Multiple Diseases of the Nervous System PDF

916 Box 14.6 SECTION II Pathology of Organ Systems  Defense Mechanisms against Injury and Infectious Agents in the CNS SKIN Structural and functional (secretions) barrier. CALVARIA, VERTEBRAE Structural barrier. MENINGES, CEREBROSPINAL FLUID Structural and functional (continuous flow of CSF) barrie...

916 Box 14.6 SECTION II Pathology of Organ Systems  Defense Mechanisms against Injury and Infectious Agents in the CNS SKIN Structural and functional (secretions) barrier. CALVARIA, VERTEBRAE Structural barrier. MENINGES, CEREBROSPINAL FLUID Structural and functional (continuous flow of CSF) barrier. BARRIER SYSTEMS Blood-Brain Barrier Structural and functional barrier formed by vascular endothelium, basement membrane, and astrocytic foot processes. This barrier regulates the movement of agents from the blood to the CNS. Blood-CSF Barrier Structural and functional barrier formed by choroid plexuses cells and the arachnoid membrane. This barrier regulates movement of agents from the blood to the CSF. GLIA LIMITANS Formed by astrocytic foot processes immediately subjacent to the pia mater. This structure may have some barrier function in preventing movement of infectious agents from CSF into the neuroparenchyma through the pia mater. MICROGLIA, TRAFFICKING MACROPHAGES Resident and migrating cells that are part of the monocytemacrophage system. IMMUNOLOGIC RESPONSES Innate and adaptive immunologic responses that form the body’s overall immune system. CNS, Central nervous system; CSF, cerebrospinal fluid. from sites of production within foci of inflammation. Activated glial cells, including astrocytes and microglia, form chemokine networks in areas of inflammation in response to cytokines produced by T lymphocytes that recognize foreign antigens. Depending on the type of antigen and the pathogenicity of the infectious agent, the inflammatory response resolves (heals) or progresses to a chronic phase with attempts at resolution and clearance of the infectious agent. The type of inflammatory response varies with the cause. A rather simplistic guideline, to which there are exceptions, is as follows: 1. Serous to suppurative or purulent responses can be the result of bacterial infection. 2. Eosinophil responses occur in salt poisoning of pigs and with parasitic larval migration. 3. Lymphoplasmacytic and histiocytic responses can be caused by viruses and protozoa. 4. Granulomatous inflammation can be the result of infection by fungi, protozoa, and some bacteria such as Mycobacterium spp. Diseases Affecting Multiple Species of Domestic Animalsc Malformationsd Hydrocephalus. By far the most common congenital CNS abnormality identified in domestic animals is hydrocephalus. It has cPostmortem examination of the CNS is discussed in E-Appendix 14.1. E-Table 1.2 for a listing of potential, suspected, or known genetic disorders in the nervous system. dSee a variety of causes, including in utero viral infection, developmental abnormalities in the ependyma or ventricular system, infection and subsequent blockage of the ventricular system, or periventricular parenchymal loss. There appears to be a genetic predisposition in some dog breeds (toy and brachycephalic), but the mechanisms have not been as clearly established in domestic animals as they have been in human beings. In laboratory animals, several neonatal in utero experimental viral infections, including mumps virus, reovirus type 1, and parainfluenza virus types 1 and 2, can induce congenital hydrocephalus. In utero infection with panleukopenia virus in cats and parainfluenza virus in dogs can also cause congenital hydrocephalus in affected offspring. Although there are some differences among the different viral infections, the basic lesion is stenosis of the mesencephalic aqueduct that results in the development of noncommunicating hydrocephalus. In the dog, closure of the mesencephalic duct can be incomplete. The virus grows in and causes destruction of ependymal cells lining the ventricular system. The infection is initially accompanied by an inflammation that resolves within 2 weeks. The notable lesion resulting from this injury to the ependyma of the mesencephalic duct is its occlusion. This end-stage lesion is not the result of an astroglial response or because of the presence of viral antigen. Instead, the original ependyma-lined aqueduct is replaced by focal aggregates of remaining ependymal cells that have separated from the adjacent tissue, which appear normal. The appearance of the final lesion is therefore more suggestive of an agenesis than a viral infection. Infection of adult laboratory animals (mice with influenza viral infection) also can induce mesencephalic duct stenosis, resulting in hydrocephalus, but in contrast to neonatal infection, there is a persistent astroglial response in the area of stenosis. 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 dilated in hydrocephalus depends on the site of the blockage: 1. Blockage of the interventricular foramen between a lateral and third ventricle leads to unilateral dilatation of that lateral ventricle. 2. Blockage of both interventricular foramina leads to bilateral dilatation of both lateral ventricles. 3. Blockage of the mesencephalic duct leads to bilateral dilatation of the lateral ventricles, the third ventricle, and the segment of the mesencephalic duct proximal to the blockage. 4. Blockage of the lateral apertures of the fourth ventricle leads to bilateral dilatation of lateral ventricles, the third ventricle, the mesencephalic duct, and the fourth ventricle. 5. Blockage of reabsorption leads to bilateral dilatation of lateral ventricles, the third ventricle, the mesencephalic duct, the fourth ventricle, and expansion of the subarachnoid space, although this is nearly impossible to appreciate grossly. As an example, after 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 CHAPTER 14 Nervous System E-Appendix 14.1 Necropsy Difficulties in the Examination of the Central Nervous System There are inherent difficulties in performing a satisfactory examination of the CNS in all animal species, including rapid autolysis and the fact that removal of the brain and spinal cord is arduous in older large animals whose bones are very hard. The gross examination of the CNS requires time and a reasonable degree of physical strength. Necropsy Procedures The brain can be removed from the cranial cavity without great difficulty, but experience gained in veterinary school (diagnostic necropsy rotations) does make the process more efficient and helps to preserve the anatomic integrity of the brain. The head is usually disarticulated from the body at the atlanto-occipital joint before brain removal. A midline incision should be cut through the skin over the calvaria from the atlanto-occipital joint to a point midway between the eyes. The skin is reflected laterally to expose the entire calvaria and the masseter, temporalis, and other muscles, and these muscles should be dissected free from the calvaria. The calvaria can be cut using a hack saw, hatchet, flat pry bar and hammer, or Stryker saw (electrically powered saw) with a large blade in large animals or a small hack saw, Stryker saw with a small blade, bone rongeurs, or bone-cutting forceps in smaller animals. The first cuts are in a plane extending from the foramen magnum to a point just behind the eye. A single cut is then made behind the eyes at right angles to the initial two cuts. If the cuts are complete and connected, the calvaria can be pulled free from the head by pulling in a rostral to caudal direction. A flat instrument, such as a Virchow skull breaker, is helpful for prying up the bone. Once the calvaria is removed, the dura mater, if not removed with the calvaria, should be cut along the midline and reflected laterally to expose the surface of the brain. The falx cerebri and tentorium cerebelli must be cut and removed before attempting to remove the brain; otherwise the brain can be torn during removal. The head is turned upside down and the cranial nerve roots severed in descending numeric order to release the brain from the cranial cavity. The force of gravity helps pull the brain out of the cavity. Spinal cord removal is generally more labor intensive than brain removal. In small animals, removal is easier if the vertebral column is first separated from the rest of the body. A dorsal laminectomy can be done using a Stryker saw and bone-cutting forceps or bone-cutting forceps alone in younger animals and very small adult animals. In large animals, vertebral column segments up to about 10 cm can be removed with a hack saw and then the spinal cord removed by holding the dura mater with forceps and cutting attachments from both ends of the vertebral canal using a scalpel. In diagnostic laboratory settings, the vertebral column of large animals can be cut transversely into cervical, thoracic, and lumbar segments. Each segment is then cut in a lateral to medial direction on a sagittal plane to the depth of the spinal cord on a heavy-duty band saw. Regardless of species and the method used to expose the spinal cord, the cord can be removed by grasping the dura mater with forceps, maintaining slight tension on the cord, and cutting the spinal nerve roots with a scalpel. The anatomic orientation of the spinal cord needs to be maintained for subsequent histopathologic evaluation. Opening the dura before formalin immersion may improve fixation, especially in large animals. Gross Examination before Fixation CNS tissues must be carefully examined for gross abnormalities before formalin fixation. The CNS is symmetrical, having right and 916.e1 left sides that mirror each other in structural and functional features across an imaginary midline. These sides should be compared for any alterations in size, symmetry, or color. The sulci, gyri, and the meninges should be examined for changes in color or texture. It is not advisable to section an unfixed specimen of brain or spinal cord unless necessary for ancillary diagnostics such as infectious disease or toxicologic testing. The necessity for these tests will be based on the clinical history, findings of the postmortem examination, and probability of a specific disease occurring in the animal. Fresh CNS tissue should be provided for these ancillary tests in quantities sufficient and satisfactory for the requested analysis but not in a manner that interferes with further macroscopic and microscopic evaluation of the CNS after fixation. The diagnostic laboratory can be consulted for specific information regarding proper sample selection. Tissue Fixation Nervous system tissues should be fixed by immersion in 10% neutral-buffered formalin for histopathologic evaluation. A formalin to tissue volume ratio of 10 to 1 or greater is recommended but may not be practical (also see Appendix F: General Principles of Tissue Fixation and Processing; Appendix G: Fixatives and Fixation; and Appendix H: Fixation and Trimming of the Brain, Spinal Cord, and Nerves) Complete fixation may take several days or more, depending on the size of the sample and the amount of formalin used. The brain should not be randomly sliced in an effort to improve fixation. After fixation, the tissue should be sliced coronally (like a “loaf of bread”) from the olfactory bulbs to the cauda equina in approximately 1-cmthick sections. The cut surfaces of each section should be carefully examined for changes in size, shape, color, and symmetry. Specimens for microscopic evaluation should be taken from any areas that have visible changes and from areas that likely would have lesions for the disorders in the list of differential diagnoses. In addition, all routine microscopic evaluations of the CNS in which gross lesions are or are not detected should include specimens from the cerebrum (at least two areas), thalamus, hippocampus, cerebellum, brainstem (at least two areas), and the cervicothoracic and thoracolumbar enlargements of the spinal cord. Alternatively, the veterinary practitioner can submit a nonsectioned brain and/or spinal cord to a diagnostic laboratory after formalin fixation, along with small pieces of fresh or frozen tissue for ancillary diagnostics, if indicated. Thoroughly fixed tissue can be wrapped in formalin-moistened gauze or paper towels and double bagged for shipment. Peripheral nerves should be sampled if the neurologic examination suggests PNS involvement. Segments of nerves can be placed on a wooden tongue depressor and allowed to sit for a few minutes before placement in formalin. This practice allows the nerve to adhere to the tongue depressor and prevents contraction artifact during fixation. Other Considerations Nervous system tissues must be handled gently because rough handling induces artifacts that can hinder histologic interpretation. Care should be taken not to compress brain or spinal cord and not to stretch peripheral nerves during removal from the body. When submitting nervous system tissues to a diagnostic laboratory, it is critically important to include the signalment, duration, and nature of the clinical signs, the clinical pathology findings, and the neurologic examination findings. For example, neurologic examination findings suggesting vestibular disease would be an indication for the pathologist to examine the vestibular nuclei. The combination of clinical and pathologic findings is often necessary to formulate the final diagnosis. CHAPTER 14 Nervous System 917 A Figure 14.31 Congenital Hydrocephalus, Brain, Calf. Note the symmetrically enlarged and dome-shaped calvaria. The bone of the calvaria is thinned and distorted from pressure from the expanding brain during gestation. (Courtesy Dr. J. King, College of Veterinary Medicine, Cornell University.) lv tv tv-ma B Figure 14.32 Calvaria, View of the Dorsal Surface, Congenital Hydrocephalus, Dog. The bone of the calvaria is thin and the fontanelles (arrows) are enlarged. The translucent membrane covering the fontanelles is periosteum. (Courtesy Drs. J. Wright and D. Duncan, College of Veterinary Medicine, North Carolina State University; and Noah’s Arkive, College of Veterinary Medicine, The University of Georgia.) obstruction within the ventricular system at, or rostral to, the lateral apertures of the fourth ventricle. Noncommunicating hydrocephalus can also occur without any evidence of obstruction to CSF flow as a result of failure of the reabsorption of CSF. Gross lesions associated with communicating and noncommunicating congenital hydrocephalus include enlargement (doming) of the cranium if obstruction occurs before the sutures have fused (Fig. 14.31). The bones of the calvaria are extremely thin, and the fontanelles are prominent (Fig. 14.32). In the brain, there is prominent enlargement of the ventricular system proximal to the point of obstruction (Fig. 14.33). 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 and cavity formation 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 Figure 14.33 Hydrocephalus, Brain, Dog. A, Midsagittal section of the head, third ventricle. Note the dilated third and lateral ventricles and the absence of most of the septum pellucidum between the left and right lateral ventricles. B, Junction between parietal and occipital lobes, level of thalamus. Bilateral dilatation of lateral ventricles (lv) dorsally and ventrolaterally. The fornix has separated and lies on the flattened floor of the ventricle. Note that the third ventricle (tv) and junctional area between the third ventricle and mesencephalic aqueduct (tv-ma) are not enlarged and are possibly even reduced in size, suggesting that the obstruction may be at, or rostral to, this plane of section. (A courtesy Dr. M.D. McGavin, College of Veterinary Medicine, University of Tennessee. B courtesy Dr. R. Storts, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University.) 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 hemorrhage and 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 918 SECTION II Pathology of Organ Systems obstruction of any of the following: the lateral apertures of the fourth ventricle, the mesencephalic 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 calvaria 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, 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. Hydromyelia. Congenital hydromyelia is an abnormal dilatation of the central canal of the spinal cord (Fig. 14.34) that leads to the formation of a cavity in which CSF may accumulate. In animals, this disorder likely results from infectious or genetic injury that results in damage to ependymal cells lining the canal and the subsequent disruption of the normal flow of CSF and the formation of abnormal CSF pressure gradients within the central canal. As CSF accumulates in the enlarging space, the increased pericanalicular pressure placed on the spinal cord compresses the white and gray matter, leading to loss of white matter and possibly neurons in gray matter. Acquired hydromyelia is rare and is caused by obstruction of the central canal CSF flow. Causes of obstruction include infection, inflammation, and neoplasia. Clinical signs in young animals with congenital hydromyelia vary, depending on the location and size of the dilatation of the central canal in the spinal cord. Signs may include ataxia, urinary incontinence, respiratory difficulty, muscle weakness in front and/or hind limbs, and abnormal proprioceptive reflexes. It can accompany other defects in the spinal cord and is seen as an abnormality associated with spinal dysraphism in Weimaraner dogs. Neural Tube Closure Defects (Dysraphia). Dysraphia means an abnormal seam, and these anomalies result from defective interaction of neuroepithelium with adjacent notochordal and mesenchymal cells during closure of the neural tube in the early stages of development. Neuroepithelium is the progenitor cell for neurons and astrocytes, oligodendrocytes, and ependymal cells. Experimental studies of closure of the neural tube show that it occurs at four distinct locations called closure initiation sites in the embryo, and disruption of this process at these sites leads to site-specific dysraphic anomalies. Closure site I contributes to the posterior neuropore (the opening at the posterior end of the embryonic neural canal), whereas closure sites II to IV contribute to the anterior neuropore (the opening at the anterior end of the embryonic neural canal). Anencephaly is caused by a failure of closure sites II or IV; spina bifida is caused by a failure of closure site I. Genes possibly A B C Figure 14.34 Hydromyelia, Spinal Cord, Dog. A, Late-stage hydromyelia. The white and gray matter of the spinal cord are missing as a result of compression atrophy from a space-occupying, fluid-filled central canal. The only recognizable remnant of nervous tissue is the dura (arrows). In less severely affected animals, there would be variable dilatation of the central canal of the spinal cord with much less severe compression atrophy. B, Mid-stage hydromyelia. Note the symmetrically distended and enlarged central canal in the spinal cord. C, Mid-stage hydromyelia. Hematoxylin and eosin (H&E) stain. (A courtesy College of Veterinary Medicine, University of Tennessee. B and C courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.) involved in neural tube closure defects include those involved in folate metabolism and transport. Dysraphic anomalies, also called neural tube closure defects, in animals are typified by anencephaly and prosencephalic hypoplasia, cranium bifidum, spina bifida, abnormal spinal cord development (neuronal migration disorders [duplication or abnormal cell migration]), and syringomyelia (E-Fig. 14.6). Anencephaly and Prosencephalic Hypoplasia. Anencephaly means an absence of the brain, but in many instances of so-called anencephaly only the rostral part of the brain (cerebral hemispheres) is absent, or very rudimentary, and to varying degrees the brainstem is preserved. Thus, this abnormality is best designated prosencephalic hypoplasia. Such anomalies result from an abnormal development of the rostral aspect of the neural tube and failure of their fusion. Although the cause for these anomalies is largely unknown, anencephaly is most commonly reported in calves, where it is accompanied by other defects. It is an extremely rare event in other domestic species. Additionally, anencephaly—after initial cranium bifidum and exencephaly (protrusion of brain not covered by skin or meninges)—has been reported to occur in rat fetuses after exposure of the pregnant dam to excessive concentrations of vitamin A and cyclophosphamide. Meningoencephalocele and Cranium Bifidum. Cranium bifidum is characterized by a dorsal midline cranial defect through which meningeal and brain tissue can protrude. The protruded material, CHAPTER 14 Nervous System E-Figure 14.6 Dysraphism from a Syrinx, Spinal Cord, L3 to S2, Cow. Note the defective closure of the neural tube (dysraphism) (arrows) that occurred secondary to the formation of a syrinx, a cavity, within the spinal cord. (Courtesy Dr. M.D. McGavin, College of Veterinary Medicine, University of Tennessee.) 918.e1 CHAPTER 14 Nervous System 919 m Figure 14.35 Meningocele (m), Brain, Calf. A defect in the caudodorsal portion of the skull has allowed the meninges to herniate into a large external pouch covered by skin. The pouch contains fluid and is lined by arachnoid and dura, which are continuous with those surrounding the brain. The cerebellum is small, and the occipital cortex truncated. Scale bar = 5 cm. (Courtesy Dr. R. Storts, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University.) which forms a sac (-cele), is covered by skin and can be lined by meninges (meningocele) or meninges accompanied by a part of the brain (meningoencephalocele) (Fig. 14.35). Although the sac is readily apparent grossly, diagnosis of the presence or absence of brain tissue typically requires histologic examination. These malformations are hereditary in pigs and cats and are also caused by griseofulvin treatment in pregnant cats during the first week of gestation. They are uncommon and sporadic in other domestic species. Meningomyelocele and Spina Bifida. Spina bifida is the vertebral counterpart of cranium bifidum. This lesion, which frequently tends to affect the caudal spine, is characterized by a dorsal defect in the closure of one to several vertebral arches that form the dorsal portions of the vertebral canal encasing the spinal cord. The lesion results from a failure of the neural tube and developing vertebral arches to close properly, which may result in herniation of either meninges (meningocele) or meninges and spinal cord (meningomyelocele) through the defect, forming a sac covered with skin. In some cases, there is no herniation of the meninges or spinal cord through the defect, and this variation is termed spina bifida occulta (Fig. 14.36). In this variation, there is an absence of skin over the affected vertebral arches, vertebral musculature is visible, and the dura mater and spinal cord can be seen in the spinal canal. Spina bifida has been reported in several species, including horses, calves, sheep, dogs (especially English bulldogs), and cats, particularly the Manx breed, in which it is inherited as an autosomal dominant trait. An additional lesion, myeloschisis, also refers to failure of the neural tube to close and is therefore similar to spina bifida, except in its severe form it results from failure of the entire spinal neural tube to close. This lesion is therefore characterized by lack of development of the entire dorsal vertebral column because the developing neural tube remained open, unable to fuse and develop normally. Neuronal Migration Disorders Lissencephaly. Lissencephaly (agyria) and a similar change called pachygyria (large, broad gyri) are developmental anomalies that result in part of or the entire cerebrum and have smooth surfaces lacking normal gyri and sulci (Fig. 14.37). The cortex is thicker than normal on a transverse section, and the normal laminar pattern of neurons is disrupted. It is reported most commonly in the Lhasa apso dog, but scattered reports also exist in kittens and lambs. Figure 14.36 Spina Bifida Occulta, Calf. There is a cleft in several vertebrae of the dorsal spinal column resulting from defective closure of the neural tube. Although not always the case, note the lack of herniation of the meninges or spinal cord through the defect. The spinal cord is not visible (i.e., occulta) because it is located in the vertebral canal at the deepest ventral extent of the cleft and is covered by edematous muscle. (Courtesy Dr. M.D. McGavin, College of Veterinary Medicine, University of Tennessee.) This lesion is thought to have a genetic basis and results from an arrest of or defect in neuronal migration during development. Recent experimental studies suggest that this migrational disorder is linked to mutations and/or deletions in the doublecortin, filamin-1, LIS1, and reelin genes. These genes control the spatial and temporal expression of proteins in the extracellular microenvironment that subsequently bind to receptors on migrating cells. Patterns of cell membrane binding signals are interpreted by migrating cells and are reflected in their movements by changes in intracellular cytoskeletal reorganization. This process allows cells to migrate to their final destinations within the CNS. Thus, alterations in signaling pathways lead to abnormal neuronal migration and CNS anomalies. The brains of many species, including birds and some laboratory animals, such as rabbits, rats, and mice, lack gyri and sulci; therefore agyria is normal in these species and has no functional significance. Malformations of the Spinal Cord Syringomyelia. Syringomyelia (congenital and acquired forms) is a disorder in which a cavity forms in the spinal cord. The cavity, called a syrinx, is not lined by ependyma and is separate from the central canal. The syrinx can extend over several spinal cord segments. The lesion is well known in human beings and has also been described most commonly in calves and also in many breeds of dogs. The syrinx can communicate with the central canal but should not be confused with hydromyelia, which means dilatation of the central canal. In instances of communication, the term syringohydromyelia should be used. The cavity contains fluid and is unlined, except for varying degrees of mural astrocytosis. Proposed causes include the presence of an anomalous vascular pattern that results in low-grade ischemia, leading to infarction or failure of cells destined for this area to develop in utero trauma in human beings or an infection that causes degeneration and cavitation. An acquired form of syringomyelia is similar to congenital syringomyelia; however, it occurs 920 SECTION II Pathology of Organ Systems CSF to continually move into the cyst, resulting in enlargement of the syrinx and additional compressive damage to the spinal cord. Clinical signs in young dogs and calves with syringomyelia vary, depending on the location and size of the spinal cord lesion. Signs may include ataxia, urinary incontinence, respiratory difficulty, muscle weakness in front and/or hind limbs, and abnormal proprioceptive reflexes. Encephaloclastic Defects Porencephaly and Hydranencephaly. The formation of fluid- A B Figure 14.37 Lissencephaly, Brain, Dog. A, Note the smooth surfaces of the cerebral hemispheres, which are without gyri and sulci. Gyri and sulci fail to form, possibly from failure of neuronal development and migration. Lissencephaly is an abnormality in domestic animals but is a normal feature in some species, including mice, rats, rabbits, and birds. B, The development and migration of neurons have been disrupted such that the cortical gray matter lacks normal lamina formed by neuronal cell bodies. Hematoxylin and eosin (H&E) stain. (A courtesy Dr. L. Roth, College of Veterinary Medicine, Cornell University. B courtesy Dr. R. Mantene, College of Veterinary Medicine, University of Illinois.) in older animals. Proposed causes include injury after trauma to the central canal or its vascular supply caused by trauma, infection, or neoplasia that result in degeneration and cavitation of the spinal cord. The presence of syringomyelia and hydromyelia in some animals with vertebral malformations also suggests that local perturbations in CSF flow and pressure may allow for these dilatations and cavities to develop. Although the central canal of the spinal cord is connected to the ventricular system via the fourth ventricle, there apparently is little active movement of CSF within the central canal. Recently it has been hypothesized that there may be alteration of “normal” CSF flow (see the section on Central Nervous System, Structure and Function, Ependyma) with redirection of the flow along a pressure gradient into the central canal and into the syrinx. It has also been suggested that pressure differences in the vertebral column cause filled cavities in the brain, termed porencephaly and hydranencephaly, usually occurs in utero during gestation. Porencephaly refers to a single cavity in a cerebral hemisphere that typically communicates with the subarachnoid space, but it can also communicate with a lateral ventricle. The cavitation results from destruction of immature neuroblasts whose loss prevents normal development as a result of faulty or aberrant neuroblast migration. Hydranencephaly is considered a severe form of porencephaly and is characterized by large areas of cavitation in areas normally occupied by the white and gray matter of the cerebral hemispheres and results from improper development of this part of the cerebrum. Hydranencephaly is often quite severe, with very little tissue present between the dilated lateral ventricles and the leptomeninges. Porencephaly types I and II have been described in human infants, and cases of porencephaly reported in animals can also be categorized using this scheme. Type I porencephaly is caused by vascular injury or vasculitis. Injury, resulting in infarction in the area of the subependymal germinal matrix, results in the formation of a cyst-like cavity within the focus of dead cells and effete erythrocytes. The germinal matrix is very sensitive to ischemia because of sparse stroma, delicate vasculature, and high metabolism. The initial focus of hemorrhage can grow by centripetal expansion, depending on the severity of hemorrhage and hypoxia, into a cyst of considerable size. Type II porencephaly is caused by injury of neuroblasts in the germinal matrix and the failure of these neuroblasts to migrate within the matrix to form the cerebral cortex. The cavity results from the expansion of the subarachnoid space into the void left by the absence of the cortex. Type II porencephaly appears to be the form of porencephaly that occurs in domestic animals. Viruses, including Akabane, bovine viral diarrhea, blue tongue, border disease, Rift Valley fever, Schmallenberg disease, and Wesselsbron disease, infect and destroy differentiating neuroblasts and neuroglial cells in the developing fetus in utero. Although neuroblasts appear to be the primary target for viral infection in these diseases, additional experimental studies need to be conducted to clarify whether endothelial cells are also infected. Grossly, porencephaly/hydranencephaly appears as thin-walled fluid-filled cavities of varied sizes in the cerebral hemispheres. Because of the lack of brain substance, the ventricles expand into this space (hydrocephalus ex vacuo), and the ependymal lining remains relatively preserved or may have scattered defects characterized by absent ependyma. The cranium and meninges are generally unaltered. In some cases, cerebellar hypoplasia (all or part of the cerebellum) and hypoplasia of the spinal cord may also occur. Microscopically, necrosis of undifferentiated cells, including potential neuroblasts and neuroglia, surrounding a fluid-filled cavity is present in the subventricular zone of the cerebral hemispheres. Degeneration and loss of motor neurons of the ventral horns of the spinal cord may also be observed. This lesion may result in denervation atrophy of limb muscles with a resultant lack of joint movement and arthrogryposis, a persistent congenital flexure or contraction of a joint. Nonsuppurative encephalitis, typified by the accumulation of macrophages, lymphocytes, and plasma cells, also occurs. CHAPTER 14 Nervous System 921 cause adhesions between adjacent cerebellar folia and focal obliteration of the subarachnoid space. Miscellaneous Diseases Schwannosis. An extremely rare but characteristic entity referred to as schwannosis is described in horses and one calf. This entity results in the formation of plaque-like masses in the brainstem and spinal cord that are formed by aberrantly proliferating Schwann cells derived from the PNS. The cause of the aberrant proliferation is unknown; however, it may reflect an exuberant repair response or represent a tumor-like process. When occurring in the spinal cord, it can be broadly defined as one of the many entities that result in myelodysplasia. Optic Nerve Aplasia/Hypoplasia. Optic nerve aplasia/hypoplasia is a relatively common congenital defect that is seen in domestic animals. It is often seen concurrently with other brain development disorders and is because of inadequate optic cup development (E-Fig. 14.8). Infectious Diseases Bacteria Brain Abscesses. Cerebral abscesses are uncommon in animals Figure 14.38 Cerebellar Hypoplasia, Cerebellum, Cat. In the cat, cerebellar hypoplasia (cerebellar hypoplasia, top specimen; normal cat, bottom specimen) most commonly is the result of in utero infection with feline panleukopenia virus (parvovirus). The virus infects and causes lysis of dividing cells in the external granule layer (on the outside of the cerebellum in the fetus). Because these cells are no longer available to migrate to form the granule layer, the cerebellum remains small. (Courtesy Dr. Y. Niyo, College of Veterinary Medicine, Iowa State University; and Noah’s Arkive, College of Veterinary Medicine, The University of Georgia.) Malformations of the Cerebellum Cerebellar Hypoplasia. In animals, the most common causes of cerebellar hypoplasia are parvoviruses (kittens: panleukopenia virus [Fig. 14.38]) and pestiviruses (calves: bovine viral diarrhea virus [Fig. 14.39; E-Fig. 14.7] and piglets: classical swine fever virus). These viruses infect and destroy mitotic cells, primarily the cells of the external granule layer of the cerebellum that are still dividing during the late gestational and early neonatal periods. Necrosis of these cells means they are not available to form the granule layer, and thus the cerebellum is hypoplastic. In calves the cerebellar lesion (cerebellar hypoplasia/atrophy), which follows infection at 150 days of gestation (midtrimester), is considered to involve two processes. One process is typified by early necrosis of the undifferentiated cells in the external granule layer. A second process involves viralinduced vasculitis and ischemia of cerebellar folial white matter. Grossly, the size of the cerebellum is reduced, but the reduction in size varies in severity, depending on the age and developmental stage of the brain when the fetus or neonate is infected. Microscopically, there is necrosis and loss of the external granule layer and degeneration and loss of Purkinje cells that are postmitotic but immature. Reasons for degeneration of Purkinje cells might include infection by the virus or lack of normal development of the cerebellar cortex. The Purkinje cells can also be malpositioned and located in the molecular layer as a result of the viral-induced alteration in development of the cerebellar cortex. In calves, edema of the folial white matter with focal hemorrhage in the cortex, followed by focal cavitation of the white matter and atrophy, may also be present. These latter lesions are because of ischemia resulting from vasculitis. Leptomeningitis, characterized by the accumulation of lymphocytes and plasma cells and occasionally fibroplasia, may and may occur either from direct extension or hematogenously. With direct extension, abscesses occur after penetrating wounds, such as calvarial fractures, or from spread of infection from adjacent tissues, such as the meninges, paranasal sinuses, and internal ear, and through the cribriform plate of the ethmoid (see Fig. 14.29). Septicemia can result in bacteria being trapped in vascular beds within the neuroparenchyma 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 of surrounding tissue. If the abscess grows quickly, tissue is more likely to be destroyed. Abscesses that are adjacent to a ventricle can potentially penetrate the ependymal lining and lead to ventriculitis. Bacteria in the CSF may be carried into the subarachnoid space and cause a leptomeningitis. Slower growing abscesses are more likely to cause tissue displacement. Chronic abscesses become encapsulated by either fibrous tissue if they are close to the leptomeninges or by astrocytic processes away from the meninges. The tissue injury that occurs in abscess formation is likely a secondary bystander effect related to the actions of the mediators of inflammation and the toxins and other products elaborated by bacteria. Lytic enzymes released from lysosomes of neutrophils and other inflammatory cytokines secreted by lymphocytes and macrophages destroy neurons and their processes. 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 that allow bacteria to attach to and move through the blood-brain barrier. This 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 at the gray-white matter interface. 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 E. 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 CHAPTER 14 Nervous System 921.e1 * * A B E-Figure 14.7 Cerebellar Hypoplasia, Cerebellum, Calf. A, The cerebellar folia are disorganized with a discontinuous granule cell layer (arrows), sparsely populated Purkinje cell layer (arrowhead), and thin molecular layer (asterisk). Hematoxylin and eosin (H&E) stain. B, Higher magnification of A illustrating the highly disorganized granule cell layer (arrows) and thinned molecular layer (asterisk). H&E stain. (A and B courtesy Dr. A.D. Miller, College of Veterinary Medicine, Cornell University.) o o p E-Figure 14.8 Optic Nerve Aplasia, Dog. Note the absence of the optic nerves (CN-II) rostral to the pituitary gland (p). Oculomotor nerve (CN-III) (arrow); anterior cerebral arteries and branches (arrowhead); olfactory nerve (CN-I) (o). (Courtesy Dr. M.D. McGavin, College of Veterinary Medicine, University of Tennessee.) 922 SECTION II Pathology of Organ Systems w m p g A B C Figure 14.39 Cerebellar Hypoplasia, Cerebellum, Calf. In the normal neonatal calf, cells of the external granule layer of the cerebellum migrate to form the granule layer (not shown). Bovine viral diarrhea virus infects and kills mitotic cells of the granule layer of the cerebellum. These cells are still dividing during the late gestational and early neonatal periods in the cat and between 100 to 180 days of gestation in the calf. Necrosis of these cells means they are not available to migrate to form the granule layer, and thus the cerebellum does not obtain full size. Depending on the stage of gestation, injury can also alter development of cells in other ways, including altered patterns of migration, resulting in various other lesions termed dysplasia. A, Cerebellar hypoplasia (arrow). In utero infection with bovine viral diarrhea virus (pestivirus) results in cytolysis of dividing germinal cells of the granule layer and vascular impairment secondary to vasculitis of the cerebellum during organogenesis. The severity of the lesion involving the granule cells is at its greatest if dividing cells are infected during the earliest stages of cellular differentiation and occurs between 100 to 180 days of gestation. B, Note the folia of the cerebellum are hypoplastic and dysplastic with a reduced thickness of the molecular layer (arrows) and haphazardly organized and thinned granule cell layer (arrowheads). Hematoxylin and eosin (H&E) stain. C, The molecular layer (m) of the cerebellum is reduced in thickness and lacks the normal number of neuronal nuclei. The Purkinje cell layer (p) has large gaps between adjacent cells as the result of the loss of neuron cell bodies or the failure of neurons to migrate properly to form this layer. Note the retention of Purkinje cells (arrows) in the granule cell layer (g). The granule cell layer has significantly reduced numbers of neurons as shown by the lack of nuclei. H&E stain. w, White matter. (A courtesy Dr. M.D. McGavin, College of Veterinary Medicine, University of Tennessee. B and C courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.) * * Figure 14.40 Chronic Cerebral Abscess, Goat. An abscess (arrows) has replaced most of the right cerebral hemisphere, enlarged it, and displaced the midline to the left. The abscess is encapsulated by a thick fibrous capsule generated by fibroblasts of the pia and perivascular spaces of the outer cortex and by fibrous astrocytes. Note the extension of the exudate into the ventricular system (asterisks). Trueperella pyogenes was cultured from the abscess. (Courtesy Dr. B.F. Porter, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University.) are often surrounded by a red zone of active hyperemia induced by inflammatory mediators acting on capillary beds. Brain abscesses can arise in some food animal species from an extension of otitis interna (see Fig. 14.29). Affected 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 subsp. equi (strangles) can cause brain abscesses via hematogenous spread (Fig. 14.41). Brain abscesses are space-occupying lesions and can have a devastating effect on brain function. Depending on size and location, compression of vital structures (nuclei that regulate cardiac and respiratory rhythms) and brain displacements (cerebellar vermis, parahippocampal gyri) are two common sequelae of acute abscesses. Abscesses can occur in the spinal cord as a result of direct extension of bacterial vertebral osteomyelitis or diskospondylitis (Fig. 14.42), after tail docking in lambs, and occasionally from hematogenous spread. Abscesses of the pituitary fossa are seen most frequently in cattle, especially in bulls with nose rings. Bacteria isolated from these cases include Pasteurella multocida and Trueperella pyogenes. The abscess can result from spread of infection arising in the caudal nasal cavity or sinuses, possibly through direct extension or via 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. Clinically, animals with brain abscesses can show abnormal mental behaviors, ataxia, head tilt, circling, and loss of vision. CHAPTER 14 Nervous System 923 A nt a B C Figure 14.41 Abscess, Right Cerebral Hemisphere, Horse. A, The cerebral cortex contains an abscess (arrow) caused by Streptococcus equi subsp. equi entering the central nervous system (CNS) via the blood. A fibrous capsule is present on the lateral, medial, and dorsal sides of the abscess (most obvious on the lateral side as a gray band). There is no obvious capsule present on the ventral side (i.e., toward the right lateral ventricle). Note also the increased size of the right hemisphere with blurring of the distinction between gray and white matter, an indication of edema. B, Microscopically, there is a thin glial capsule (astrocytosis) in the interface (dashed line) between the abscess (a) and nervous tissue (nt). Note the abundant neutrophils mixed with detached and degenerating nervous system cells and cellular debris. Early stages of acute inflammation are affecting the tissue to the right of the dashed line. Hematoxylin and eosin (H&E) stain. C, Higher magnification of B. Note the extensive necrosuppurative inflammatory exudate forming the abscess. H&E stain. Inset, Chains of Gram-positive (blue staining) cocci in the inflammatory exudate from an abscess caused by Streptococcus equi subsp. zooepidemicus. Gram stain. (A courtesy Dr. K. Read, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University; and Noah’s Arkive, College of Veterinary Medicine, The University of Georgia. B, C, and Inset courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.) Diffuse Encephalitis. Common bacteria have the potential to produce disease in the CNS by hematogenous spread and vasculitis (see the section on Diseases Affecting Multiple Species of Domestic Animals, Infectious Diseases, Bacteria, Neonatal Septicemia). Ependymitis and Choroid Plexitis. Infectious agents, especially pus-forming bacteria such as the coliforms 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. Inflammation of the ependyma is called ependymitis, and 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 924 SECTION II Pathology of Organ Systems Figure 14.42 Vertebral Abscess, Thoracic Spinal Cord, Pig. This abscess involves the epaxial musculature and extends into the dorsolateral aspect of the T12 and T13 vertebrae and spinal canal (arrows), resulting in compression of the spinal cord. Clinically, the pig exhibited paraplegia and a neurogenic bladder. Gradual compression of the spinal cord in cases like this results in progressive axonal degeneration. Trueperella pyogenes was cultured. (Courtesy Dr. B.F. Porter, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University.) system and choroid plexuses that are granular and gray-white, with areas of active hyperemia and hemorrhage. If the bacteria traverse through the lateral apertures of the fourth ventricle, they can enter and spread throughout the subarachnoid space, possibly inducing suppurative leptomeningitis. The exudate can also obstruct CSF flow, leading to noncommunicating hydrocephalus. Although most cases are caused by bacteria, cats infected with feline infectious peritonitis (FIP) can develop protein-rich fluid and exudate within the ventricular system that can lead to plugging of the mesencephalic aqueduct with subsequent hydrocephalus. Microscopically, the exudate consists of inflammatory cells (especially neutrophils), often accompanied by fibrin, erythrocytes, and bacteria. Meningitis. Meningitis refers to inflammation of the meninges (Fig. 14.43). In animals, meningitis is most commonly caused by bacteria such as E. coli and Streptococcus spp. that reach 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), whereas inflammation of the dura mater is called pachymeningitis. Leptomeningitis can be acute, subacute, or chronic, and, depending on the cause, suppurative, eosinophilic, nonsuppurative, or granulomatous. Inflammation of the external periosteal dura can occur with osteomyelitis, extradural abscesses, and skull fractures, whereas inflammation of the inner dura occurs with leptomeningitis. In animals, strict leptomeningitis secondary to viral infection is very rare. Most viral infections result in meningoencephalitis. Neonatal Septicemia. Systemic bacterial infections in neonates are a common cause of acute meningitis (leptomeningitis). Common causes of neonatal sepsis include E. coli, Streptococcus spp., Salmonella spp., Pasteurella spp., and Haemophilus spp. The release of endotoxins and bacterial cell wall components, such as lipopolysaccharide, teichoic acid, and proteoglycans, in the CNS vasculature leads to the secretion of cytokines (TNF, interleukin, plateletactivating factor, prostaglandins, thromboxane, and leukotrienes) from the endothelium and trafficking CNS macrophages, followed by adhesion of neutrophils, injury to the endothelium and bloodbrain barrier, and vasculitis resulting in brain swelling, edema, and increased intracranial pressure. A B Figure 14.43 Suppurative Bacterial Meningitis, Cerebrum, Horse. A, Pale yellow-white thick exudate consistent with an infiltrate of neutrophils admixed with bacteria, cellular debris, edema fluid, and fibrin fills the subarachnoid space and extends into the sulci. The gyri are flattened, indicating brain swelling. B, The arachnoid space of the leptomeninges in this sulcus contains a mixture of neutrophils (arrows), mononuclear inflammatory cells, cellular debris, edema fluid, and fibrin. Hematoxylin and eosin (H&E) stain. (A courtesy Dr. M.D. McGavin, College of Veterinary Medicine, University of Tennessee. B courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.) Although there are differences in the diseases caused by these infectious agents, they tend to produce fibrinopurulent inflammation of serosal surfaces. The leptomeninges, choroid plexus, and ependyma of the CNS—in addition to sites often preferentially involved in hematogenous spread of bacteria like the 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). Bacteria reach the CNS hematogenously, but the initial port of entry is umbilical, oral, respiratory, or intrauterine. Infection can also be acquired via surgical procedures such as castration and ear notching. Gross CNS lesions are commonly present and include congestion, hemorrhage, and diffuse to focal cloudiness or opacity in the leptomeninges (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 choroid plexitis and/or ependymitis. Microscopic lesions vary according to the agent involved. The lesions generally consist of deposits of fibrin and an infiltration of mainly neutrophils in and around the blood vessels of the leptomeninges, choroid plexus, and ependyma. The epithelium of the choroid plexus and ependymal lining of the ventricles can be disrupted by cellular degeneration, disorganization, and necrosis, and the process CHAPTER 14 Nervous System Box 14.7  CNS Bacterial Infections in Young Animals Calves Escherichia coli: Leptomeningitis, choroiditis, ependymitis and ventriculitis, synovitis, ophthalmitis, and perioptic neuritis Pasteurella/Mannheimia spp.: Leptomeningitis, ependymitis and ventriculitis Streptococcus spp.: Leptomeningitis, synovitis, ophthalmitis Foals Escherichia coli: Leptomeningitis, ventriculitis, polyserositis, synovitis Streptococcus spp.: Leptomeningitis, polyserositis, synovitis Salmonella typhimurium: Leptomeningitis, ependymitis and ventriculitis, choroiditis, synovitis Lambs Escherichia coli: Leptomeningitis, ependymitis and ventriculitis, peritonitis, synovitis Pasteurella/Mannheimia spp.: Leptomeningitis Piglets Escherichia coli: Leptomeningitis, ophthalmitis Glaesserella parasuis (previously known as Haemophilus parasuis): Leptomeningitis, polyserositis, synovitis Streptococcus suis type I and II: Leptomeningitis, choroiditis, ependymitis, cranial neuritis, myelitis Salmonella choleraesuis: Leptomeningitis, ophthalmitis can extend into the adjacent parenchyma. Vasculitis with thrombosis and hemorrhage can be associated with lesions caused by E. coli. Another example of a neonatal bacterial pathogen is Glaesserella parasuis (previously known as Haemophilus parasuis), which causes leptomeningitis, polyserositis, and polyarthritis of 8- to 16-week old pigs. The lesions are typically fibrinopurulent. Lesions caused by Salmonella spp. are not limited to the perinatal period. CNS involvement in salmonellosis is generally limited to foals, calves, and pigs, and in contrast to the infections mentioned earlier, 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. Regardless of the tissue involved, vasculitis, thrombosis, necrosis, and hemorrhage tend to accompany Salmonella infections. Bacterial infection with CNS and visceral involvement occurs in neonatal and weanling pigs, most notably because of several strains of Streptococcus suis. Some strains generally cause disease in suckling pigs ranging in age from 1 to 6 weeks, whereas other strains affect pigs 6 to 14 weeks of age. Some S. suis serotypes cause meningitis not only in pigs but also in human beings, particularly those working with pigs or handling porcine tissues. 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 the brainstem, cerebellum, and 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. Viruses. The viruses causing CNS disease in domestic animals are listed in Table 14.3. Arboviruses Japanese Encephalitis. See E-Appendix 14.2. Louping Ill. See E-Appendix 14.2. 925 Herpesviruses. Encephalitic herpesviruses, 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 inflammatory effects induced by cytokines and chemokines. Although necrosis appears to be the principal mechanism for cell injury, apoptotic cell death also plays a role. Neurotropic herpesviruses enter the CNS principally by retrograde axonal transport; however, entry by hematogenous spread 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, such as the trigeminal ganglion of pigs infected with pseudorabies virus. Stress or other factors can activate latent virus, resulting in encephalitis. Rhabdoviruses Rabies Encephalitis. Rabies virus (family Rhabdoviridae) is one of the most neurotropic of all viruses infecting mammals. It is generally transmitted by a bite from an infected animal; however, infection has also been uncommonly reported after respiratory exposure to virus in bat caves, accidental laboratory exposure, and corneal transplants. The mechanism for spread of rabies virus from the inoculation site to the CNS is illustrated in Fig. 14.44. Rabies virus may first replicate locally at the site of inoculation. Infection of and replication in local skeletal muscle myocytes is an important initiating event. The virus then enters peripheral nerve terminals by binding to nicotinic acetylcholine receptors at the neuromuscular junction. The probability is greater that the virus will be taken up by both axon terminals and myocytes after a large inoculation dose. If the virus directly enters peripheral nerve terminals, the incubation period will more likely be short, regardless of whether muscle cells are infected. With progressively lower doses of virus, however, there is a greater possibility that the virus will enter either nerve terminals or myocytes but not both. This situation can result in a short incubation period if the virus directly enters nerve terminals as described previously or could result in a more prolonged incubation period if there was initial infection and retention of virus in myocytes before its release and uptake by nerve terminals. The virus moves from the periphery to the CNS by fast retrograde axoplasmic transport, apparently via sensory or motor nerves, at a rate of 12 to 100 mm per day. Experimental data suggest that rabies virus phosphoprotein interacts with dynein LC8, a microtubule motor protein used in retrograde axonal transport. With sensory axons, the first cell bodies to be encountered after inoculation of a rear leg would be those of spinal ganglia, whose neuronal processes extend to the dorsal horn of the spinal cord. For motor axons, the cell bodies of the lower motor neurons in ventral horn gray matter or neuronal cell bodies of the autonomic ganglia are the ones initially infected. It is not known whether viral infection and replication in neurons of dorsal root ganglia are essential for infection of the CNS. The virus then moves into the spinal cord and ascends to the brain using both anterograde and retrograde axoplasmic flow. During the spread of the virus between neurons within the CNS, there is also simultaneous centrifugal movement via anterograde axonal transport of the virus peripherally from the CNS to axons of cranial nerves. This process results in infection of various tissues, including the oral cavity and salivary glands, permitting transmission of the disease in saliva. An additionally important feature of rabies is that infection of nervous and nonnervous tissue, such as the salivary glands, occurs at the same time, which permits affected animals to have the required aggressive behavior to facilitate passage of the disease via a bite wound. After axoplasmic spread of the virus from an inoculated rear leg to neurons of the associated segments of the spinal cord, rapid spread of infection to the brain occurs via long ascending and descending fiber tracts, bypassing the gray matter of the rostral spinal cord. CHAPTER 14 Nervous System E-Appendix 14.2 Infectious Diseases Diseases Affecting Multiple Species of Domestic Animals Borna Disease Borna disease is an encephalomyelitis caused by an unusual enveloped RNA virus that replicates in the nucleus of neurons, has no cytopathic effect, and until 1997, its virions had not been visualized ultrastructurally. The disease has been recognized in central Europe for more than 250 years but likely exists worldwide. Borna disease virus has been classified as the prototype of a relatively new virus family, Bornaviridae. It most commonly infects horses and sheep, but cases have also been reported in dogs, cats, and cattle. Borna disease virus infection in horses was originally considered to result in a high mortality, up to 80% to 100% after 1 to 3 weeks of clinical illness. More recent evidence indicates that the majority of infected animals are either asymptomatic or have mild clinical disease that can be accompanied by behavioral changes, followed by recovery. The clinically severe disease in the horse is still largely confined to certain regions in Germany and Switzerland. Proposed peripheral spread of virus by axonal transport in the autonomic and enteric divisions of the PNS has led to the suggestion that infection of these neurons might cause lesions responsible for colic and other gastroenteric dysfunctions in horses. Experimental evidence indicates that infection of the CNS via olfactory nerves follows intranasal viral exposure. The virus is highly neurotropic, similar to rabies virus, and is transported by retrograde axonal transport from the periphery to the CNS. Infection of astrocytes, oligodendrocytes, ependyma, choroid plexus epithelial cells, and Schwann cells occurs by direct extension when these cells are in close proximity to virus-infected neurons. The virus can also infect the retina by retrograde axonal transport via the optic nerve and cause blindness under experimental conditions. After reaching the CNS, the virus spreads intra-axonally and transsynaptically (proposed) as described for rabies virus. The virus can then also spread centrifugally via the PNS, resulting in infection of various nonneural tissues, including the lacrimal and salivary glands, endocrine tissues such as the pituitary and adrenal glands, and other tissues. Peripheral blood monocytes can be infected. Experimentally, the specific lesions that develop in the CNS appear to depend on a viral-induced, cell-mediated immune mechanism. Antibodies to Borna disease virus do not appear to play a significant role in the disease process. There are no major gross lesions in the CNS. Microscopic lesions are limited to the nervous system, consisting of a nonsuppurative encephalomyelitis with neuronal degeneration. Lesions are confined largely to the gray matter and are most severe in the midbrain, midbrain-diencephalon junction, hypothalamus, and hippocampus. Inflammation of the meninges and spinal cord is generally mild. Small, round to oval, eosinophilic intranuclear inclusions (JoestDegen bodies) occur in neurons of the brainstem, hippocampus, and cerebrospinal ganglia. In the PNS, inflammation occurs in the cranial, spinal, and autonomic ganglia and in the peripheral nerves. Louping Ill Louping ill, a tick-transmitted sheep encephalomyelitis, has been recognized in the British Isles for at least 200 years. It is primarily a disease of sheep but also affects cattle, horses, pigs, goats, red deer, dogs, human beings, and the red grouse. It is caused by a flavivirus (family Flaviviridae) and occurs in the British Isles and Norway. A similar disease of sheep occurs in Turkey, Greece, Bulgaria, and Spain. Some cases have been determined to be caused by similar flaviviruses (tick-borne encephalitis virus) but are distinct from each 925.e1 other and from louping ill virus. The disease occurs in the spring and summer when ticks are active. After infection caused by the tick Ixodes ricinus, the virus replicates in lymph nodes and spleen and reenters the bloodstream to cause a high-titered viremia, which is the probable route of infection of neurons. Excretion of the virus in milk of infected ewes and goats has also been reported, suggesting that transmission by ingestion is of possible significance in suckling kids. No major gross lesions are present. Microscopic lesions are characterized by a meningoencephalomyelitis, which is primarily nonsuppurative, although occasional neutrophils can be present. Specific changes also include neuronal degeneration, necrosis, and neuronophagia, most consistently occurring in cerebellar Purkinje cells but also affecting neurons of the medulla oblongata, pons, and spinal cord. Lesions in Purkinje cells have been proposed to be at least partially responsible for the unique clinical signs of a peculiar leaping gait displayed by affected animals. No inflammation of spinal ganglia occurs, but inflammation has been detected in sciatic nerves. Japanese Encephalitis Japanese encephalitis is a particularly important disease in human beings, but infection also occurs in horses, pigs, cattle, and sheep. The causative virus is classified as a member of the family Flaviviridae (closely related to St. Louis encephalitis and West Nile virus) and is transmitted by mosquitoes, mainly Culex tritaeniorhynchus. In nature, infection is maintained in a cycle involving vector mosquitoes, birds, and pigs. Although young susceptible pigs can have signs, detectable illness is not a feature of viral infection in adult or pregnant pigs. Nevertheless, transplacental fetal infection can result in mummification and stillbirth of fetuses or the birth of weak live pigs with nervous signs accompanied by nonsuppurative encephalitis and neuronal degeneration. Factors involved in the pathogenesis of this viral infection include the finding that in rats the ability of the virus to infect neurons is closely associated with neuronal immaturity. Such an agedependent susceptibility to infection has also been noted with other flaviviruses, including St. Louis encephalitis virus and yellow fever virus. The fact that fetal and neonatal pigs and young horses appear to be more susceptible than adult animals suggests that such a correlation could also exist in naturally occurring infections. Grossly, CNS lesions include mild leptomeningeal congestion and hyperemia and occasional hemorrhages within the brain and spinal cord. Microscopically, neurons in the CNS are the target cell. Lesions are characterized by an early leptomeningitis and encephalitis in which neutrophils predominate, followed by nonsuppurative encephalomyelitis. This virus also causes degeneration of neurons, especially cerebellar Purkinje cells, with necrosis, neuronophagia, microgliosis, and axonal degeneration. Neuronal necrosis is accompanied by lymphocytic perivascular cuffs. There are no inclusion bodies. The lesions are distributed diffusely throughout the nervous system but affect the gray matter more than the white matter. Welldocumented outbreaks of meningoencephalomyelitis caused by Japanese encephalitis virus in horses have been reported. Young or immature horses are more susceptible to infection than older animals. Its geographic distribution includes India, China, and southeastern Asia. Diseases of Ruminants (Cattle, Sheep, and Goats) Sporadic Bovine Encephalomyelitis Sporadic bovine encephalomyelitis (chlamydial encephalomyelitis) is uncommon and is caused by either Chlamydia pecorum or C. psittaci. The disease was first described in the United States, but cases have since occurred in other countries. Chlamydiaceae are obligate 925.e2 SECTION II Pathology of Organ Systems intracellular bacteria. C. psittaci is inhaled or ingested via an oronasal route and infects epithelial cells of oronasal mucous membranes and lungs, endothelial cells, monocytes, and lymphocytes. It appears to spread systemically to infect endothelial cells within the CNS via leukocytic trafficking in monocytes and lymphocytes. Lesions are nonsuppurative meningoencephalomyelitis and serofibrinous polyserositis, arthritis, and tenosynovitis. Special histochemical stains may be required to satisfactorily identify elementary bodies in mononuclear inflammatory cells, but advanced molecular testing like PCR is often needed to assist with the diagnosis. Gross changes in the CNS, when present, are limited to active hyperemia and edema of the leptomeninges. Microscopic lesions extend throughout the neuraxis and consist of leptomeningeal and perivascular infiltrates of macrophages, plasma cells, and a few neutrophils. The basilar leptomeninges are most severely affected. Leukocytes extend into the adventitia of blood vessels accompanied by endothelial swelling and necrosis leading to vasculitis, thrombosis, and ischemia. Additional lesions include neuronal degeneration and parenchymal necrosis with microgliosis. Immune-mediated mechanisms have been suggested as the cause of the vasculitis. Calves younger than 6 to 12 months of age are most susceptible. Affected animals initially are ataxic but terminally become recumbent and develop opisthotonos. Diseases of Pigs Classical Swine Fever Classical swine fever (hog cholera) of pigs is caused by a pestivirus. It has a worldwide distribution, except for several countries, including the United States, from which it has been successfully eradicated. Infection under natural conditions occurs by the oronasal route. The virus initially infects epithelial cells of the tonsillar crypts and surrounding lymphoid tissue and then spreads to mandibular and pharyngeal lymph nodes, where it replicates. The virus disseminates via leukocytic trafficking to the spleen, bone marrow, visceral lymph nodes, and lymphoid tissue of the intestine, where high titers of virus are attained. Target cells for virus replication include endothelial cells, lymphocytes, macrophages, and epithelial cells. Hematogenous spread of the virus via leukocytic trafficking to endothelial cells throughout the infected pig is usually completed in 5 to 6 days. Infected animals die of disseminated intravascular coagulation. Lesions of the acute disease, which primarily result from a tropism of the virus for vascular endothelium with subsequent hemorrhage, are present in many organs, including the kidneys, intestinal serosa, lymph nodes, spleen, liver, bone marrow, lungs, skin, heart, stomach, gallbladder, and CNS. Grossly, cerebral edema may be observed. Microscopic lesions of the CNS occur in both gray and white matter and tend to be most prominent in the medulla oblongata, pons, colliculi, and thalamus but also occur in the cerebrum, cerebellum, and spinal cord. Lesions are characterized by swelling, proliferation, and necrosis of endothelium, as well as perivascular lymphocytic cuffing, hemorrhage, thrombosis, microgliosis, and neuronal degeneration. Choroiditis and leptomeningitis also occur. In utero infections can lead to cerebellar hypoplasia and microencephaly in affected piglets. Clinical signs resulting from involvement of the CNS include ataxia, paresis, and convulsions. Enterovirus-Induced Porcine Polioencephalomyelitis Teschen disease and Talfan disease, the enterovirus encephalomyelitides of pigs caused by porcine enteroviruses (family Picornaviridae), are characterized by polioencephalomyelitis. Teschen disease is the most virulent manifestation of the entity and is caused by porcine enterovirus 1. Many other porcine enteroviruses exist and cause a variety of neurologic and nonneurologic clinical manifestations. Natural infection occurs by the oral route and is followed by viral localization and replication in the tonsils, Peyer’s patches, cervical and mesenteric lymph nodes, and the intestinal tract (primarily ileum and large intestine). These viruses then enter the bloodstream and spread hematogenously through the blood-brain barrier to the CNS, where they target motor neurons. No gross lesions are detectable. The degree of cerebral, cerebellar, and spinal cord involvement varies with the specific virus. All forms of the disease are characterized microscopically by a nonsuppurative polioencephalomyelitis, which targets motor neurons of the ventral gray horns and craniospinal ganglia. These viruses cause degeneration of neurons with acute swelling, central chromatolysis, necrosis, neuronophagia, microgliosis, and axonal degeneration. Neuronal necrosis is accompanied by lymphocytic perivascular cuffs, especially in the spinal cord. Astrocytosis also occurs. Ganglioneuritis, particularly of dorsal root ganglia of the spinal cord, and variable leptomeningitis of varying severity also occur. Clinical signs include ataxia, excessive squealing, altered or lost vocalization, irritability, muscular tremors/rigidity, grinding of the teeth, and convulsions. In the different diseases, severity varies from death of affected animals (Teschen disease occurring sporadically in Europe and Africa) to less severe disease with signs that include fever, diarrhea, and paralysis, sometimes most severe in the hind limbs, in North America and some other regions of the world (Talfan disease). Hemagglutinating Encephalomyelitis Viral Infection of Pigs In 1958 a disease of nursing pigs characterized by high morbidity, vomiting, anorexia, constipation, and severe progressive emaciation was reported in Ontario, Canada. The causal agent was found to be a coronavirus. Infection by the oronasal route, which has been demonstrated experimentally, is followed by viral replication in epithelial cells of the nasal mucosa, tonsils, lungs, and small intestine. After local replication, the virus spreads to the CNS by retrograde axonal transport in the peripheral nerves, which include the trigeminal and olfactory nerves, vagus, and extensions from intestinal plexuses. Neurons of craniospinal ganglia also are infected. The vomiting associated with the disease is presumed to result from altered function of neurons (in the vagal nucleus and its ganglion, and gastric intramural plexuses in the enteric division of the PNS) secondary to viral infection. Gross lesions of the CNS are not present. Microscopic lesions occur in the respiratory tract, stomach, CNS, and PNS. Similar to enterovirus encephalomyelitis, lesions in the CNS are most pronounced in the gray matter and are characterized by a nonsuppurative meningoencephalomyelitis with neuronal degeneration, lymphocytic perivascular cuffs, and microglial nodules. The caudal brainstem, particularly the medulla and pons, and spinal cord are affected. In the peripheral ganglia, the lesions are nonsuppurative inflammation and neuronal degeneration. Clinically, affected animals may show vomiting, depression, hyperesthesia, trembling, ataxia, convulsions, and paddling of the limbs if laterally recumbent. 926 SECTION II Pathology of Organ Systems Table 14.3 Select Viruses Causing CNS Disease in Domestic Animals Virus Genus Disease Type of Injury Arbovirus Encephalitis/myelitis/meningitis/vasculitis Encephalitis/myelitis/meningitis Encephalitis/myelitis/meningitis Encephalitis/myelitis Malformations Encephalitis/myelitis for both Encephalitis/myelitis Malformations/encephalitis Malformations/encephalitis Parvovirus Pestivirus Equine encephalomyelitis Japanese encephalitis Louping ill West Nile viral encephalomyelitis Wesselsbron virus Bovine astrovirus; Porcine astrovirus Borna disease Akabane disease Arthrogryposis hydranencephaly complex (Cache Valley fever) Rift Valley fever, Schmallenberg virus Feline infectious peritonitis Hemagglutinating encephalomyelitis Enterovirus-induced porcine polioencephalomyelitis Equine herpesvirus 1 myeloencephalopathy Bovine malignant catarrhal fever Infectious bovine rhinotracheitis Pseudorabies Canine herpesvirus Visna Caprine arthritis encephalitis Bluetongue Canine distemper Old-dog encephalitis Feline panleukopenia virus Classical swine fever Polyomavirus Rhabdovirus Bovine viral diarrhea Border disease Progressive multifocal leukoencephalopathy Rabies Astrovirus Bornavirus Bunyavirus Coronavirus Enterovirus Herpesvirus Lentivirus Orbivirus Paramyxovirus Malformations/encephalitis Vasculitis/encephalitis/myelitis/meningitis Encephalitis/myelitis/meningitis/ganglioneuritis Encephalitis/myelitis Encephalitis/myelitis/meningitis/vasculitis Encephalitis/myelitis/meningitis/vasculitis Encephalitis Encephalitis/myelitis/meningitis Encephalitis/meningitis Encephalitis/myelitis/demyelination Encephalitis/myelitis/demyelination Malformations/encephalitis Demyelination/encephalitis/myelitis Encephalitis/demyelination/meningitis/vasculitis Malformations/meningitis Malformations/hypomyelination/encephalitis/meningitis/ vasculitis Malformations/meningitis/dysmyelination/hypomyelination Malformations/hypomyelination Demyelination Encephalitis/myelitis/meningitis/vasculitis/ganglioneuritis CNS, Central nervous system. 7 8 6 5 4 3 2 1 Figure 14.44 Pathogenesis of Rabies. After a bite wound, the rabies virus (1) initially replicates in muscle (can enter peripheral nerves directly), (2) enters and (3) ascends (retrograde axonal transport) the peripheral nerve (4) to the dorsal root ganglion, (5) enters the spinal cord and (6) ascends (7) to the brain via ascending and descending nerve fiber tracts, infects brain cells, spreads to salivary glands and (8) the eye and is excreted in saliva. This early spread of the virus explains how induction of behavioral changes occurs before there is sufficient injury to cause paralysis and how dissemination of infection occurs before there is time for a notable immune response. Spread of infection within neurons of the CNS occurs via both anterograde and retrograde axoplasmic flow, with corresponding neuron-to-neuron spread by axosomatic-axodendritic and somatoaxonal-dendroaxonal transfer of virus. Transsynaptic spread can occur through the budding of developing virions from the neuronal cytoplasm (cell body or dendrite) into a synapsing axon or in the form of bare viral nucleocapsid (ribonucleoproteintranscriptase complexes) in the absence of a complete virion. In vivo experimental studies using a laboratory strain of rabies virus showed that the virus caused a downregulation of approximately 90% of genes in the brain to more than fourfold lower levels. Affected genes were those involved in regulation of cell metabolism, protein synthesis, growth, and differentiation. Other experimental studies have shown increased quantities of nitric oxide in brains of rabies-infected animals, suggesting that nitric oxide neurotoxicity may mediate neuronal dysfunction. The rabies virus has also been shown to induce apoptotic cell death of brain neurons in mouse models. The exact mechanism of rabies virus–induced neuronal injury in domestic and wildlife species remains to be fully determined. Gross lesions are often absent but can include hemorrhage, especially in the spinal cord gray matter. Microscopic lesions consist of a variable leptomeningitis with perivascular cuffing by lymphocytes, macrophages, and plasma cells. Other changes include microgliosis, neuronal degeneration, and ganglioneuritis. Infected neurons often are minimally altered morphologically, and in some cases the only lesion noted is intracytoplasmic, eosinophilic inclusion bodies, which are called Negri bodies (Fig. 14.45; E-Fig. 14.9). Nonneural lesions are CHAPTER 14 Nervous System 927 animals in which the excitatory phase is extremely short or absent and the disease progresses quickly to the paralytic phase. When conducting a necropsy on an animal suspected of having rabies, it is important to remember (1) to provide additional protection (double gloves, mask, eye protection, and proper ventilation) for the prosector above that used for routine postmortem examination, and (2) to collect the appropriate brain sample (medulla and cerebellum) for examination by immunofluorescence. The remainder of the brain should be fixed in formalin for histopathologic examination. Bornaviruses Borna Disease. See E-Appendix 14.2. Figure 14.45 Rabies, Negri Body, Brainstem, Neurons, Cow. Multiple large pale eosinophilic inclusions (Negri bodies) are present in the cytoplasm of the neuron cell body (arrow). In cattle, Negri bodies are commonly seen in Purkinje cells and in other neurons, such as those of the red nucleus and cerebral cortex. Hematoxylin and eosin (H&E) stain. (Courtesy Dr. B.F. Porter, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University.) limited to a variable nonsuppurative sialitis accompanied by necrosis and the presence of Negri bodies in salivary epithelial cells. Negri bodies have long been the hallmark of rabies infection, but they are not present in all cases. The inclusions are intracytoplasmic and initially develop as an aggregation of strands of viral nucleocapsid, which rather quickly transforms into an ill-defined granular matrix. Mature rabies virions, which bud from the nearby endoplasmic reticulum, can also be located around the periphery of the matrix. With time, the Negri body becomes larger and detectable by light microscopy. In H&E-stained sections, the Negri body classically has one or more small, clear areas called inner bodies that form as a result of invagination of cytoplasmic components (that include virions) in the matrix of the inclusion. Negri bodies also tend to occur more frequently in large neurons such as the pyramidal neurons of the hippocampus (most common in carnivores), cerebellar Purkinje cells (most common in herbivores), and neurons of the medulla oblongata. The preferred tissues for rabies examination by light microscopy and by fluorescent antibody technique for virus include the hippocampus, cerebellum, medulla, and the trigeminal ganglion. The typical samples submitted for fluorescent antibody staining are the medulla and cerebellum. A spongiform lesion, indistinguishable qualitatively from the lesion characteristic for several of the spongiform encephalopathies, was described in rabies by Charlton in 1984. This lesion was initially detected in experimental rabies in skunks and foxes and later in the naturally occurring disease in skunks, foxes, horses, cattle, cats, and sheep. The lesion occurs most prominently in the neuropil of the thalamus and cerebral cortex, initially as intracytoplasmic membrane-bound vacuoles in neuronal dendrites, and less commonly in axons and astrocytes. The vacuoles enlarge, compress surrounding tissue, and ultimately rupture, forming a tissue space. Although the mechanism responsible for the development of this lesion has not been determined, it is thought to result from an indirect effect of the rabies virus on neural tissue, possibly involving an alteration of neurotransmitter metabolism. The clinical signs in domestic animals are similar between species with some differences. The clinical disease in the dog has been divided into three phases: prodromal, excitatory, and paralytic. In the prodromal phase, which lasts 2 to 3 days, the animal can have a subtle change in temperament. Furious rabies refers to animals in which the excitatory phase is predominant, and dumb rabies refers to Fungi. A variety of fungi infect the CNS of animals. Potential pathogens include Aspergillus, Candida, Cryptococcus neoformans, and members of the zygomycetes group. CNS infections also occur with the systemic dimorphic fungi Blastomyces dermatitidis, Histoplasma capsulatum, and Coccidioides spp. (C. immitis or C. posadasii) (E-Fig. 14.10). Most reported cases of fungal disease represent opportunistic infections in immunocompromised individuals. These agents reach the CNS by leukocytic trafficking and hematogenous spread from primary sites of infection located in other areas of the body. Fungi that exist as hyphae in tissue typically cause vasculitis, leading to thrombosis and infarction. Various species of dematiaceous fungi causing phaeohyphomycosis (Cladophialophora bantiana, Cladosporium spp., Ochroconis gallopava) produce pigmented lesions that may be visible grossly. Fungi usually elicit a granulomatous to pyogranulomatous inflammatory response, as characterized by B. dermatitidis (Fig. 14.46). This response can be locally extensive, or distinct granulomas can form in the CNS and meninges. Grossly, CNS lesions consist of moderately well demarcated, expansile, yellow-brown foci that displace and disrupt normal tissue. Microscopically, the exudate consists of neutrophils, macrophages, and multinucleated giant cells. The latter two cell types may contain fungi in their cytoplasm. B. dermatitidis yeast are spherical, 8 to 25 μm in diameter, and exhibit broad-based budding. The inflammatory response leads to axonal, neuronal, and myelin disruption. CNS infections with Coccidioides spp. or H. capsulatum elicit an inflammatory response similar to that which occurs in B. dermatitidis infections. In coccidioidomycosis, the fungal cells are extracellular, and intracellular spherules (30 to 60 μm in diameter) contain endospores ( 5.4), the microbe can multiply. A Thrombotic Meningoencephalitis B 967 C Figure 14.90 Listeriosis, Medulla, Cow. A, Microabscesses. Note the areas of faint blue discoloration in this subgross magnification of the medulla (arrows). The less well-defined blue areas are aggregates of neutrophils (microabscesses), and the blue linear lesions are perivascular cuffs. Listeria monocytogenes, the causative agent, uses retrograde axonal transport via the cranial nerves to enter the central nervous system (CNS) and localize in the medulla (brainstem) and proximal cervical spinal cord. The lesion is rarely visible on gross observation. Hematoxylin and eosin (H&E) stain. B, Early microabscesses (arrows) and inflammation are the result of inflammatory mediators that have injured axons (arrowheads) and will lead to Wallerian degeneration, seen here at the stage of swollen eosinophilic axons. H&E stain. C, L. monocytogenes, which is Grampositive (blue coccobacilli), can sometimes be detected in microabscesses in a histologic section stained with a Gram stain. Gram stain. (Courtesy Dr. M.D. McGavin, College of Veterinary Medicine, University of Tennessee.) variety of phospholipids, including sphingomyelin (a component of myelin) and phospholipids in cell membranes (see Fig. 4.33). Axonal injury and neuronal death are likely attributable to inflammatory processes, especially to the action of listeriolysin and lipases. Gross lesions are usually absent, but leptomeningeal opacity, foci of yellow-brown discoloration (0.1 to 0.2 mm in diameter in the area of the nuclei of cranial nerves V, VII, IX, X, and XII), hemorrhage, necrosis in the terminal brainstem, and cloudy CSF can all be observed. Microscopically, a meningoencephalitis centered on the pons and medulla and involving both gray and white matter is characteristic (Fig. 14.90, A). The lesions, however, can extend from the diencephalon to the caudal medulla or cranial cervical spinal cord. Small, early lesions consist of loose clusters of microglial cells. With time, these lesions enlarge and contain variable numbers of neutrophils (see Fig. 14.90, B). Later in the process, microabscesses form, and neutrophils are the principal inflammatory cell. Although uncommon, some microabscesses contain macrophages as the principal cell type. Necrosis and accumulation of gitter cells can be prominent in some cases. Numerous Gram-positive bacilli can be detected histologically in some lesions (see Fig. 14.90, C). Additionally, tissue samples of the pons and/or medulla can be cultured microbiologically for the isolation and identification of the bacterium. Nevertheless, both histologic and microbiologic evaluations usually take 2 or 3 days or longer, and treatment of the herd may need to begin immediately. Therefore, impression smears of the cut surface of the pons and/or medulla where the infection centers in the CNS can be made, stained, and examined for short Gram-positive rods characteristic of this bacterium. Leptomeningitis is regularly present and is often severe, and the exudate is composed predominantly of mononuclear cells H. somni, a small Gram-negative bacillus, causes septicemia in cattle with variable clinical presentations, including pneumonia, polyarthritis, myocarditis, abortion, and meningoencephalitis. The disease is most prevalent in feedlot cattle but can occur in other situations. All manifestations, particularly meningoencephalitis, tend to be sporadic with single to multiple animals in a herd affected. The CNS form of the disease has been termed thrombotic meningoencephalitis (previously referred to as thromboembolic meningoencephalitis). Mural thrombi from local vascular injury rather than thromboemboli from distal sites of vascular injury, such as the lungs, are the major type of thrombus in this disease. The pathogenesis of H. somni infection is not completely understood. Many cattle harbor the microbe in the upper digestive tract without evidence of disease, but under some circumstances it invades to cause severe clinical infection. The mechanism(s) of invasion into the bloodstream is not definitely known, but the respiratory tract is the initial site of bacterial replication followed by hematogenous spread to the CNS. The bacterium produces profound damage to endothelial cells, from which the majority of its thrombotic lesions develop. One of the primary bacterial virulence factors, lipooligosaccharide, has been shown in experimental studies to cause apoptosis of endothelial cells. This mechanism likely contributes to the profound damage of endothelial cells occurring with this disease. Once endothelial cells are damaged, thrombosis occurs, and tissues dependent on the obstructed blood vessel undergo infarction and necrosis. Gross lesions in the CNS are irregularly sized foci of hemorrhage and necrosis scattered randomly and visible both externally and on cut surfaces (Fig. 14.91). Lesions are most frequent in the cerebrum, commonly at the cortical gray matter–white matter interface. The location of the lesion may reflect a change in the diameter and flow patterns of blood vessels, allowing bacteria to preferentially damage these areas. The spinal cord can also be affected. Other lesions include brain swelling caused by edema and leptomeningitis with cloudiness of the CSF. Microscopic lesions in all organs, including the CNS, consist of a marked vasculitis and vascular necrosis, which are followed by thrombosis and infarction. The vasculitis is associated with regional edema and infiltration of neutrophils and macrophages in and around the affected blood vessel. Colonies of small Gram-negative bacilli can be found in the thrombi, affected blood vessels, and in the infarcted tissue. Clinically, affected cows are initially ataxic and circle, head press, and appear blind. As the disease progresses, they may have convulsions, become comatose, and die. 968 SECTION II Pathology of Organ Systems A Figure 14.92 Malignant Catarrhal Fever, Cerebrum, Bovine. Large perivascular cuffs define this encephalitis, which are composed of relatively monomorphic populations of “blastic” lymphocytes. Hematoxylin and eosin (H&E) stain. (Courtesy Dr. A.D. Miller, College of Veterinary Medicine, Cornell University.) B C Figure 14.91 Thrombotic Meningoencephalitis, Cerebrum, Steer. A, On the surface of the cerebral cortex (arrows) are several red-brown lesions (infarcts). These lesions are areas of necrosis, hemorrhage, and inflammation secondary to vasculitis and thrombosis caused by Histophilus somni. Such septic infarcts are distributed randomly (hematogenous portal of entry) throughout the central nervous system (CNS), including the spinal cord. The lesions depicted here are unusually severe. B, Cerebrum, cut-surface, steer. Note the numerous infarcts (arrows) of varied sizes caused by the bacterium. C, A thrombus (arrow) is present in the vascular lumen. Note the acute inflammatory response, edema, fibrinogenesis, and hemorrhage in the vessel wall. Hematoxylin and eosin (H&E) stain. (A courtesy Dr. H. Leipold, College of Veterinary Medicine, Kansas State University. B courtesy Dr. D. O’Toole, Wyoming State Veterinary Laboratory. C courtesy Dr. M.D. McGavin, College of Veterinary Medicine, University of Tennessee.) Bovine Malignant Catarrhal Fever Malignant catarrhal fever (MCF) 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. MCF 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, lymphoid organs, and epithelium (particularly of the respiratory and GI tracts), but the kidneys, liver, eyes, joints, and CNS can also be affected. 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 sheepassociated and wildebeest-derived forms, although several other less common causes of the disease have also been described, including a wild-tailed deer-associated MCF. The causative agents involved belong to the herpesvirus subfamily Gammaherpesvirinae. The disease occurring outside Africa, caused by ovine herpesvirus 2, often involves close contact of presumed “carrier” sheep with susceptible ruminants. The disease has been reported in musk ox (Ovibos moschatus), Nubian ibex (Capra nubiana), gemsbok (Oryx gazella), and, uncommonly, in domesticated pigs. In Africa and occasionally in wildlife facilities outside the continent, the source of the infection (designated Alcelaphine herpesvirus 1) is the wildebeest. Two other antigenically related viruses, which apparently do not cause natural disease, include Alcelaphine herpesvirus 2 and Hippotraginae herpesvirus 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 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, especially the retia mirabilia (see Chapter 2, Vascular Disorders and Thrombosis and Chapter 10, Cardiovascular System, Pericardial Cavity, and Lymphatic Vessels) and occasionally in the spinal cord, with the white matter most consistently involved. The lymphocytic inflammatory infiltrate typically consists of large numbers of “blastic” lymphocytes because of the lymphoproliferation induced by the virus (Fig. 14.92; E-Fig. 14.20). Other lesions in the affected CNS include variable neuronal degeneration, microgliosis, choroiditis, necrosis of ependymal cells, and ganglioneuritis. CHAPTER 14 Nervous System A B E-Figure 14.20 Malignant Catarrhal Fever, Cow. A, The blood vessels of the cerebral arterial circle (Circle of Willis) contain a white-gray exudate that is mostly commonly connected to the rete mirabile (see E-Figs. 2.2 to 2.7). B, The inflammation is characterized by a transmural lymphocytic arteritis-periarteritis and endophlebitis affecting rete mirabile. Hematoxylin and eosin (H&E) stain. (Courtesy Dr. D. O’Toole, Wyoming State Veterinary.) 968.e1 CHAPTER 14 Nervous System 969 Clinical signs referable to CNS infection may include trembling, shivering, ataxia, and nystagmus. viruses have a shared tropism for fetal tissues and cause congenital malformations and encephalitis. Bovine Alphaherpesvirus Meningoencephalitis Astrovirus Although bovine herpesvirus 1 (BHV-1) occasionally causes a nonsuppurative meningoencephalitis, primarily in young cattle, two variants of BHV-1 isolated in Argentina and Australia (referred to as BHV-1, subtypes 3a and 3b, respectively) and more recently BHV-5 (isolated most commonly in South America and less commonly in North America) have a particular tropism for the CNS. Recent evidence suggests that BHV-5 uses an intranasal route to infect and replicate in the nasal mucosa and then enters the CNS by retrograde axonal transport predominantly through olfactory nerves. Gross lesions in the CNS are nonspecific and include meningeal congestion, petechiation, hemorrhage, and malacia in the frontal and olfactory cortices. Microscopic lesions consist of dense perivascular infiltrates of lymphocytes, plasma cells, and macrophages accompanied by neuronal degeneration, vasculitis, necrosis, and presence