressive trauma to the cervical spinal cord (Fig. 14-71). This disease occurs primarily in young rapidly growing large breeds of horses and dogs. Reports indicate that the disease is not caused by a straightforward mechanism but apparently involves several factors (multifactorial disease). For example, stallions that have a genetic predisposition for rapid growth and large body size are reported to be at greater risk of developing the disease. Oversupplementation with protein, vitamins, and minerals used to promote rapid growth may also be another environmental factor in developing cervical stenotic myelopathy.

Gross and microscopic lesions of the CNS in cervical stenotic myelopathy are similar to the lesions in intervertebral disk herniation. The severity depends on the speed and degree to which the compression is applied and the specific area of the cord that is involved. Central nervous tissue can tolerate a considerable degree of compression if it is applied slowly. Rapid compression can lead to quickly developing hypoxia-ischemia, necrosis, and direct damage to compressed axons. Lesions detected include a spectrum of changes characterized by axonal injury and disruption of myelin sheaths resulting in Wallerian degeneration and necrosis of the gray or white matter or of both. Lesions can be visible grossly from the exterior but are more commonly seen on cross-section of the spinal cord.

Microscopically, particularly at the site of injury, there is initial swelling of axons followed after several days by loss of architecture of the CNS as a result of necrosis and a beginning accumulation of gitter cells that have phagocytosed the lipid-rich tissue debris. Eventually the necrotic area is cleared and a cystic space is formed, which is surrounded by varying degrees of astrocytosis and astrogliosis, although not usually prominent unless there is severe destruction. Rostral and caudal to this location, the lesion is primarily one of Wallerian degeneration in the white matter, and the pattern of lesion development seen depends on the level of the spinal cord that is examined relative to the site of compression. At the site of injury, all parts of the white and gray matter of the spinal cord are affected and often necrotic, if the compressive force is sufficient. Rostral to this site, white matter degeneration is generally limited to the ascending tracts in the dorsal funiculi and the superficial portions of the dorsolateral part of the lateral funiculi. Caudal to the area of injury, degeneration is limited to the descending tracts in the ventral funiculi, and the more central portions of the lateral funiculi. It should also be noted that (1) a lesion may occur at the point of compression because of ischemia, but a lesion can also occur on the opposite side of the compression also because of ischemia that results from compression of the tissue against bone on that side, and (2) Wallerian degeneration can be observed in distal segments of affected axons far from the point of compression within the spinal cord. In the former case, compressive forces can be transferred through the spinal cord to axons and blood vessels away from the contact point, whereas in the latter example, degeneration of the distal axon segments can extend for a length of centimeters to meters away from the point of contact.

Cervical stenotic myelopathy has been known for many years to affect horses and more recently has been recognized in the large dog breeds. The disease in the horse has been referred to by several designations: the wobbler syndrome, wobbles, equine incoordination, and more recently, cervical stenotic myelopathy. The disease has been described in many horse breeds.

Cervical stenotic myelopathy in the horse has been divided into two syndromes: cervical static stenosis and cervical vertebral instability (dynamic stenosis). Cervical static stenosis commonly affects horses 1 to 4 years of age. The spinal cord is compressed at C5 through C7 as the result of an acquired dorsal or dorsolateral narrowing of the spinal canal (see Fig. 14-71). The stenosis is due to formation of bone that requires time to develop. The compressive effect with this type of stenosis is present regardless of head position. The second form of cervical stenotic myelopathy (cervical vertebral instability [dynamic stenosis]) occurs in horses ranging in age from 8 to 18 months and is characterized by a narrowing of the spinal canal during flexion of the neck, primarily at C3 through C5 vertebrae.

A disease process with many similarities to that in the horse also affects the dog. It has been known as wobbler syndrome, vertebral instability, vertebral subluxation, and cervical spondylolisthesis. The disease has been most frequently described in the Great Dane and Doberman pinscher breeds but has also been reported in the Saint Bernard, Irish setter, fox terrier, basset hound, Rhodesian ridgeback, and Old English sheepdog. Dogs can have signs develop between 8 months and 1 year of age, with a range of 1 month to 9 years. Great Danes tend to have lesions develop at a young age (8 months to 1 year), whereas Doberman pinschers are generally older, often more than 1 year of age. The vertebral and associated spinal cord lesions in the dog have been reported to most often involve the caudal cervical area from C5 through C7 vertebrae. An exception is the basset hound in which C3 is affected.

Tumors: In the brain, diseases, such as neoplasia, cause compression of adjacent nervous tissue. Compression of CNS tissue causes neuronal dysfunction by impeding normal anterograde and retrograde axoplasmic flow in axons (see the later discussion of specific types of CNS tumors).

Viruses: