Peripheral Nervous System PDF

CHAPTER 14 Nervous System A 983 A B B Figure 14.109 Pyogranulomatous Meningitis and Ventriculitis, Feline Infectious Peritonitis (FIP), Cat. A, Cerebral cortex. A white-yellow exudate (arrows) distorts and obscures the blood vessels in the meninges. B, A cross-sectional view of the lateral ventricle...

CHAPTER 14 Nervous System A 983 A B B Figure 14.109 Pyogranulomatous Meningitis and Ventriculitis, Feline Infectious Peritonitis (FIP), Cat. A, Cerebral cortex. A white-yellow exudate (arrows) distorts and obscures the blood vessels in the meninges. B, A cross-sectional view of the lateral ventricles that contain coagulated cerebrospinal fluid (arrow) typical of this infection. (A courtesy Dr. B.F. Porter, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University and B courtesy Dr. A.D. Miller, College of Veterinary Medicine, Cornell University.) Figure 14.110 Pyogranulomatous Meningoencephalitis, Feline Infectious Peritonitis (FIP), Cat. A, Circumferentially around the brainstem, the meninges is expanded by a mixed inflammatory infiltrate (arrows). Hematoxylin and eosin (H&E) stain. B, Ventriculitis and ependymitis are evident. Note the prominent perivascular cuffs of lymphocytes, plasma cells, and macrophages (arrows). H&E stain. (Courtesy Dr. B.F. Porter, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University.) clinical signs can include depression, ataxia, seizures, behavioral changes, and blindness. involvement can include behavioral changes, dullness, coma, paresis, ataxia, paralysis, and seizures. Peripheral Nervous System Feline Ischemic Encephalopathy The peripheral nervous system (PNS) is typically divided into three parts: the somatic division, the autonomic division, and the enteric division. The somatic division is formed by sensory neurons (afferent components of cranial and spinal nerves, sensory receptors, and cranial and spinal ganglia) and motor neurons (efferent components of cranial and spinal nerves and lower motor neurons) that innervate skeletal muscle via myoneural junctions (Fig. 14.112). The autonomic and enteric divisions consist of networks of afferent and efferent nerves and their ganglia that regulate various involuntary functions via sympathetic and parasympathetic fibers, including glandular secretions and contractility and relaxation of smooth muscle of the vascular and alimentary systems. Afferent and efferent nerve fibers of the autonomic and enteric divisions are carried in the afferent and efferent branches of the somatic division (cranial and spinal nerves). Peripheral nerves are composed of groups of axons of varying caliber, both myelinated and nonmyelinated (Fig. 14.113). As with the CNS, axonal components include neurofilaments and microtubules. Neurofilaments provide structural support, whereas microtubules are intimately involved in bidirectional axoplasmic flow of Feline ischemic encephalopathy is associated with aberrant cerebrospinal migration of Cuterebra fly larvae that enter the brain via the nasal cavity. A vasospasm of the middle cerebral artery, possibly resulting from a substance elaborated by the parasite, is the most likely mechanism behind the lesions. The gross lesions of acute disease are often unilateral and occur in the white and gray matter of the cerebral hemispheres, usually in the area supplied by the middle cerebral artery (Fig. 14.111). The necrosis can be multifocal or involve most of one hemisphere. Hemorrhages can occur in the neuroparenchyma or leptomeninges. Microscopically, superficial laminar cortical necrosis with ischemic cell change is typical, and frank parenchymal necrosis consistent with infarction is also possible. Parasite track lesions characterized by necrosis, hemorrhage, and a mixed inflammatory infiltrate may also be observed. With thorough examination, the offending arthropod can sometimes be identified within the cranial cavity. Feline ischemic encephalopathy affects cats of any age and has an acute onset. Clinical signs usually reflect unilateral cerebral involvement. The disease most often occurs in the summer months, and Structure and Function CHAPTER 14 Nervous System 983.e1 A A B E-Figure 14.22 Pyogranulomatous Vasculitis, Feline Infectious Peritonitis, Cat. A, Ventral brain, cerebral vasculature of the circle of Willis. A white-yellow pyogranulomatous inflammation distorts and obscures the blood vessels. Lesions are attributed to viral induced inflammation that targets vessel walls (arrows). The character of the inflammatory response can vary from an exudate with accumulation of serous fluid and fibrin mixed with neutrophils and histiocytes to a reaction that is more pyogranulomatous and in which commonly there are lymphocytes and plasma cells. The severity and magnitude of the lesion depicted here is much more dramatic than usual. B, A cross-sectional view of A. The pyogranuloma (arrows) is principally in the subarachnoid space and has compressed the adjacent cerebral cortex. (A and B courtesy Dr. J. Sundberg, College of Veterinary Medicine, University of Illinois.) B E-Figure 14.23 Pyogranulomatous Vasculitis, Feline Infectious Peritonitis (FIP), Cat. A, Periventricular white matter (arrows) beneath the fourth ventricle (between the medullary vellum and medulla). The pyogranulomatous inflammation that occurs with FIP causes vascular and perivascular injury, vasogenic edema, and parenchymal disruption. Hematoxylin and eosin (H&E) stain. B, A higher magnification of A. Ventriculitis and ependymitis are evident. Note the prominent perivascular cuffs of small mononuclear cells and macrophages. H&E stain. Inset, Higher magnification of B. H&E stain. (Courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.) 984 SECTION II Pathology of Organ Systems A lv B Figure 14.111 Feline Ischemic Encephalopathy, Brain. A, Lateral view of a collapsed area of the cerebral cortex. Note the torturous pattern of the vascular supply, likely a component of the reparative response to ischemic injury. B, Transverse section at the junction between the left parietal and occipital lobes, level of thalamus, cat. Chronic feline ischemic encephalopathy. The dorsolateral aspect of the left cerebral hemisphere has undergone necrosis, followed by cyst formation and collapse after phagocytic removal of the necrotic debris. Cystic spaces (arrows) have replaced the previously existing parenchyma, and the left lateral ventricle (lv) has expanded into the area of lost tissue (hydrocephalus ex vacuo). (A courtesy Drs. V. Hsiao and A. Gillen, College of Veterinary Medicine, University of Illinois. B courtesy Dr. R. Storts, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University.) Figure 14.112 Myoneural Junctions. Peripheral nerve with terminal axons ending at myoneural junctions on muscle fibers (arrow). Dissected and glycerol-mounted muscle fibers. (Courtesy Dr. M.D. McGavin, College of Veterinary Medicine, University of Tennessee.) structural components, nutrients, and trophic factors to and from the cell body. Transport from the neuron cell body to the distal axon (anterograde flow) occurs at fast (400 mm per day or approximately 0.25 mm per minute) and slow (1 to 4 mm per day) rates. Retrograde transport from the distal axon to the cell body progresses at a rate of 200 mm per day (approximately 0.125 mm per minute) (see E-Fig. 14.3). Supporting cells in the PNS include Schwann cells, fibroblasts of the endoneurium, and the satellite glial cells (SGCs) of the sensory and autonomic ganglia. Schwann cells surround both myelinated and nonmyelinated axons and are responsible for formation of the myelin sheath (see Fig. 14.113). In contrast to the CNS, where an oligodendrocyte can send out numerous processes to myelinate internodes of several different axons, a Schwann cell myelinates only one internode of a single axon. As a result, the entire length of an axon in the PNS is myelinated by many individual Schwann cells. Although Schwann cells do not appear to play a role in axon guidance during formation of the PNS, these cells are necessary for maintenance of axons, and they secrete neurotrophic factors that play a role in regeneration. Axons are grouped into fascicles surrounded by loosely organized tissue fibrils and specialized endoneurial fibroblastic cells with phagocytic capabilities (see Fig. 14.113). When an axon is damaged badly enough to cause Wallerian degeneration, removal of the debris is by these putative endogenous phagocytic cells, augmented by an influx of blood monocytes. Mast cells and small blood vessels are also present among the nerve fibers. Depending on species and anatomic location, endothelial cells of endoneurial blood vessels can be joined by tight junctions, preventing free passage of some macromolecules and providing an incomplete blood-nerve barrier. Collagen bundles and modified fibroblastic cells, termed perineurial cells, form the perineurium that ensheathes individual nerve fascicles. The perineurium contributes some barrier properties by preventing the free diffusion of macromolecules into the nerve fascicles. The fibrous epineurium is continuous with the dura mater as a peripheral nerve joins the CNS and encloses groups of nerve fascicles. The epineurium contains fibroblasts, mast cells, and adipocytes, the latter probably providing some protection to the nerve. SGCs are found in all PNS ganglia, both sensory and autonomic. These cells envelop neurons, forming a distinct functional unit of the neuron and its associated SGCs. The functions of SGCs have yet to be fully elucidated, but they appear to share some functions with astrocytes. The autonomic and enteric divisions of the PNS function primarily to transmit impulses from the CNS to peripheral organs (efferent nerves) that regulate (involuntary control) the function of these organ systems (heart, vascular system, visceral smooth muscle, and exocrine and endocrine glands). These effects include the rate and force of contraction and relaxation of smooth muscle (visceral organs and blood vessels) and striated muscle (heart). Afferent nerves, which transmit from the periphery to the CNS, mediate visceral sensation and vasomotor and respiratory reflexes through baroreceptors and chemoreceptors in the carotid sinus and aortic arch. Autonomic and enteric functions are regulated in the medulla oblongata, pons, and hypothalamus. The autonomic division has two structural and functional components: the sympathetic and parasympathetic systems. These systems usually have opposing effects on innervated organ systems. For example, the parasympathetic system acts to lessen the effects of increased vasoconstriction (smooth muscle) and contractility (heart rate) exerted by the sympathetic system. The enteric division of the PNS exerts effects on blood flow and digestive processes, such as motility, secretion, and absorption. CHAPTER 14 Nervous System 985 Skin Pain receptors Muscle Axon Node of Ranvier Myelin sheath Nerve bundle (fascicle) Blood vessels Axon Motor end plate Endoneurium Perineurium Epineurium Spinal ganglion Spinal cord Dorsal root Ventral root Figure 14.113 Organization of a Peripheral Nerve and Sensory and Motor Branches and Their Coverings. The main components of the enteric nervous system are myenteric plexuses (Auerbach’s plexuses) and submucosal plexuses (Meissner’s plexuses). Injury to these plexuses can lead to dysautonomias, which are discussed in a later section. Dysfunction/Responses to Injury See Central Nervous System, Dysfunction/Responses to Injury. Responses of the Axon to Injury See the section on Central Nervous System, Dysfunction/Responses to Injury, Neurons, Wallerian Degeneration and Central Chromatolysis. Portals of Entry/Pathways of Spread See Central Nervous System, Portals of Entry/Pathways of Spread. Defense Mechanisms/Barrier Systems Blood-Nerve Barrier The blood-nerve barrier regulates the free movement of certain substances from the blood to the endoneurium of peripheral nerves. Barrier properties are conferred by tight junctions between endothelial cells of the capillaries of the endoneurium and perineurium and by selective transport systems in the endothelial cells. Diseases Affecting Multiple Species of Domestic Animals Many disorders affecting the CNS are also manifested in lesions in the PNS, either (1) because of damage to neuron cell bodies of lower motor neurons residing in the CNS or (2) because the PNS is equally vulnerable to the disease. An example in the first case is lysosomal storage disorders, which result in substrate accumulation in cell bodies of lower motor neurons. Cell death and axonal degeneration of the PNS are the end points of a chronic and progressive process of substrate accumulation that interferes with cellular biochemical processes and transport systems. In the second case, substrate also accumulates in cell bodies of sensory neurons located in dorsal root ganglia, resulting in cell death and axonal degeneration. Some disorders primarily affect the PNS. Depending on whether the lesion is in a sensory nerve, motor nerve, or both, disorders of the PNS can manifest clinically as a motor disturbance, sensory deprivation, or a combination of motor and sensory alterations. The term used for the disease depends on whether the primary problem involves neurons (neuronopathy), axons (axonopathy), myelin (myelinopathy), or nerves in general (neuropathy), but the terminology has not always been used consistently. Space constraints do not allow an exhaustive coverage of all disorders of the PNS here. Many of the reported disorders seem to represent isolated occurrences in a specific breed. This section covers the major types of PNS disorders with reference to specific disorders for illustrative purposes. Congenital/Hereditary/Familial Disorders Hereditary sensory neuropathy of English pointers affects dogs between 2 and 12 months of age, and the presenting signs are insensitivity to pain and self-mutilation of the paws (E-Fig. 14.24). Lesions include loss of neurons in dorsal root ganglia with replacement by SGCs (Nageotte nodules) and degeneration and loss of axons within the dorsal spinal nerve roots and peripheral nerves with proliferation of Schwann cells (Büngner’s bands). Similar conditions have been reported in German short-haired pointers and English springer spaniels. Sensory neuropathy of border collies is characterized by progressive ataxia, proprioceptive deficits, hyperextension of the limbs, self-mutilation of the distal limbs, and urinary incontinence. Signs develop between 2 and 7 months of age. The primary lesion appears to be degeneration and loss of sensory axons within peripheral nerves with lesser involvement of motor axons. A mutation in the FAM134B gene has been discovered in affected dogs, and the same mutation has been seen in mixed breed dogs diagnosed with sensory neuropathy. CHAPTER 14 Nervous System E-Figure 14.24 Neuro-Pododermatitis (Acral Mutilation Syndrome), Dog. This disorder, a primary sensory peripheral neuronopathy with selfmutilation and insensitivity to pain, is caused by the absence of (or small) dorsal root ganglia, reduction in size of dorsal nerve rootlets, and degeneration and loss of myelinated and nonmyelinated sensory axons. This dog wore off its footpads when placed on a concrete run. Satellite cell proliferation is commonly present in other large autonomic ganglia (i.e., celiac ganglion). (Courtesy College of Veterinary Medicine, University of Illinois.) 985.e1 986 SECTION II Pathology of Organ Systems exhibit central chromatolysis, nerve fiber bundles are edematous, and supporting cells can be remarkably hyperplastic. This lesion is thought to arise from inflammatory cytokine-mediated injury to autonomic neurons, and it may cause alterations of intestinal motility. It appears that the morphologic changes observed in autonomic and enteric neuron cell bodies are reversible with resolution of the peritonitis. Myelination Disorders Figure 14.114 Dysautonomia, Trigeminal Ganglion, Horse. Neuronal central chromatolysis, nuclear pyknosis, and neuronal loss are the characteristic histologic features (arrow) of equine dysautonomia. Hematoxylin and eosin (H&E) stain. (Courtesy Dr. S. Priestnall, Royal Veterinary College, University of London, England.) Other dog breeds known to develop degenerative diseases of the PNS with a probable genetic basis include the Golden retriever, Jack Russell terrier, Scottish terrier, boxer, Rottweiler, Dalmatian, and German shepherd. In cats, the Birman, snowshoe, and Bengal breeds may develop similar conditions. Ganglioradiculitis Ganglioradiculitis, also called sensory neuronopathy, is a rare disease of adult dogs. Clinical signs include ataxia, reduced or absent spinal reflexes, hypersalivation, facial hypoalgesia, and dysphagia. Lymphocytic infiltration of spinal dorsal root ganglia and other ganglia results in neuronal loss and axonal degeneration. Grossly, the dorsal funiculi throughout the spinal cord are pale from secondary demyelination. The disease appears to have an autoimmune basis. Dysautonomias Dysautonomia is a disorder that results in failure of the sympathetic and parasympathetic components of the autonomic nervous system. The disease has been described in horses (equine grass sickness), cats (Key-Gaskell syndrome), and dogs. The disease is idiopathic, and proposed causes include autoimmunity, environmental toxins, and biotoxins. The equine disease is discussed in the section on Peripheral Nervous System, Diseases of Horses. Lesions are observed in peripheral ganglia and vary from central chromatolysis and nuclear pyknosis in more acute cases to loss of neurons and proliferation of SGCs in cases of longer duration (Fig. 14.114). Involvement of dorsal root ganglia, spinal cord motor neurons, and cranial nerve nuclei may also be observed. Minimal to mild leukocytic infiltrates can occur, but the lesions are not overtly inflammatory. In cats and dogs, clinical signs are varied and include GI disturbances, urinary incontinence, mydriasis, prolapsed third eyelids, bradycardia, and other signs associated with autonomic dysfunction. Peritonitis-Induced Autonomic Dysfunction Degeneration of autonomic neurons in the myenteric and submucosal ganglia can occur in animals with peritonitis. The degree of neuronal degeneration appears to be related to the severity and type of inflammatory response in the peritoneal cavity and the ability of inflammatory mediators and other potentially toxic molecules to reach the ganglia hematogenously or by diffusion. Affected neurons In contrast to the CNS, disorders of myelin formation are rare in the PNS. These disorders are thought to have a genetic predisposition. In dogs, hypomyelination has been described in golden retrievers with onset at approximately 7 weeks of age. Clinical signs include a peculiar hopping gait, depressed spinal reflexes, and circumduction of the limbs while walking. Lesions in peripheral nerves include thin myelin sheaths, an increased number of Schwann cells, and neurolemma cells with abnormally increased cytoplasmic volume. There is no evidence of active demyelination or effective remyelination. The lesions are believed to involve a defect in Schwann cells or an abnormal axon–Schwann cell interaction. In calves, a myelinopathic peripheral neuropathy has been described in Santa Gertrudis–Brahman crossbreeds. Microscopically, lesions are present in the vagus nerves, somatic peripheral nerves of the brachial plexuses, and the sciatic nerves. Dorsal and ventral spinal nerve roots have similar lesions. There is thickening of the myelin sheaths as a result of excess myelin arranged about the axons or as irregularly folded myelin sheaths not surrounding axons. Onset of clinical signs is at 6 to 10 months of age. Clinical signs are dysphagia, abnormal rumination with bloat, and a weak shuffling gait. A variety of injuries can cause primary demyelination in the PNS. In response to injury, Schwann cells proliferate to restore the myelin sheaths, often forming longitudinal columns along the course of a degenerated axon termed Büngner’s bands. Remyelination results in internodes that are shorter than the internodes of adjacent normal myelinated axons, and this change is used microscopically to detect areas of remyelination in peripheral nerves. Another lesion that occurs with repeated episodes of demyelination is proliferation of Schwann cell processes, resulting in concentric whorls called onion bulbs that surround the axon. An example of primary demyelination is the shrub coyotillo (Karwinskia humboldtiana), which affects ruminants from the southwestern United States to northern South America. Seeds in the fruit contain polyphenolic compounds, including a substance called karwinol A that induces primary demyelination of peripheral nerves. Based on electron microscopic evaluation of lesions, the damage appears to be due directly to axonal injury caused by consolidation of neurofilaments and margination of microtubules. Clinical signs include weakness and incoordination in the rear limbs and a high stepping gait. Endocrine Disorders Endocrine disorders such as diabetes mellitus and hypothyroidism can affect the PNS. The lesions of these neuropathies are not well characterized and can include evidence of primary demyelination, remyelination, and axonal degeneration. Distal portions of the axon are commonly affected. The extent to which demyelination or axonal degeneration is the primary lesion remains to be determined. From a clinical standpoint, it may be difficult to distinguish neurologic signs from those signs attributed to hormonal-influenced injury of myofibers. Clinical signs can be caused by sensory and motor deficits. Diabetic neuropathy of cats resembles the human condition. Affected cats have rear limb weakness, muscle wasting, depressed patellar reflexes, and a characteristic plantigrade stance. CHAPTER 14 Nervous System Nutritional Disorders Nutritional axonopathies are relatively uncommon and are chiefly caused by deficiencies of vitamin A and some of the B vitamins. Vitamin A deficiency indirectly causes a peripheral neuropathy by affecting bone growth and remodeling. In calves and pigs, the neuropathy is because of narrowing of the optic foramina caused by continued bone deposition with decreased resorption, resulting in compression of the optic nerves, Wallerian degeneration, and blindness. B vitamin deficiencies are primarily diseases of pigs and poultry. In pigs, deficiency of pantothenic acid causes a sensory neuropathy with axonal degeneration, demyelination, chromatolysis, and neuron loss in the dorsal root ganglia, resulting in proprioceptive deficits, goose-stepping, and dysmetria. Riboflavin deficiency in poultry, named curled-toe paralysis, is primarily a demyelinating neuropathy. Peripheral nerves are swollen because of endoneurial edema, and there is subsequent demyelination with mild axonal degeneration. Toxic Disorders A number of toxins can affect the PNS with or without damage in the CNS. The initial toxic effect can be at the level of the neuron cell body, the axon, or the myelin sheath. Examples of toxins targeting neuronal cell bodies are organomercurial compounds such as methylmercury and the cancer chemotherapeutic agent doxorubicin. Methylmercury is particularly toxic because it directly alters biochemical reactions. In mercury poisoning, sensory neuron cell bodies of the dorsal root ganglion are preferentially involved, and the motor neurons are spared, whereas with doxorubicin, both dorsal root ganglion and autonomic cell bodies are affected. An example of chemical toxins causing distal axonal degeneration are the vinca alkaloids, vincristine and colchicine, both causing disassembly of microtubules and inhibiting axoplasmic flow. Paclitaxel (Taxol), an alkaloid from the western yew (Taxus brevifolia), also causes an axonopathy. An outbreak of distal polyneuropathy has been reported in cats fed commercial diets contaminated with the ionophore salinomycin, which is used as a coccidiostatic drug in poultry and a growth promoter in cattle. Some toxins seem to cause different patterns of injury in the CNS and PNS. For example, lead causes neuronal necrosis in the CNS, whereas it results in demyelination in the PNS. Autoimmune Disorders Myasthenia Gravis. Myasthenia gravis is a disorder of neuromuscular impulse transmission at myoneural junctions that results in flaccid paralysis of skeletal muscle. The disease can be caused by an autoimmune mechanism (acquired) or result from inherited genetic abnormalities (congenital). In autoimmune myasthenia gravis, the antibody binds to acetylcholine receptors on postsynaptic muscle membranes, and this interaction blocks binding of acetylcholine to the receptors. Acquired myasthenia gravis often occurs concurrently with thymic abnormalities such as thymoma and thymic hyperplasia. The presence of a population of myoid cells in the normal thymus are believed to play a role in the pathogenesis because these cells express acetylcholine receptors and muscle proteins. In dogs, acquired myasthenia gravis has also been associated with hypothyroidism. Congenital myasthenia gravis is caused by a genetically determined deficiency in the number of acetylcholine receptors expressed in motor end plates. Clinical signs of myasthenia gravis include weakness, fatigue, and dysphagia. Megaesophagus is common, leading to regurgitation and aspiration pneumonia. Microscopic lesions are not observed in muscles or nerves. The diagnosis can be made by detection of circulating antibodies to acetylcholine receptors or by observing the response to administration of the anticholinesterase drug edrophonium chloride. 987 Infectious Diseases Bacteria Botulism. Botulism is caused by the neurotoxin of Clostridium botulinum. Seven types of the toxin (A to G) are recognized. The bacterium is a ubiquitous Gram-positive spore-forming anaerobe commonly found in soil. This disease primarily affects horses, cattle, and birds. The most common source of the toxin is a decaying animal carcass, but decaying plant material can also be a source. Adult horses contract the disease principally through the ingestion of preformed toxin in contaminated feeds, usually haylage that is prepared and stored improperly. In these cases, the toxin is absorbed from the alimentary system and enters the bloodstream. Less commonly, adult horses contract the disease through tissue injury such as a hoof abscess or skin wound. Spores of C. botulinum are either carried into wounds by contaminated foreign objects such as nails or into gastric ulcers by ingestion of contaminated soil. In either case, the spores germinate only in necrotic tissue that can provide an anaerobic environment. The bacteria replicate and produce the toxin, which is absorbed through the capillary endothelium and enters the bloodstream. The toxin of C. botulinum causes no macroscopic and microscopic lesions. Once botulinum toxin is in the bloodstream, it enters myoneural junctions and binds to receptors on presynaptic terminals of peripheral cholinergic synapses (see Fig. 4.31). The toxin is internalized into vesicles, translocated to the cytosol, and then mediates the proteolysis of components of the calcium-induced exocytosis apparatus, thus interfering with acetylcholine release. Inhibition of the release of acetylcholine results in flaccid paralysis of muscles innervated by cholinergic cranial and spinal nerves, but there is no impairment of adrenergic or sensory nerves. Clinically, affected animals have progressive paralysis of the muscles of the limbs, mandible, larynx/pharynx, upper eyelid, tongue, and tail. Death is usually the result of respiratory failure, caused by flaccid paralysis of the diaphragm. Blockage of acetylcholine release at presynaptic cholinergic terminals is permanent. Improvement occurs only when axons develop new terminals to replace those damaged by the toxin. Viruses and Protozoa. Inflammation caused by infectious agents is relatively uncommon in the PNS, but some viral and protozoal infections can involve peripheral nerves and ganglia. Although most viral infections do not affect both the CNS and PNS, rabies is a notable exception. Ganglioneuritis involving dorsal root, trigeminal, and other ganglia is common in rabies. The vomiting in pigs infected with hemagglutinating encephalomyelitis virus is thought to result from altered function of autonomic ganglia and gastric intramural plexuses. Protozoal infections involving the PNS are also uncommon, and probably the best-known example is polyradiculoneuritis caused by Neospora caninum and Toxoplasma gondii, primarily in the dog. Lysosomal Storage Disorders Globoid Cell Leukodystrophy. Peripheral nerves may be affected in globoid cell leukodystrophy, and lesions are characterized by primary demyelination followed by axonal degeneration. Small sensory branches of peripheral nerves can be biopsied to make the diagnosis (Fig. 14.115). Microscopically, affected nerves have pronounced loss of myelin and abundant globoid cells (activated blood monocytes). Other lysosomal storage diseases known to affect the PNS include α-l-fucosidosis (nerve enlargement because of macrophage infiltration), α- and β-mannosidosis (vacuolated Schwann cells), and gangliosidoses (vacuoles in neurons with demyelination). 988 SECTION II Pathology of Organ Systems Increased parasympathetic stimulation Decreased sympathetic stimulation Reduced vascular tone Massive vasodilation Decreased systemic vascular resistance Diminished cardiac output Figure 14.115 Globoid Cell Leukodystrophy, Small Branch of a Peripheral Sensory Nerve, Dog. Primary demyelination, secondary axonal degeneration, and globoid cells (arrows) between the nerve fibers (also see Figs. 14.64 and 14.65). Hematoxylin and eosin (H&E) stain. (Courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.) Traumatic Injury Trauma to peripheral nerves (lower motor or sensory) is relatively common and can result from lacerations, violent stretching and tearing, compression, or contusion. Reaction patterns after PNS injury are analogous to those in the CNS, but peripheral nerves have a greater capacity for repair. Three lesion patterns have been described. Mild injury that leaves the axon intact can result in temporary conduction block (neurapraxia), but total recovery of function occurs. More severe damage that destroys the axon but leaves the connective tissue framework intact (axonotmesis) results in Wallerian degeneration distal to the point of injury, but the potential for regeneration and reinnervation is good. Finally, severance of the nerve with destruction of the supporting framework (neurotmesis) results in Wallerian degeneration distal to the injury with the potential for regeneration but little chance of normal reinnervation. With neurotmesis, destruction of the supporting framework results in fibrosis between the proximal and distal ends of the nerve, and this gap may be large depending on the severity of the injury. Fibrous tissue can obstruct the regenerating proximal axon from reaching the distal supporting framework of the axon. If the regenerative response is exuberant but unproductive, a “potentially” palpable bulbous-like growth can form at the severed stump of the proximal axon called a “neuroma.” An example of this phenomenon is the tail dock neuroma that can form at the site of tail amputation in puppies, piglets, and lambs. Neurogenic Shock. Neurogenic shock is caused by an alteration in the function of the autonomic nervous system and its regulation of muscle tone in systemic blood vascular beds (Fig. 14.116). The onset of neurogenic shock usually coincides with traumatic injury to the CNS, but the factors that determine whether it occurs are poorly understood. It is thought to be caused by massive discharge of the autonomic nervous system. After trauma, there is immediate vasoconstriction of vascular smooth muscle. Vasoconstriction is quickly followed by vasodilation, expanded circulatory volume, and a reduction in blood pressure, leading to shock. Neurogenic cardiomyopathy (brain-heart syndrome) is likely a manifestation of neurogenic shock and vasoconstriction of arterioles, leading to myocardial necrosis (see the section on Peripheral Nervous System, Diseases of Dogs). Reduced tissue perfusion Compromised cellular metabolism Figure 14.116 Mechanism of Neurogenic Shock. (Courtesy Dr. A.D. Miller, College of Veterinary Medicine, Cornell University; and Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.) Neoplasms The objective of this section is not to be all encompassing regarding neoplasms of the PNS but to review one of the best-known examples of how neoplasia can involve this system. Although neoplasms of the PNS are often lumped into categories of either benign or malignant nerve sheath neoplasms, pathologists currently recognize three distinct types of nerve sheath neoplasms: schwannomas, perineuriomas, and neurofibromas. Schwannomas and perineuriomas are derived from Schwann cells and perineurial cells respectively, whereas neurofibromas include elements derived from Schwann cells and fibroblasts. Malignant neoplasms have more anaplastic cytoarchitectural features and aggressive growth into adjacent normal tissue. Nerve sheath neoplasms occur in both cranial (Fig. 14.117) and spinal nerves (Fig. 14.118) of the PNS. Those that arise associated with cranial nerves can produce a number of clinical signs including unilateral muscle atrophy and Horner’s syndrome. Schwannomas of animals are most commonly recognized in the dog and less commonly in the cat, horse, and cow. In the dog, the neoplasm typically affects the cranial (fifth) or spinal nerve roots (posterior cervical–anterior thoracic roots of the brachial plexus and their extensions and roots at the thoracic and lumbar levels). Although true schwannomas of the dermal soft tissues have been reported, there should always be careful consideration of soft tissue sarcomas that can have similar morphologic features. Grossly, schwannomas are nodular or varicose thickenings along nerve trunks or nerve roots. They can be firm or soft (gelatinous) and white or gray. Schwannomas of the spinal cord nerve roots can remain inside the dura mater or extend through a vertebral foramen to the exterior. Histologically, schwannomas are composed entirely of neoplastic Schwann cells and are typically composed of two morphologic patterns, known as Antoni type A and type B, that occur in variable proportions within the neoplasm. Antoni A tissue is cellular and consists of monomorphic sheets, fascicles, and whorls of spindleshaped Schwann cells. These cells have poorly defined eosinophilic cytoplasm and pointed basophilic nuclei and are present in a collagenous stroma of variable extent. The nuclei of these cells are commonly arranged in rows, between which are parallel arrays (stacks) CHAPTER 14 Nervous System 989 A B C Figure 14.117 Nerve Sheath Neoplasms. A, Inner surface of the cranial vault, cranial nerves, dog. These neoplasms are usually lobulated, welldefined, tan, solitary to multiple masses that arise from the coverings of a cranial or spinal nerve (arrows). In the central nervous system (CNS), the trigeminal nerve is usually affected, and the masseter and temporalis muscles innervated by it may atrophy. Neoplasms compress the nerves, causing Wallerian degeneration. B, Brain from dog in A. Peripheral nerve sheath neoplasms (arrows). C, Cells are arranged in interwoven bundles that have a spindloid morphology. Hematoxylin and eosin (H&E) stain. (Courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.) of their cytoplasmic processes, and this arrangement is called a Verocay body. Antoni B areas are also composed of Schwann cells, but their cytoplasm is inconspicuous, and their nuclei appear to be suspended in a copious myxoid, often microcystic, matrix. Other histologic findings include hyalinized stroma and the absence of nerve fibers. These neoplasms can reliably be stained immunohistochemically with antibodies to laminin or type IV collagen that highlight the basal lamina produced by the neoplastic Schwann cells. S-100 immunoreactivity is typically diffuse throughout the neoplasm. Neurofibromas consist of Schwann cells, perineurial cells, and fibroblasts. This type of neoplasm is not common in domestic animals. Figure 14.118 Nerve Sheath Neoplasm, Spinal Nerve, Cow. These neoplasms occur most commonly in cows and dogs. Although schwannoma has been proposed as the best term to classify these neoplasms, the term nerve sheath neoplasm groups all morphologic diagnoses under a common umbrella. (Courtesy College of Veterinary Medicine, University of Illinois.) Nevertheless, a unique form occurs in the cow as part of a benign neurofibromatosis-like syndrome in which it occurs most commonly in mature animals, although the lesion has also been reported in young calves and involves the cranial eighth nerve, brachial plexus, and intercostal nerves. Additionally, autonomic nerves of the liver, heart, mediastinum, and thorax can be affected. The skin can be infrequently involved. Some microscopic features of the neurofibroma include elongated spindle cells with poorly defined pale eosinophilic cytoplasm, tapering wavy or buckled nuclei, and numerous small nerve fibers (which are not present in schwannomas). These neoplastic components are situated in a variably prominent fibromyxoid to myxoid matrix (myxoid neurofibroma), although another variant of the neoplasm contains prominent collagen (collagenous neurofibroma). Neurofibromas have far less immunoreactivity for either laminin or S-100, with the latter staining the Schwann cell component, but not the other cell types. The last nerve sheath neoplasm is the perineurioma. It usually behaves as a benign neoplasm. It is a very rare variant of the nerve sheath neoplasms reported in the dog. It consists of tight, concentric whorls of perineurial cells that surround a central axon. IHC stains for neurofilament proteins often highlight the central axon, whereas stains like laminin highlight the spindle cell population. All of the aforementioned neoplasms can undergo malignant transformation and are then referred to as malignant nerve sheath neoplasms. They typically invade surrounding structures or can, based on location, invade or surround the spinal cord. Malignant nerve sheath neoplasms are by far more common than benign variants. Diseases of Horses Colonic aganglionosis Colonic aganglionosis (lethal white foal syndrome) is a disorder involving development of the enteric division of the PNS and is analogous to Hirschsprung disease in infants. This disease occurs most commonly in foals of American paint horses with overo 990 SECTION II Pathology of Organ Systems markings. Affected foals have white or nearly white skin color. Specific information on these skin marking patterns can be obtained from the American Paint Horse Association. The gene, which results in the “colonic aganglionosis” phenotype being expressed, is inherited as a homozygous dominant. Mutations in the endothelin-B receptor gene are detected in affected horses and in some patients with Hirschsprung disease. Both glial-derived neurotrophic factor and endothelin-3 are required for normal development of the enteric nervous system and enteric ganglia. It is proposed that glial-derived neurotrophic factor is required for proliferation and differentiation of neuronal precursor cells destined to populate the gut. Endothelin-3 might modulate these effects by inhibiting differentiation, thus allowing sufficient time for precursor cells to migrate and populate the intestinal wall in a cranial to caudal progression before they differentiate to form enteric ganglia. The lumen of the large intestine is often small or narrowed in affected animals. Microscopically, the myenteric and submucosal enteric ganglia are absent, and the areas affected vary but can extend anywhere between the ileum and distal large colon. Affected foals die within days after birth from functional blockage of the ileum and/or colon because of the lack of innervation and thus normal gut motility. Equine Grass Sickness (Equine Dysautonomia) Equine dysautonomia is a disease that affects the postganglionic sympathetic and parasympathetic neurons and is most commonly reported in the United Kingdom and a variety of European countries. In addition, prevertebral and paravertebral ganglia are commonly affected, as are cranial nerve nuclei of the brainstem. The lesions consist of neuronal chromatolysis followed by degeneration and loss of lower motor neurons of the general visceral efferent nuclei of cranial nerves III and X and the general somatic efferent nuclei of cranial nerves III, V, VII, and XII. It has been suggested that equine dysautonomia should be classified as a multisystem disease. Clinically, injury of neurons results in dysphagia, reflux esophagitis, and gut stasis (colic). Although the cause is unknown, oxidative stress, fungal toxins, changes in weather, and exposure to C. botulinum neurotoxins have been proposed. Pasture grasses stressed by rapid growth or sudden cold weather can have reduced concentrations of antioxidants and increased concentrations of glutamate and aspartate (excitotoxic amino acids) and the neurotoxin malonate. It has been proposed that ingestion of high concentrations of these compounds either directly (excitotoxicity-apoptotic cell death) or indirectly (nitric oxide toxicity) induces neuronal injury within the autonomic nervous system, resulting in alimentary system dysfunction. Current research is focused on the role that C. botulinum type C plays in the development of the disease. Higher levels of immunoglobulin A against C. botulinum type C1 neurotoxin have been reported in acute cases. Historical evidence also suggests that use of C. botulinum vaccination may prevent some aspects of the disease. There are no gross lesions in the PNS except for, potentially, lesions related to paralytic ileus (e.g., distended GI tract, impacted large intestine, esophagitis due to reflux); however, microscopically and principally in the small intestine (ileum), but also involving other ganglia and plexuses, the cell bodies of neurons in ganglia of the autonomic and enteric divisions of the PNS are chromatolytic, have displaced and pyknotic nuclei, are swollen and vacuolated, and with time there is neuronal loss and satellite cell proliferation in affected ganglia (see Fig. 14.114). Interstitial cells of Cajal are also reduced in number. Equine dysautonomia affects horses, ponies, and donkeys primarily between the ages of 2 and 7 years old. The disorder occurs principally between the months of April and July. Injury to enteric neurons results clinically in acute to chronic dysphagia and gut stasis (colic). The only way to diagnose equine grass sickness antemortem is by taking a full-thickness biopsy of the small intestine. Equine Motor Neuron Disease EMND resembles amyotrophic lateral sclerosis in human beings. Because vitamin E concentrations are very low in affected horses, this and other dietary antioxidant deficiencies have been suggested as a possible factor in the mechanism of EMND. Thus, dietary factors, especially the long-term absence (>1 year) of green feeds with high vitamin E concentrations, have been implicated in the pathogenesis of the disease. Vitamin E supplementation may be useful in treating this disease if detected and treated early in its course. Neural injury in EMND involves the cell bodies and axons of lower motor neurons (ventral horn cells, cranial nerves). Microscopically, cell bodies are swollen, have chromatolysis, and contain spheroids. As the disease progresses, the cell bodies become shrunken and degenerate and are removed by neuronophagia. When the cell bodies are lost, the resulting empty neuronal space can be replaced by astrocytosis. The axons of affected lower motor neurons have lesions consistent with Wallerian degeneration. Abundant amounts of lipofuscin are often found in neurons and endothelial cells. The injury in lower motor neurons has been attributed to an oxidative stress mechanism because vitamin E is an antioxidant that offsets the harmful effects of free radicals and reactive oxygen species that can cause membrane lipid peroxidation. It is not, however, linked to a mutation in the equine Cu/Zn superoxide dismutase gene. This gene regulates the production of the enzyme superoxide dismutase, whose function is to convert free radicals and reactive oxygen species (highly toxic to cells) to hydrogen peroxide (much less toxic to cells). The enzyme catalase is used to convert hydrogen peroxide to water and oxygen molecules. The muscle lesion in EMND is atrophy of type I myofibers secondary to loss of type 1 lower motor neurons. Clinically, EMND is characterized by progressive degeneration and loss of lower motor neurons resulting in muscle atrophy, weight loss, difficulty standing, and muscle fasciculation. Significant overlap between EMND and EDM can occur such that lesions seen with each entity can occur in the same horse supporting a shared pathogenesis between the two diseases. Equine Degenerative Myeloencephalopathy EDM is discussed in the section on the Central Nervous System, Diseases of Horses. Recurrent Laryngeal Paralysis Laryngeal paralysis (roarer syndrome) is caused by axonal injury to the left recurrent laryngeal nerve, which results in neurogenic atrophy of the left dorsal, lateral, and transverse cricoarytenoid muscles and consequently dysfunction of the larynx and laryngeal folds (see Fig. 15.16). The cricoarytenoid dorsalis muscle is the main abductor muscle of the larynx, which keeps the arytenoid cartilages in a lateral position. The possible causes of this axonopathy are multiple, and there may be different causes for different age groups of animals and different forms of the disease. Known causes include (1) transection of the axon by extension of inflammation from the guttural pouches because the nerve runs through the pouch within a connective tissue fold and (2) other trauma to the nerve. There is evidence that laryngeal paralysis is inherited in some horses. Currently a genetic age-onset abnormality of axoplasmic flow appears to be the most likely cause in horses in which trauma and inflammation can be excluded as causes. Affected horses have disabilities of performance and a characteristic and diagnostic “roaring” sound with inspiration. Laryngeal CHAPTER 14 Nervous System hemiplegia can affect the right or left dorsal cricoarytenoid muscles; however, 95% of cases involve the left side. The cause of this specificity is unclear. Some have suggested it is related to the long course of the left recurrent laryngeal, which extends down into the chest and loops under the arch of the aorta to return to the larynx. Curiously, studies have shown that other long nerves in the horse can also show degenerative changes, which may indicate that this disorder is a polyneuropathy, rather than a specific disease of the recurrent laryngeal nerve. Gross lesions can vary from being recognizable to being inapparent. Microscopically, the lesion is Wallerian degeneration. Affected nerves are often shrunken with loss of axons and myelin, and Büngner’s bands can be plentiful. Laryngeal hemiparesis is primarily a disease of large horse breeds between the ages of 2 and 7 years old. Diseases of Ruminants (Cattle, Sheep, and Goats) There are no diseases of ruminants; see the section on Peripheral Nervous System, Diseases Affecting Multiple Species of Domestic Animals. Diseases of Pigs There are no diseases of pigs; see the section on Peripheral Nervous System, Diseases Affecting Multiple Species of Domestic Animals. Diseases of Dogs Dysautonomias A discussion on hereditary dysautonomias can be found in the section on Peripheral Nervous System, Diseases Affecting Multiple Species of Domestic Animals. Peritonitis-Induced Dysautonomias Peritonitis-induced dysautonomias are discussed in the section on Peripheral Nervous System, Diseases Affecting Multiple Species of Domestic Animals. Acute Idiopathic Polyneuritis Acute idiopathic polyneuritis (coonhound paralysis) is an acute, fulminating polyradiculoneuritis with ascending paralysis that occurs in dogs after the bite or scratch of a raccoon. By definition, polyradiculitis refers to disease or injury involving multiple cranial or spinal nerve roots, whereas polyradiculoneuritis refers to disease or injury involving multiple cranial or spinal nerve roots and their corresponding peripheral nerves. Coonhound paralysis has been compared with Guillain-Barré syndrome (GBS). This human syndrome typically follows a viral illness, vaccination, or some other antecedent disease that results in an autoimmune response resulting in primary demyelination of cranial and spinal rootlets and nerves and delayed conduction of action potentials down the axon. Humoral and cell-mediated components are suspected to be involved in the autoimmune response. Coonhound paralysis, like GBS, is believed to represent an autoimmune primary demyelination. Despite the lack of close association of macrophages with the degenerating myelin and axons early in the development of the lesions, secretion of TNF-α by these cells could explain both the demyelination and axonal degeneration. Acute idiopathic polyneuritis has been reported in dogs without an association with raccoons and also occurs rarely in cats, suggesting multiple factors might be involved in this type of nerve damage. Lesions in coonhound paralysis are most severe in ventral spinal nerve rootlets and progressively diminish distally in the peripheral nerve. Involvement of dorsal spinal nerve rootlets and ganglia is not constant and relatively minor. Lesions in the ventral nerve rootlets consist of segmental demyelination with a variable influx of neutrophils, 991 2 1 1 Figure 14.119 Polyradiculoneuritis, Coonhound Paralysis, Peripheral Nerve, Dog. This disease results from an autoimmune response leading to primary demyelination of cranial and spinal rootlets and nerves. Myelin sheaths in this peripheral nerve are distended and fragmented along their length (arrowheads) and have been infiltrated by a mixed population of inflammatory cells consisting of lymphocytes, macrophages (1), and plasma cells (2). Enlarged spaces in the myelin sheath, termed digestion chambers (arrows), which form in response to inflammatory and degradative processes, contain myelin debris and macrophages (not shown in this example). Axonal degeneration can occur secondary to primary demyelination. Hematoxylin and eosin (H&E) stain. (Courtesy Drs. R.A. Doty, J.J. Andrews, and J.F. Zachary, College of Veterinary Medicine, University of Illinois.) depending on the acuteness and severity of clinical signs, along with lymphocytes, plasma cells, and macrophages (Fig. 14.119). Axonal degeneration is a common sequela. Evidence of remyelination with Büngner’s bands and axonal sprouting occur during the recovery phase, but the effectiveness of the latter to establish continuity of the nerve rootlet and thus reinnervation of muscle is limited. A chronic polyradiculoneuritis with infiltrations of lymphocytes, plasma cells, or macrophages; demyelination; and variable axonal degeneration in cranial and spinal nerve rootlets and cranial nerves is also reported in dogs and cats. With repeated episodes of demyelination, onion bulbs can be apparent. Both sensory and motor nerves can be involved with sensory disturbances and muscle atrophy. Clinically, affected dogs have signs of coonhound paralysis that develop 1 to 2 weeks after exposure to raccoon saliva. Initial signs of hyperesthesia, weakness, and ataxia are replaced in 1 to 2 days by tetraparesis and/or tetraparalysis that may last from weeks to months. Dogs can die of respiratory paralysis. Recovery is common, but the paralysis can be prolonged in dogs with extensive muscular atrophy. Neurogenic Cardiomyopathy (Brain-Heart Syndrome) Neurogenic cardiomyopathy is a syndrome in dogs characterized by unexpected death 5 to 10 days after diffuse CNS injury (usually hit by car). Affected dogs die of cardiac arrhythmias caused by myocardial degeneration. Grossly, the myocardium has numerous discrete and coalescing pale white streaks and/or poorly defined areas of necrosis. Neurogenic cardiomyopathy is thought to be caused by overstimulation of the heart by autonomic neurotransmitters and systemic catecholamines released at the time of trauma. It is unknown why there is a 5- to 10-day delay in the development of myocardial necrosis. Diseases of Cats There are no diseases of cats; see the section on Peripheral Nervous System, Diseases Affecting Multiple Species of Domestic Animals. Suggested Readings are listed at www.expertconsult.com.