Nervous Dysfunction PDF

902 A SECTION II Pathology of Organ Systems B Figure 14.14 Layers of the Meninges. A, Brain, dog. The dura mater is a thick opaque layer. Here it covers the rostral (cranial) half of the brain and has been dissected away from the caudal half of the brain to expose the underlying leptomeninges. In ol...

902 A SECTION II Pathology of Organ Systems B Figure 14.14 Layers of the Meninges. A, Brain, dog. The dura mater is a thick opaque layer. Here it covers the rostral (cranial) half of the brain and has been dissected away from the caudal half of the brain to expose the underlying leptomeninges. In old animals, the dura mater often fuses with the periosteum of the calvaria, and at necropsy, it is usually removed attached to the calvaria. The leptomeninges are present, but because they are so transparent, they are barely visible on the surface of the caudal half of the brain between gyri. B, Spinal cord, horse. The dura mater is the thick opaque layer dissected from and lying to the right of the spinal cord. The leptomeninges (pia-arachnoid layer) are present on the exposed surface of the spinal cord but are not readily visible in this photograph. Arrows indicate spinal nerve roots. (Courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.) The arachnoid consists of both the multilayered membrane composed of cells that overlap one another and the trabeculae that join it to the pia. The arachnoid has tight junctions between its cells, although other junctions have also been described. It contains no blood vessels and has an outer smooth surface formed by mesothelial-like cells that abut similar cells in the dura mater. The mesothelium-like surfaces of the dura and arachnoid oppose and slide over each other, analogous to the parietal and visceral surfaces of other serous membranes. The pia mater is closely adherent to the surface of the brain and spinal cord and is penetrated by a large number of blood vessels that supply the underlying nervous tissue (Fig. 14.15). The pia mater consists of flat, thin, overlapping connective tissue cells (fibroblasts) that are separated from the underlying neural tissue by variable amounts of loose collagen fibers and the glia limitans. In many areas, the pia, which lacks a basal lamina, is only one-cell-layer thick and has fenestrations, allowing for direct exposure of the glia limitans to the subarachnoid space. Pial and arachnoid cells also ensheathe blood vessels, collagen bundles, and nerves that are within or cross the subarachnoid space and also around arteries that penetrate into the CNS up to 1 to 2 mm. Macrophages are also present in the leptomeninges. Endothelium The basic functions of CNS endothelium are to form the bloodbrain barrier, maintain a nonthrombogenic boundary between coagulation cascade molecules and luminal surfaces of endothelial cells, regulate hemostasis, and participate in the inflammatory response. The endothelial cells of the blood-brain barrier actively transport the molecules that the brain consumes rapidly and in large quantities, such as glucose, amino acids, lactate, and ribonucleosides. Vasculature of the CNS. The arterial vasculature transports and delivers its cellular- and plasma-based components between and among organ systems. The plasma-based components include ions (e.g., Na+2, K+), molecules (e.g., glucose), gases (e.g., oxygen), hormones (e.g., thyroxine), and other substances that play important roles in neuronal function and thus are maintained in plasma at predetermined concentrations (i.e., homeostasis). The pathogeneses of many disorders of the CNS, especially of the cerebrum, reflect (1) an alteration in plasma homeostasis or (2) the fact that the arterial vasculature is simply used as a direct conduit by infectious agents, toxins, and neoplastic cells to travel to the cerebrum and directly or indirectly affect neurons and their supporting cells. Examples of such disorders include thrombotic meningoencephalitis (see Fig. 14.91), cytotoxic cerebral edema (see Fig. 14.28), ischemic encephalopathy (see Fig. 14.111), and metastatic neoplasia (see Fig. 14.77). Neurons are highly active cells and consume about 20% of an animal’s total requirement for energy. They have very limited quantities of “stored” cytosolic glycogen and thus are highly dependent on a homeostatic supply of oxygen and glucose via the arterial vasculature for oxidative phosphorylation in neuronal mitochondria and the production of ATP (see Chapter 1, Mechanisms and Morphology of Cellular Injury, Adaptation, and Death). ATP, in part, is used to establish and maintain the processes involved in the generation of action potentials, ion and water concentrations (i.e., osmolarity) across cell membranes through ion pumps, and axonal transport. Many of the disorders of the CNS that are correlated with alterations in arterial blood supply and plasma homeostasis occur in the cerebrum. The cerebrum is supplied with arterial blood via the cranial (rostral), middle, and caudal cerebral arteries. The cerebral arteries arise from the cerebral arterial circle (formally known as the circle of Willis), which, in turn, arises from a “threefold” arterial blood supply formed by the internal carotid arteries (right and left) and the single basilar-vertebral artery. Arterial blood reaches the brain and the cerebral arterial circle through an extensive network of sequentially connected arteries arising from the aorta arch (see Chapter 2, Vascular Disorders and Thrombosis and Chapter 10, Cardiovascular System, Pericardial Cavity, and Lymphatic Vessels). In general, the brachiocephalic arteries give rise to the common carotid arteries that ascend to the head, whereas the subclavian arteries give rise to the vertebral arteries; however, there is variation in the sequential connectivity of these arteries among species. Similar sequentially connected arterial blood supplies exist for the cerebellum and brainstem. Rete mirabile. A rete mirabile (pl. retia mirabilia) is a network of blood vessels that functions as a vascular “countercurrent exchanger” that acts to maintain (1) a homeostatic temperature in specific tissues or organ systems, (2) homeostatic concentrations of specific ions and gases, or (3) blood pressure in specific tissue areas or organs within normal homeostatic ranges. See Chapter 2, Vascular Disorders and Thrombosis for a detailed discussion (see E-Figs. 2.2 to 2.5). The most common and well-characterized retia, especially in cattle and bison, are the carotid retia mirabilia (or retia mirabilia cerebri). They are located in and around the right and left internal carotid arteries as they pass by the pituitary gland (see E-Fig. 2.6) along the cranial floor where they intermingle with large venous channels (cavernous sinuses) that lie on each side of the gland. This structural arrangement (i.e., bloodstreams flowing in opposite directions) enables large volumes of arterial blood to interact with venous blood to achieve the functional purpose of maintaining temperature homeostasis in the cerebrum (see E-Fig. 2.7). Dysfunction/Responses to Injury Concepts in Understanding Injury in the CNS Before the responses of the CNS to injury are discussed, some fundamental concepts are reviewed in Box 14.2. CHAPTER 14 Nervous System 903 A Periosteum of vertebra Dura mater Venule Arteriole Arachnoid Subarachnoid space Dorsal nerve root Pia mater B Figure 14.15 Histologic Section of Spinal Cord and Meninges. A, Low magnification of a cross-section of the spinal cord and meninges with spinal nerve rootlets and a dorsal root ganglion from which B was selected (box). Hematoxylin and eosin (H&E) stain. B, The inner surface of the dura mater and the outer surface of the arachnoid mater are covered with mesothelial cells, and the space between them is the subdural space. Blood vessels and nerves of the dorsal and ventral roots traverse in the subarachnoid space. H&E stain. (Courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.) Neurons Neurons are the most vulnerable cells in the nervous system and probably within the body. They have large requirements for energy to maintain normal metabolism, transport systems, and the formation of cytoskeleton proteins in the axon, which can extend over long distances (>1 m). Because neurons lack adequate intracellular glucose reserves, they are completely dependent on an adequate blood supply to provide glucose. Additionally, neurons are vulnerable to free radical oxidative stresses and have a limited ability to buffer shifts of calcium ions into the cell, which can interfere with oxidative phosphorylation and ATP production. Neurons are especially sensitive to excessive stimulation with excitatory amino acid neurotransmitters called excitotoxins (e.g., glutamate and aspartate). These neurotransmitters are released in a wide variety of neuronal injuries, especially ischemia. Under normal conditions, astrocytic processes surrounding synapses have efficient uptake systems to remove excitotoxins, and neurons are not injured. In excessive quantities, persistent binding of excitotoxins to receptors can lead to neuronal degeneration and death. The microscopic appearance of the neuronal cell body can vary according to the injury. Characteristic changes of the neuronal cell body are reviewed in Box 14.3. Neuronal Cell Death. Neurons can die after injury as a result of one of two mechanisms: apoptotic cell death or necrotic cell death. These mechanisms are summarized next and discussed in greater detail in Chapter 1, Mechanisms and Morphology of Cellular Injury, Adaptation, and Death. Both apoptotic and necrotic neuronal cell death can occur concurrently or in temporal or spatial sequences within the nervous system. Although apoptotic and necrotic neuronal death represent different responses of neurons to injury, a network of receptors, messenger systems, and mechanisms of cytotoxicity are involved in both apoptotic and necrotic cell death. Factors that determine whether the apoptotic or necrotic pathway is activated include the character of the initiating ligand or injury, type of cell membrane receptors activated, and caspases expressed in response to injury. Apoptotic Cell Death (Programmed Cell Death). Apoptosis is a single cell-initiated, gene-directed, and self-destructive regulatory mechanism that leads to “programmed” cell death. This mechanism is used (1) during the development of the nervous system to remove excess embryonic cells, (2) to remove “aged” cells (i.e., cell turnover), and (3) to maintain cell number homeostasis in organ systems that have regenerative capacity (endocrine glands). 904 SECTION II Pathology of Organ Systems Box 14.2  Concepts in Understanding Responses of the CNS to Injury The cells of the CNS vary in their susceptibility to injury (neurons > oligodendrocytes > astrocytes > microglia > blood vessels). Neurons are the most sensitive to injury, whereas glial and other cells are more resistant to injury. 1. Neurons have only small energy stores; therefore they depend on an intact blood flow to supply oxygen and nutrients, particularly glucose. Neurons with the highest metabolic rate, such as some neurons in the cerebral cortex, will die 6 to 10 minutes after the cessation of blood flow after cardiac arrest. 2. It was long thought that regeneration of neurons did not occur in the adult nervous system, but studies have shown that populations of neural stem cells are capable of forming neurons, not just glial cells. This phenomenon is being explored as a potential therapy for neurodegenerative diseases. 3. If nerve fibers in the CNS are cut by transection of the cord, no or little regeneration of nerve fibers results. Therefore, if sufficient motor nerve fibers are cut, there is paralysis; if not, there is a neurologic deficit. 4. If fibers in the PNS are cut, they can regenerate under certain circumstances. This outcome depends on axoplasmic flow, alignment of the proximal and distal portions of the nerve, and the preservation and alignment of the proximal and distal portions of the endoneurial tube (the structure in which the axon lies). 5. Healing in the CNS is different than in the rest of the body. There are few fibroblasts in the CNS, and they are principally found only in the leptomeninges and in the outer few millimeters of the CNS, where they are pulled into the cerebral cortex with blood vessels. Therefore wounds deep in the CNS heal by proliferation of astrocyte processes. Astrocytic processes fill small dead spaces of less than a few millimeters and encapsulate large dead spaces and abscesses. Superficial wounds or wounds that extend through the leptomeninges heal by synthesis and deposition of collagen by fibroblasts (fibrous connective tissue) and by proliferation of astrocytic processes. In contrast to the fibroblast, however, astrocytic processes produce a very poor capsule, which can break down easily. 6. The cranial cavity is nearly filled by the brain, its coverings, and fluids. Therefore many lesions, such as neoplasms, abscesses, hemorrhages, and hydrocephalus, produce clinical signs because they are space-occupying lesions. 7. The blood-brain barrier can exert control over drugs and antibodies and prevent them from entering the intact brain. It is also a barrier to infection and is formed by the tight junctions of the endothelial cells, aided by basement membrane, and the end feet of the astrocytes, which lie on the outside of the capillary. 8. Although the CNS has the ability to resist infection and injury, once the CNS is infected, it has a low degree of resistance compared with other tissues of the body. Infectious agents that are relatively nonpathogenic in other organs, such as Cryptococcus neoformans, may produce death when they infect the CNS. A disease process that only mildly damages other organ systems can have catastrophic effects in the CNS. CNS, Central nervous system; PNS, peripheral nervous system. Box 14.3  Microscopic Changes That Can Occur in the Neuronal Cell Body 1. Central chromatolysis after axonal injury, degenerative conditions, viral infection, or inherited conditions 2. Ischemic cell change 3. Enlargement of the cell body in lysosomal storage diseases 4. Accumulation of lipofuscin pigment in aging 5. Accumulation of neurofilaments in certain neuronal degenerative disorders 6. Inclusion body formation in certain viral diseases 7. Cytoplasmic vacuolation in spongiform encephalopathies Apoptotic neuronal death is characterized by a sequence of cellular degenerative steps that can be identified biochemically and morphologically. After appropriate signals are recognized and interpreted by cell membrane receptors (Fas, tumor necrosis factor [TNF] receptor-1, TNFrelated apoptosis-inducing ligand receptors), a family of proteins known as caspases are activated. Caspases cleave cellular substrates that are required for cellular function, including cytoskeleton proteins and nuclear proteins such as DNA repair enzymes. Caspases also activate other degradative enzymes, such as deoxyribonucleases, which cleave nuclear DNA. Apoptosis results in characteristic morphologic changes in cells such as shrinkage, cytoplasmic condensation and blebbing, and chromatin clumping and fragmentation (see Figs. 1.13, 1.14, 1.15, and E-Fig. 1.2). As cells continue to shrink, nuclear chromatin is cleaved into smaller units and is packaged for removal by macrophages. Inflammation is not induced by apoptotic cell death. Triggers of apoptosis include viral infection, mild ischemia, excitotoxins, hormones, corticosteroids, and proinflammatory cytokines. The role of apoptotic neuronal death in specific neurologic disorders is discussed in greater detail in subsequent sections. Necrotic Cell Death. In contrast to apoptosis, necrosis usually affects groups of cells and elicits an inflammatory response. It is characterized by hydropic degeneration, swelling of mitochondria, loss of ionic gradient control across the cell membrane, activation of numerous cytoplasmic and lysosomal enzymes, pyknosis and fragmentation of the nucleus, and eventual cell lysis (see Figs. 1.12, 1.13, 1.18, and E-Fig. 1.2). Acute Neuronal Necrosis. Acute neuronal necrosis (also sometimes referred to as acidophilic or ischemic necrosis) is a common response to a variety of CNS injuries, such as cerebral ischemia, inflammation, bacterial toxins, thermal injury, heavy metals, nutritional deficiencies (e.g., thiamine deficiency), and trauma. Additionally, conditions that reduce ATP generation through oxidative phosphorylation also lead to neuronal degeneration and death. Such conditions include (1) interference with cytochrome oxidase activity in cyanide poisoning, (2) competitive inhibition of oxygen uptake in carbon monoxide poisoning, and (3) inadequate availability of glucose for neuronal metabolism in hypoglycemia. The susceptibility of cells of the CNS to ischemia in decreasing order of susceptibility are neurons, oligodendrocytes, astrocytes, microglia, and endothelial cells. Some neurons are more sensitive to injury than others, a phenomenon called selective neuronal vulnerability. Purkinje cells, some striatal neurons, hippocampal pyramidal cells, and neurons of the third, fifth, and sixth cerebral cortical laminae have the highest vulnerability. A regional vulnerability of neurons has also been reported (cerebral cortex and striatum > thalamus > brainstem > spinal cord). It is hypothesized that the most vulnerable neurons likely produce the most excitotoxins, such as glutamate, and are the most sensitive to them. Because of the microanatomic arrangement of the cerebral cortex, ischemic neurons often occur in a laminar pattern. This microanatomic pattern accounts for the laminar lesions observed in thiamine deficiency–induced polioencephalomalacia in ruminants and in other disorders such as salt poisoning and lead toxicosis. IHC stains for neuronal specific markers often delineate a linear pattern of neuronal necrosis better than that observed with H&E staining. CHAPTER 14 Nervous System A 905 B Figure 14.16 Neuronal Necrosis (Acute), So-Called Ischemic Cell Change, Cerebrum, Dog. A, Neuronal ischemia. Neuronal cell bodies of cerebral cortical laminae are red, angular, and shrunken (arrows), and their nuclei are contracted and dense. This lesion can be caused by neuronal ischemia. Hematoxylin and eosin (H&E) stain. B, Neuronophagia. This necrotic neuron cell body (center of figure) is surrounded and infiltrated by macrophages that will phagocytose the cell debris. H&E stain. (A courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois. B courtesy Dr. M.D. McGavin, College of Veterinary Medicine, University of Tennessee.) After CNS injury, there is an early increase in ATP-dependent release of normally sequestered intracellular calcium ions from altered mitochondria and endoplasmic reticulum. Also, during this time, neuronal depolarization potentiates the release of the excitatory neurotransmitter glutamate. Persistent activation of glutamate receptors of target cells results in a disturbance referred to as excitotoxicity. This altered activity leads to a notable influx of extracellular calcium into cells, causing further impairment of mitochondrial function and the generation of reactive oxygen species such as superoxide, hydrogen peroxide, hydroxyl radicals, and nitric oxide. These reactive oxygen species, exerting their effects especially on lipid-rich cell membranes, can enhance the existing excitotoxicity, cause further influx of calcium into cells as a result of membrane damage, and ultimately result in neuronal dysfunction and death. Additionally, reperfusion of ischemic tissue after the initial ischemic injury can enhance the generation of reactive oxygen metabolites, thus amplifying the tissue damage. Other influencing factors include the temperature of the brain at the time of ischemia, with lower temperatures (as little as 2° C decrease) having a sparing effect and elevated temperatures having an enhanced effect on neuronal injury. Neurons depend on a continuous supply of oxygen to remain viable, and vulnerable neurons will degenerate if the supply is interrupted for several minutes. Ischemic cell change can also result from metabolic disturbances that interfere with oxygen use, including conditions such as thiamine deficiency and cyanide toxicosis. In H&Estained sections, the cytoplasm of the neuronal cell body is shrunken, deeply eosinophilic, and frequently sharply angular to triangular in shape (Fig. 14.16). The nucleus is reduced in size or pyknotic, often triangular, and frequently assumes a central position in the cell. The nucleolus and Nissl substance are usually not detectable. Ischemic neurons die and are removed either by lysis or by a process called neuronophagia, which is phagocytosis by resident microglial cells and recruited macrophages (see Fig. 14.16). After necrosis, the neuronal cell body is replaced by astrocytes and their processes. Chronic Neuronal Loss (Brain Atrophy). Neuronal death and loss of neurons can occur as a result of progressive disease processes of long duration. This loss, termed simple neuronal atrophy, is seen with slowly progressive neurologic disorders, such as cerebral cortical atrophy of aging, ceroid-lipofuscinosis, and various manifestations of selective or multisystem neuronal degeneration. Gross lesions are usually not visible, but when cerebrocortical neurons die, there can be atrophy of cerebral gyri, which results in widening of the sulci (Fig. 14.17). Microscopic lesions include a A B Figure 14.17 Cerebral Cortical Atrophy, Horse. A, Atrophy is seen with a variety of slowly progressive neurologic disorders in which there is a progressive loss of neurons. These disorders include cerebral cortical atrophy of aging and ceroid-lipofuscinosis. The characteristic gross lesions are narrowing of the cerebral gyri with a consequent widening of the sulci. B, Neuronal lipofuscinosis. Lipofuscin (arrows) often accumulates in the cell bodies of neurons from animals with cerebral cortical atrophy of aging and ceroid-lipofuscinosis. Hematoxylin and eosin (H&E) stain. (A courtesy the Department of Veterinary Biosciences, The Ohio State University; B courtesy Dr. M.D. McGavin, College of Veterinary Medicine, University of Tennessee.) 906 SECTION II Pathology of Organ Systems A B Figure 14.18 Wallerian Degeneration, Transverse Section of Spinal Cord, Dog. A, Longitudinal section. Arrows illustrate swollen axons. Hematoxylin and eosin (H&E) stain. B, Transverse section. Laceration and/or severe compression of myelinated axons cause a specific sequence of structural and functional changes in the axon and the myelin distal from the point of injury, referred to as Wallerian degeneration (see E-Fig. 14.5). Axons are initially swollen (arrows) and eventually removed by phagocytosis to leave clear spaces. The cell bodies of affected neurons may exhibit central chromatolysis as they attempt to regenerate the lost portion of the axon (not shown; see Fig. 14.19). H&E stain. (Courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.) diminished number of neurons, astrocytosis, and atrophy and loss of neurons in functionally related systems. Progressively worsening neurologic dysfunction results as the afferent and efferent neurons that directly interact with dead neurons are similarly affected and eventually degenerate. This process of neuronal loss secondary to loss of contact with other neurons is called transneuronal or transsynaptic degeneration. Wallerian Degeneration and Central Chromatolysis. Injury to axons of the CNS and PNS can result from a variety of causes, including traumatic transection leading to Wallerian degeneration, compression and crushing, therapeutic neurectomies, nerve stretching injury, and intoxication. In 1850 Dr. Augustus Volney Waller described the pattern of microscopic lesions in axons and myelin sheaths after transection. These changes are what we now refer to as Wallerian degeneration. Although Waller described this process in peripheral nerves, the term Wallerian degeneration is also used to describe axonal injury in the CNS. Focal damage to an axon results in decreased or halted axonal transport, which manifests most prominently as segmental swellings in the axon called spheroids (Fig. 14.18). Eventually, the myelin sheath dilates, myelin degenerates, and infiltrating macrophages digest the axonal and myelin debris (forming digestion chambers). In the neuronal cell body of the damaged axon, lesions include swelling of the neuronal cell body, peripheral displacement of the nucleus, and dispersion of centrally located Nissl substance (central chromatolysis) (Fig. 14.19). Chromatolytic neurons can also develop in a wide variety of neurologic disorders, including viral infection and degenerative disorders like equine motor neuron disease (EMND). The development of Wallerian degeneration is directly related to the diameter of the axon, with a larger axon undergoing a faster rate of Wallerian degeneration. More information on this topic is available at www.expertconsult. com. Figure 14.19 Central Chromatolysis, Neuron Cell Body, Sheep. Compare with Figs. 14.4, B, and 14.7. Affected neuron has an eccentric nucleus and pale central cytoplasm with peripherally dispersed Nissl substance (arrow). Hematoxylin and eosin (H&E) stain. (Courtesy Dr. A.D. Miller, College of Veterinary Medicine, Cornell University.) Astrocytes Common astrocytic reactions in CNS injury are swelling, hypertrophy, division, and the laying down of intermediate filaments in cell processes. The term astrocytosis means that astrocytes have increased in size and number in response to injury, whereas astrogliosis implies an increased length, complexity, and branching of astrocytic processes. These two terms are sometimes used synonymously and differentiation is generally not necessary because both reactions typically occur in reparative lesions. Swelling is an acute response and is reversible, or it may progress with time to hypertrophy. Swollen astrocytes have clear-staining or CHAPTER 14 Nervous System Wallerian degeneration in the CNS follows the same sequence of events as in peripheral nerve fibers, but the speed of degeneration and phagocytosis is slower, and the capacity of the axon to fully regenerate is limited (E-Fig. 14.5). In addition, an axon of the PNS has the advantage of (1) efficient phagocytosis with removal of debris, (2) Schwann cells to remyelinate the regenerated axon, and (3) an endoneurial tube to guide the axon as it extends into the distal segment. On the other hand, an axon of the CNS has (1) few microglia (sparse in the white matter) to remove myelin debris and (2) oligodendrocytes with a more limited capability to remyelinate axons. In the CNS, severed axons have a very limited ability to regenerate and successfully reinnervate their appropriate sensory or motor structures. In the PNS, if the severed nerves have a large distance between the cut ends, fibrous tissue scarring can prevent the axons from the proximal segment from entering the distal endoneurial tubes and thus prevent the reparative response. The sequence of Wallerian degeneration in the PNS (similar in CNS except for significant regeneration; see previously) includes the following: 1. Degeneration and fragmentation of axon and myelin within several days. The proximal segment degenerates back to the next node of Ranvier, but all of the distal segment dies. 2. Removal of axonal and myelin debris by phagocytosis. Some phagocytes are from the blood, and some phagocytosis is by Schwann cells. All of the debris is cleared out of the endoneurial tube within a few weeks. 3. Regeneration of the axon if the endoneurium is intact to allow the axon of the proximal segment to enter and slide down the tube. 4. Remyelinization by Schwann cells, which often arrange themselves in rows along the endoneurial tube and are termed Büngner’s bands. Microscopically, another early lesion in Wallerian degeneration is central chromatolysis, characterized by swelling of the neuronal cell body, dispersion of centrally located Nissl substance, and peripheral displacement of the nucleus (see Fig. 14.19). The time of onset depends on how much of the axon has been lost and thus on how close to the neuronal cell body the axon has been transected. Onset can begin within 24 to 48 hours and reach its maximum in approximately 18 days after axonal injury. Chromatolysis is indicative of enhanced synthesis of transport and structural proteins required for regeneration of the axon and reestablishment of fast and slow axonal transport systems. The extent to which chromatolysis develops is related to the degree and location of axonal injury. It is more prominent when the injury is close to the cell body, and such injuries can lead to neuronal death. The time required for recovery of cell bodies can be several months, depending on the severity of the axonal injury and the length of axon regenerated. The change in the axon distal to the point of injury is first evident within 24 hours of injury. Wallerian degeneration is initially characterized by irregularity of the axonal diameter, which is followed after 48 to 72 hours by fragmentation of the axon and myelin along its length (see Fig. 14.19). This axonal alteration is followed by disintegration, and usually there is no evidence of the axon remaining by the second week after the injury. Changes in the myelin sheath surrounding myelinated axons are evident by 28 to 96 hours after injury when axonal disintegration is well advanced. Initially there are irregularities in the sheath accompanied by folding, lamellar splitting, fracturing, and fragmentation (secondary demyelination). The fragmented myelin can form droplets (termed ellipsoids), which surround and enclose isolated fragments and debris of the former axon. Both axonal and myelin debris are then removed by macrophages through phagocytosis (forming 906.e1 digestion chambers in regions of necrosis). Degeneration of myelin is usually completed by the end of the second week, although evidence of myelin debris can be detected up to 1 to 3 months after axonal injury (the time required for macrophages in the PNS to phagocytose and clear the debris). Myelin debris can be detected in the CNS for a much longer time after injury. If the neuronal cell body survives the injury to its axon, regeneration from the proximal stump in the PNS can occur. The degree of axonal regeneration depends on the status of the endoneurial tube (sheath) distal to the original point of injury (see E-Fig. 14.5). The normal endoneurial tube (sheath) and its contents consist (from outside inward) of (1) a connective tissue investment referred to as the endoneurium, (2) the basement membrane that surrounds the Schwann cells plus the Schwann cell cytoplasm, (3) the myelin sheath of myelinated axons, and (4) the axon. Approximately 24 to 72 hours after axonal injury, the endoneurial tube (sheath), formed by persisting basement membrane and endoneurium, contains degenerating remnants of the previously existing axon along with Schwann cells. Schwann cells begin to proliferate and eventually form Büngner’s bands. If the endoneurial tube (sheath) remains intact, as can occur after a compression injury to a peripheral nerve, neural regeneration can occur through the formation of axonal sprouts. A regenerating sprout from the proximal axonal stump can enter the column of Schwann cells and regenerate uninterrupted along its original pathway to the periphery, reestablishing innervation with an end organ (skeletal muscle). Such axons then become remyelinated and regain their physiologic function of impulse transmission. Because of axoplasmic flow, a regenerating neuron lengthens at a rate of approximately 1 to 4 mm/day. The time required for axonal regeneration can vary, depending on the length of axon to be regenerated. Examples of times required for morphologic and functional recovery after crush injury of a peripheral nerve are 250 to 300 days and 456 to 486 days, respectively. If, however, the integrity of the endoneurial tube (sheath) is destroyed, as would occur after complete severance of a peripheral nerve, regeneration might not occur because the proximal axonal stump might be prevented from reaching the distal endoneurial tube (sheath) by proliferated fibrous connective tissue (scar formation) at the site of axonal severance. Regenerating axons may also enter inappropriate endoneurial tubes (sheaths), resulting in improper impulse transmission, such as a sensory neuron axonal sprout entering an endoneurial tube intended for a nerve innervating a muscle. The microscopic lesions for Wallerian degeneration within the CNS are similar to those described for the PNS, except that in the CNS, degenerated axons and myelin sheaths can remain for months to years before complete removal. With injury to the CNS, some cell bodies have central chromatolysis, whereas others initially have central chromatolysis followed by atrophy and death. Affected axons and their myelin sheaths undergo a rather characteristic series of changes as they degenerate. Initially, axons form linear and bulbous swellings at and some distance from the site of injury. These enlargements are termed axonal spheroids. Spheroids consist of neurofilaments, microtubules, and cellular organelles. Because injury to the axon results in dysfunction of axoplasmic flow, any disruption of anterograde and retrograde axonal transport results in the accumulation of neurofilaments, microtubules, cellular organelles, and recycled molecules at or near the point of injury. The axonal enlargements can be seen at the site of injury as early as a few hours after injury and remain prominent, particularly for the first week or so (see Fig. 14.19). The surrounding myelin sheath is usually distended to create a space between the sheath and the axonal swelling. Progressively, such affected axons and myelin sheaths Dendrite Muscle Nissl substance Axon hillock Axon Myelin lamella Nucleus Internode Myelinating cell Node of Ranvier Cell body Axon terminal 1 Proximal segment of axon dies back to the node of Ranvier Traumatic injury cuts the nerve Entire distal segment of the axon dies (Wallerian degeneration) Neuromuscular junction Macrophages phagocytose debris 2 Distal axon degenerates Proximal axon degenerates Axon terminals and neuromuscular junctions degenerate Chromatolysis of Nissl substance Swollen cell body 3 Myelinating cells guide the direction of the regenerating axon sprouts back to reinnervate the muscle Axon sprouts 4 Regenerated axon extends back to muscle Nissl substance returns to normal Cell body returns to normal Internodes are shorter Axon terminals and neuromuscular junctions reestablished 5 E-Figure 14.5 Peripheral Nerve Degeneration and Regeneration (Also Applicable to Neurons within the Central Nervous System [CNS]). (Courtesy Dr. A.D. Miller, College of Veterinary Medicine, Cornell University; and Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.) CHAPTER 14 Nervous System fragment along their length, forming ellipsoids as in the PNS. Eventually ellipsoids are removed through degeneration and phagocytosis, leaving an empty space, or one still containing myelin debris and macrophages. The latter lesion is termed a digestion chamber. With time and continued lysis and phagocytosis of the debris, most of the lesion will consist of enlarged empty spaces. The absence of swollen 906.e3 axons in such dilated spaces, especially in the early stages after CNS trauma, does not necessarily mean that the entire axon has degenerated and been removed, which can require several months. It might instead be the site of separation of an enlarged axon from the adjacent axon at the level of the section being examined. CHAPTER 14 Nervous System vacuolated cytoplasm. Astrocytes swell after ischemia because of the increased uptake of sodium, chloride, and potassium ions and water in an effort to maintain homeostasis. It is important to remember that such swelling depends on the astrocyte being viable and still having a semipermeable plasma membrane, even though its function may be altered. If the degree and duration of ischemia are sufficiently severe to result in cell death, the plasma membrane becomes fully permeable, and the cell does not swell but shrinks and undergoes disintegration, as described for the ischemic cell change of neurons. If injury is severe, astrocytic processes fragment and disappear followed by lysis of the cell body. Hypertrophied astrocytes, often referred to as reactive, represent a response to a milder and more protracted injury. Because of increases in intermediate filaments, mainly GFAP, the cytoplasm becomes apparent along with increased length and branching of the processes with H&E staining. The increase of intermediate filaments and the intensity of GFAP IHC staining in these cells are so dramatic that some have defined reactive astrocytes on the basis of this change. These cells have eccentric nuclei and abundant pink homogeneous cytoplasm, in contrast to the lack of visible cytoplasm in normal astrocytes. Reactive astrocytes are also called gemistocytes (Fig. 14.20). Animals with hepatic or renal encephalopathy and with idiopathic hyperammonemia have clusters of enlarged astrocytes with pale nuclei called Alzheimer’s type II astrocytes (see Fig. 14.10, D). Astrocytic proliferation can occur in CNS injury, but in most instances, proliferative capacity is limited. When it occurs, the most dramatic examples are associated with attempts by reactive astrocytes to “wall off” abscesses and neoplasms or to fill in cavitated areas that result after lysis of necrotic neurons with their processes. The astrocytes that form in regions of necrosis are more commonly fibrillary in appearance. In large numbers, they may form a glial scar, which is a network of interlaced astrocytic processes that provides a loose barrier separating the injured brain from the more normal adjacent tissue. In this respect, the astrocytes act to reform a glia limitans around the injured region of the CNS in an effort to restore the blood-brain barrier and reestablish fluid and electrolyte balances. Oligodendrocytes Both perineuronal and interfascicular oligodendrocytes react to injury by cell swelling, hypertrophy, and degeneration. Only oligodendroglia precursor cells can proliferate to replace degenerate cells. The role that satellite oligodendrocytes play in normal neuronal function and neuronal injury has not been definitively clarified. Microscopically, these cells undergo hypertrophy around injured neurons; this response to injury has been called satellitosis, although other glial cells can also contribute to satellitosis (see Fig. 14.10, B). Degeneration of interfascicular oligodendrocytes caused by ischemia, certain viruses, lead toxicity, and autoimmunity can result in selective degeneration of myelin sheaths referred to as primary demyelination. Primary demyelination is the loss of myelin around an intact axon, and this process results in the alteration of the conduction velocity of an action potential down the axon, leading to clinical dysfunction (Fig. 14.21). Mechanisms of primary demyelination are summarized in Box 14.4. Protracted or repetitive injury to myelinating cells and their myelin sheaths can lead to irreversible neuronal atrophy. Interfascicular oligodendrocytes appear to have limited regenerative capacity after injury, but endogenous populations of neural precursor cells (NPCs) and oligodendrocyte precursor cells (OPCs) have the ability to replace damaged oligodendrocytes. The response of these precursor cells is hindered by the inhibitory nature of the postinjury microenvironment, and finding ways to improve this response is an intense area of research. 907 A B Figure 14.20 Gemistocytes (Reactive Astrocytes), Cerebrum, Dog. A, When astrocytes react to injury, initially by hypertrophy and later by the synthesis of increased glial filaments (astrocytosis), the nuclei enlarge and often the cytoplasm, which is not normally visible in hematoxylin and eosin (H&E)-stained sections, will become visible. This type of reactive astrocyte is called a gemistocyte (plump astrocyte) (arrows). They occur in disorders in which there is alteration of intracellular and extracellular fluid balances or injury to the parenchyma, where healing will occur by glial scarring (e.g., astrocytosis to encapsulate a deep abscess or fill in a small area of dead space). H&E stain. B, Gemistocytes (arrows) are identified by immunohistochemical staining (brown color) with antibody to glial fibrillary acid protein. Immunohistochemistry diaminobenzidine (IHC DAB) stain. (A courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois. B courtesy Dr. A.D. Miller, College of Veterinary Medicine, Cornell University.) CNS or PNS injury can also lead to loss of myelin secondary to injury of the axon and its cell body, a process called secondary demyelination. When axons are injured, myelin lamellae forming the internodes are retracted and removed by phagocytosis. In some instances, oligodendrocytes or Schwann cells, the myelin-forming cells in the PNS, also degenerate. Ependymal Cells Responses to injury of ependymal and choroid plexus epithelial cells include atrophy, degeneration, and necrosis. Enlargement of the ventricles, as occurs with hydrocephalus, results in compression and atrophy of ependymal cells. The cilia and microvilli of affected cells are reduced in number, and there is a reduction in cell organelles such as endoplasmic reticulum and mitochondria. Ventricular enlargement can also result in stretching and tearing of the ependymal lining, resulting in exposure of the subependymal neuroparenchyma to the CSF. Mammalian ependymal cells appear to have limited regenerative ability, and astrocytosis generally occurs 908 SECTION II Pathology of Organ Systems Normal axons (spread of action potential down an axon) A Unmyelinated axon (ion exchange continuous conduction) B Myelinated axons (saltatory conduction) Demyelinated axons (spread of action potential down an axon) C Partial demyelination D Complete demyelination Figure 14.21 Axonal Action Potential Conduction and the Effect of Demyelination. The speed of the conduction process is determined by the diameter of the axon and the degree of myelination. As axons increase in diameter, the resistance to ion flow decreases, allowing the action potential to flow faster. In addition, the degree of myelination is directly proportional to the diameter of the axon. Thus, the concept that the more myelin the faster the speed of the impulse is true up to the point in which the myelin is normal in thickness. For an axon whose myelin is reduced, conduction of the action potential is slower. Under normal conditions, locomotion is a well-coordinated event that requires precise timing (speed) of impulse conduction. If the speed of the action potential is altered by disease, especially demyelination, then the conduction of the action potential will be delayed, and what are normally coordinated movements become uncoordinated. A, In unmyelinated axons, action potentials are conducted at a relatively “slower” velocity by the process of ion exchange continuous conduction (see E-Fig. 14.4). B, In myelinated axons, action potentials are conducted at a relatively “faster” velocity by a mechanism called saltatory conduction. Optimal function of saltatory conduction is dependent on having the proper degree of myelination of the axon (as determined by axonal diameter) throughout the full length of the axon. C, In axons that have lost some but not all of their myelin lamellae from one or more internodes, the speed of saltatory conduction is reduced because of leakage of the action potential across this thinner myelin sheath, resulting in clinical dysfunction. D, In axons that have lost all of their myelin from one or more internodes (complete primary demyelination of the internode), the speed of saltatory conduction is reduced because of the conversion from saltatory conduction to ion exchange continuous conduction in the areas where internodes have lost their myelin. Thus, the speed and timing of the action potential is substantially reduced, leading to clinical dysfunction. (Courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.) Box 14.4  Mechanisms of Primary Demyelination 1. Inherited enzyme defects resulting in formation of abnormal myelin Leukodystrophies in human beings and animals 2. Impairment of myelin synthesis and maintenance Infection Mouse hepatitis virus in mice and progressive multifocal leukoencephalopathy in human beings; in both cases, oligodendrocytes are selectively destroyed by viral agents, and myelin cannot be maintained. Nutritional Lack of maintenance of myelin is because of copper deficiency, malnutrition, vitamin B12 deficiency. Toxins Cyanide poisoning Cuprizone toxicity 3. Loss of myelin as a consequence of cytotoxic edema (status spongiosus) Hexachlorophene poisoning, usually prolonged edema 4. Destruction of myelin by detergent-like metabolites Lysolecithin, a metabolite of phospholipase A (normally present in the nervous system) may destroy myelin. 5. Immunologic destruction of myelin Cell mediated Experimental allergic encephalitis Landry-Guillain-Barré (human beings) Coonhound paralysis Marek’s disease (chickens) Various stages of multiple sclerosis in human beings Various stages of canine distemper CHAPTER 14 Nervous System 909 in areas of ependymal loss. Spinal cord ependymal cells have been shown to serve as stem cells capable of forming other glial cell types after CNS injury, especially astrocytes. Inflammation of the ependyma, called ependymitis, can occur after dissemination of an infectious agent, especially bacteria, into the CSF. Infectious agents most commonly gain entrance to the CSF hematogenously via the choroid plexuses, by direct contamination from a rupture of a cerebral abscess into the ventricular system, and by retrograde reflux through the lateral apertures from the subarachnoid space in cases of leptomeningitis. In the case of bacterial infection, the suppurative exudate that forms in the CSF can cause obstructive hydrocephalus. either focally, forming glial nodules (Fig. 14.22), or more diffusely. In concert with astrocytes and neurons, microglia help coordinate inflammatory events in the CNS. Resident microglia and bloodderived macrophages express MHC class I and II antigens, serve as antigen-presenting cells, and possess a broad armament of adhesion molecules, cytokines, and chemokines. Once activated, these cells can also produce nitric oxide, reactive oxygen intermediates, and other chemical mediators of inflammation that can damage the CNS. When tissue necrosis occurs, macrophages derived from blood monocytes accumulate and phagocytize cellular debris. These cells are called gitter cells (Fig. 14.23). Microglia Meninges Microglia are often the first cells in the CNS to react to injury, and the magnitude of the response correlates with the severity of damage. The responses of microglia to injury include hypertrophy, hyperplasia, phagocytosis of cellular and myelin debris, and neuronophagia. After injury, microglia progress through a stage of activation, becoming fully immunocompetent reactive cells. Depending on the nature of the injury, these reactive cells readily proliferate, Figure 14.22 Glial Nodule, Brainstem, Dog. These nodules (right-center of figure), formed by reactive microglial cells and infiltrating macrophages, occur most frequently in viral and protozoal encephalitides. Hematoxylin and eosin (H&E) stain. (Courtesy Dr. M.D. McGavin, College of Veterinary Medicine, University of Tennessee.) A Pathologic processes that initially involve the meninges can secondarily invade the neuroparenchyma. Conversely, processes that primarily affect the neuroparenchyma can secondarily affect the meninges, most commonly the leptomeninges. Meningitis refers to inflammation of the meninges. The term generally refers to inflammation of the leptomeninges (also called leptomeningitis), whereas inflammation restricted to the dura mater is called pachymeningitis. Meningitis can be suppurative, nonsuppurative, or granulomatous, and the inflammatory cells are chiefly in the subarachnoid space. Infectious agents spread to the meninges hematogenously, by direct extension, by leukocytic trafficking, or by retrograde axonal transport. The external periosteal dura can become inflamed secondary to osteomyelitis, extradural abscesses, and skull fractures, and inflammation of the inner dura can occur as an extension of leptomeningitis. Proliferation of cells of the inner dura mater, arachnoid membrane, and pia mater can occur in response to irritation. Additional lesions likely related to aging or degeneration include formation of cellular nests of meningeal cells on the outer surface of the arachnoid membrane, mineralization of the arachnoid membrane, and mineralization or ossification of the spinal dura. Dural ossification in older dogs tends to affect the ventral, cervical, and lumbar dura mater and is most common in large breeds. These lesions are of little clinical significance. Vascular Responses to Injury Because many disease processes are spread through the body via the circulatory system, endothelial cells are subject to a variety of injuries. Bacterial hematogenous CNS diseases often occur at the interface between the white and gray matter in the cerebral hemispheres. This B Figure 14.23 Gitter Cells, Central Nervous System (CNS). A, Cerebrum, early polioencephalomalacia, cow. Note the angular, eosinophilic neurons with pyknotic nuclei (ischemic cell change). Macrophages (arrows) in the perivascular space have been recruited from the circulating monocytes. These cells phagocytose cellular debris from the necrotic neurons and the myelin from the nerve fibers undergoing degeneration after the death of their neurons. Microglia also participate in this phagocytic response. Macrophages that have ingested degenerate myelin or other cellular debris have foamy cytoplasm and are termed gitter cells. Hematoxylin and eosin (H&E) stain. B, Older region of necrosis, spinal cord, dog. The normal parenchyma has liquefied, and the debris has been ingested by gitter cells (arrows), which has resulted in the cytoplasm of these cells becoming foamy. They are now designated as gitter cells or, simply, foamy macrophages. Note the remnants of the viable vascular network scattered throughout the liquefied parenchyma (arrowheads). H&E stain. (A courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois. B courtesy Dr. B.F. Porter, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University.) 910 SECTION II Pathology of Organ Systems A Figure 14.24 Malacia, Vascular Occlusion, Ischemia, Infarction, Cerebrum, Cat. Several red-pink foci (arrows) are areas of ischemic necrosis secondary to vascular occlusion caused by cerebral metastasis of a bronchoalveolar carcinoma. (Courtesy Drs. C.A. Lichtensteiger and R.A. Doty, College of Veterinary Medicine, University of Illinois.) phenomenon is thought to result from abrupt changes in vascular flow or luminal diameter of vessels at the interface. These changes may make endothelial cells more susceptible to injury, vasculitis, and thrombosis or predispose the vessels to entrapment of neoplastic or bacterial emboli. Endothelial injury can be reversible or nonreversible. Injury resulting in endothelial dysfunction can include the activation and release of vasoactive mediators, such as histamine, leading to local and/or systemic changes in vascular flow, pressure, and permeability. Bacterial products and elicited inflammatory cytokines can directly or indirectly cause vasculitis, leading to thrombosis and disseminated intravascular coagulation. Thrombotic meningoencephalitis of cattle caused by the bacterium Histophilus somni is an example of this type of injury (see Fig. 14.91). Certain herpesviruses and protozoa can also infect endothelial cells and cause endothelial necrosis with vasculitis, hemorrhage, and thrombosis. Angioinvasive fungi, such as Aspergillus, directly invade blood vessels, resulting in necrosis of the endothelium. Vasculitis resulting in thrombosis can cause tissue ischemia, infarction, and vasogenic edema of the affected area. A review of endothelial injury can be found in Chapter 2, Vascular Disorders and Thrombosis. Angioinvasive fungi are discussed in Chapter 4, Mechanisms of Microbial Infections. Infarction. Infarction means necrosis of a tissue after reduction of its arterial blood supply (ischemia). The rate at which ischemia occurs in the CNS determines the degree of injury that follows. The more rapid the onset of ischemia, the more severe the lesion. If the obstruction is sudden, as caused by an embolus, many of the neurons can die within minutes and other components within hours (Fig. 14.24). This outcome also applies to compressive injuries that produce a sudden reduction in blood flow, such as the sudden compression that occurs in rapidly occurring Hansen type I disk herniation in the dog. With atherosclerosis and other diseases that cause a gradual reduction in blood flow, there is often sufficient time for anastomotic vessels to dilate and compensate. Anastomoses of the arteries that penetrate from the ventral and cortical surfaces of the brain are insufficient to prevent infarction after sudden occlusion of one B Figure 14.25 Central Nervous System (CNS) Infarct, Brain, Thalamus, Dog. A, The pattern of a focal, sharply demarcated region of yellow discoloration and malacia (softening) (arrow) in the left central thalamus indicates an infarct. Scale bar = 1 cm. B, Macrophages have migrated into the infarct and are phagocytosing myelin and neural cell debris to “clean up” the lesion. Hematoxylin and eosin (H&E) stain. (A courtesy Dr. R. Storts, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University. B courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.) or more of these arteries. With slowly developing, space-occupying conditions like Hansen type II disk herniations and meningiomas, there may be atrophy of the adjacent neural tissue. Cerebral necrosis can result from other causes, including cessation of cerebral circulation caused by cardiac arrest, sudden hypotension caused by reduced cardiac output, and reduced or absent oxygen in inspired air. Additional causes include altered function of hemoglobin as a result of carbon monoxide poisoning, inhibition of tissue respiration after cyanide poisoning, ingesting toxic substances and poisons, and nutritional deficiencies. When an artery supplying the CNS is suddenly occluded, blood supply to cells at the center of the infarcted area is rapidly stopped, resulting in cell death. Neurons at the border of this area continue to receive some blood from unobstructed vessels. It is proposed that the axonal terminals of degenerated ischemic neurons in the center of the infarct release excessive amounts of the neurotransmitter glutamate, causing injury to still viable neurons in the borders, which increases the extent of the infarct. Glutamate binds to receptors on the viable neurons, causing an increase in intracellular calcium ion concentration. This buildup of calcium ions contributes to a multifunctional cascade that leads to neuronal death. When the infarct includes hemorrhage, tissue displacement and pressure-induced mechanical injury can result in additional damage. Although they occur through the same mechanisms, areas of cerebral infarction differ somewhat in gross appearance from infarcts in other tissues (Fig. 14.25). The abundance of lipids and enzymes CHAPTER 14 Nervous System Table 14.1 911 Chronologic Sequence of Changes within Infarcted Tissue (in the Living Animal) after an Ischemic Event Time after Ischemic Event Tissue Change Immediate (seconds) Few minutes 20 minutes 1–2 hours 2 hours 3–5 hours 6–24 hours 8–24 (up to 48) hours 1–2 days 2 days 3–5 days 5–7 days 8–10 days 3 weeks–6 months Cessation of blood flow (ischemia) and accumulation of waste products Cellular injury and death; necrosis and edema; hemorrhage (especially in gray matter) First microscopic evidence of neuronal injury (perfusion-fixation) First microscopic evidence of neuronal injury (immersion-fixation) Pale staining of infarct microscopically (white matter); swelling of capillary endothelium; increase in size of astrocytic nuclei Ischemic cell change in most neurons; swelling of oligodendrocytes and astrocytes; beginning of astrocytic swelling and retraction and fragmentation of processes (clasmatodendrosis) Beginning neutrophilic infiltration; alteration of myelin (pale staining), 8–24 hours; degeneration and decrease of oligodendrocytes, 8–24 hours; clasmatodendrosis and degeneration*; cytoplasm of astrocytes visible, 8–24 hours*; vascular degeneration and fibrin deposition, 8–24 hours; thrombosis,† 6–24 hours; beginning endothelial proliferation at margin of infarct, 9 hours Initial gross detection of infarct unless hemorrhagic; infarct edematous (swollen), soft, pale, or hemorrhagic and demarcated Swelling of axons and myelin sheaths; prominent neutrophilic infiltration Prominent loss of neuroectodermal cells; continued proliferation of endothelial cells; reduced number of neutrophils; beginning increase in mononuclear cells (gitter cells) Prominent number of mononuclear cells (gitter cells); disappearance of neutrophils; continued endothelial cell proliferation; number of capillaries appears increased; beginning of astrocytic proliferation (often at margin of infarct) Grossly, swelling of infarct reaches maximum Reduction in gross swelling of infarct; liquefaction necrosis; prominent number of mononuclear cells (gitter cells); continued endothelial cell proliferation; beginning fibroblastic activity with collagen formation, variable but most prominent in CNS tissue adjacent to the meninges; beginning increase of astroglial fiber production, 5–13 days Mononuclear cells decreased; astroglial fiber density increased (especially at margin); astrocytic proliferation reduced; astrocytes return to original appearance; cystic stage of infarct, 2–4 months; vascular network may be present within cyst; endothelial cell proliferation reduced *The degree of astrocytic injury depends on the location (e.g., central or peripheral) of the cells within the infarct. †Obviously, thrombosis may occur earlier than 6 hours. This is the time when it may initially be prominent. CNS, Central nervous system. in the CNS, as well as the relative lack of fibrous connective tissue stroma, results in the affected areas eventually becoming soft from liquefactive necrosis. The gross appearance of infarction may also differ according to location. Lesions affecting the gray matter tend to be hemorrhagic, whereas infarction of the white matter is often pale. This difference is probably due in part to relatively fewer vascular anastomoses in the white matter, resulting in reduced density of the capillary meshwork. Infarcted tissue goes through a characteristic sequence of changes that can permit a relatively accurate determination of the age of the infarct. An outline of the chronologic events that occur after an ischemic episode that lasts more than 5 to 6 minutes and is followed by resuscitation of an animal is given in Table 14.1. As can be seen, the tissue changes take different periods of time to develop, and these times vary with the extent and duration of the initial ischemic event. After removal of cellular and myelin debris, the infarct is repaired by astrocytes. If the infarct is small (