Large Animal Neurology. Joe Mayhew

and shrinkage are two changes frequently seen in neurons and are reasonably reliable findings if they are present in well‐preserved tissue. Pale, basophilic swelling of the cytoplasm and nucleus is often the earliest observable change in infections, toxicities and hyperthermia, and it might be reversible. When there are excessive numbers of glial cells, notably microglia, surrounding such altered neurons, this is referred to as satellitosis. Where there is actual neuronophagia, then the change is irreversible. Shrinkage of a neuronal soma (cell body) is often seen in hyperthermia, hypoxia, and trauma. The process of shrinkage with loss of Nissl substance, eosinophilic homogenization or chromatolysis of the cytoplasm, and a shrunken, densely basophilic nucleus is referred to as ischemic neuronal cell change. It can be indicative of ischemia, hypoglycemia and other toxic and metabolic insults, and these cells are somewhat simplistically referred to as ischemic neurons. Simple atrophy of CNS neurons with axonal loss is part of the aging process. When chronic, trans‐synaptic atrophy occurs, and is present in many delayed onset, degenerative disorders, or abiotrophies. Neurofibrils in affected atrophic axons undergo shrinkage, hyperchromia, and beading.

      Injury to neuronal processes can be divided functionally and morphologically into three stages. Neurapraxis is the state of loss of function only; axonotmesis is the severance of axons; and neurotmesis is the severance of the entire neuronal fiber, both axon and myelin sheath. In the PNS, degeneration and regeneration occur following interruption of axons. The nerve fiber that is distal to the site of damage disintegrates in 3–4 days, and more slowly the myelin degenerates as ellipsoids and droplets to be phagocytosed. The end plate, or receptor organ, atrophies and disintegrates, and Schwann cells begin proliferation. The nerve fiber proximal to the site of damage disintegrates minimally back toward the cell body, but the cell body shows a reactive change, including central chromatolysis and swelling with margination of the nucleus. Regeneration of several axonal stumps, with budding into proliferated Schwann cell membranes and endoneurial columns, begins within days, with further axonal growth at about 1–4 mm a day. Individual fiber replacement can be complete, but total quantitative nerve function is not. This degenerative and regenerative process was elegantly described in frog glossopharyngeal and hypoglossal nerves after axonotomy in a seminal paper²⁴ by the British physiologist Augustus Volney Waller (1816–1870) at the age of 34 years. The overall pathologic process is referred to as Wallerian or Wallerian‐like degeneration and regeneration, and is now generally applied to injury to both peripheral and central axons due not only to trauma but also to inflammatory, immune‐mediated, and other mechanisms.^25,26

In the CNS, Wallerian‐like degeneration occurs following focal axonal damage, but the regenerative process is markedly curtailed. The mapping of degenerated, distal neuronal fibers following damage is used to help define the site(s) of lesions in the CNS, particularly in the brainstem and spinal cord (see Figure 4.5 for a depiction of spinal cord histologic sectioning that can assist in mapping out the precise site of focal CNS lesions.). Thus, in a pathology report, if degeneration is only described in fibers in sensory (afferent) white matter pathways cranial to C₆, and only in motor (efferent) fibers caudal to C₆, then a focal lesion at C₆ is most likely present. However, if afferent and efferent fiber degeneration is present in the T₁₀ segment, there must be at least one lesion cranial to T₁₀ and one lesion caudal to T₁₀, or diffuse degeneration of neuronal fibers‐QED.

      With many metabolic, toxic, and nutritional insults, axons may undergo degenerative changes that are often recognized as swelling. Such swollen axons, or spheroids, can be prominent in particular nuclear regions where neuroaxonal dystrophy is occurring. This process is common in some nutritional diseases and intoxications, and in certain hereditary disorders; it also occurs during the aging process.

      Accumulation of pigments containing iron and calcium in and especially around neurons and blood vessels may indicate a previous influx of blood pigments to the area. Such pigmentations occur with aging, along with often spectacular intraneuronal accumulation of lipofuscin: the aging or wear and tear pigment. Accumulation of specific lysosomal products is the hallmark of the inherited lysosomal storage diseases as well as a few intoxications mimicking these enzyme deficiencies.

      Axonal swellings (spheroids) and pigment accumulations (mainly lipofuscin) can be prominent in basal nuclear regions, the medulla oblongata, and intermediate zone of spinal gray matter of aged animals. Effete, or worn‐out, cells tend to accumulate at subependymal sites, particularly adjacent to the rostral ventricles. These changes are often accompanied by mineral and iron deposits near vessels in older patients making cautious histopathological interpretation necessary.

       Astrocytes

      Astrocytes that are present in the gray and white matter are a major component of the cytoskeleton framework of the CNS. Their processes, with basal laminae, form part of the blood–brain and blood–CSF barriers, and they appear to act as a guide to migrating neurons during development. They tend to be relatively resistant to noxious stimuli and are associated with reparative processes. The common response to CNS damage is astrocyte hyperplasia and hypertrophy with prominence of their processes—fibrillary astrogliosis. For poorly understood reasons, the repair of larger areas of damaged CNS parenchyma often does not occur, leaving a void that is occupied by CSF‐like fluid surrounded by a lamina of astrocyte processes. Shrinkage and necrosis of astrocytes occurs with the death of other CNS elements during infarction, hemorrhage, and pressure. Astrocytes imbibe tissue fluid after it has leaked into extracellular spaces, and this is an early finding in various edematous states such as trauma, infarction, and vascular disorders. Astrocytes do act as phagocytes but to a lesser degree than resident microglia and invading macrophages. Reactive astrocytes are often found at the periphery of subacute and chronic lesions, surrounding any remaining holes left from larger loss of brain tissue (Figure 4.3). They often show prominent nuclear enlargement and eosinophilic cytoplasmic swelling and are then called gemistocytes.

       Oligodendrocytes

      The oligodendrocyte cell bodies can show hydropic swelling in many edematous states, although the edematous fluid is often quickly transferred to astrocytes and microglial cells. The delicate oligodendrocyte processes, including those producing lipid‐rich, myelin sheaths, are very susceptible to noxious stimuli. With such insults, often the enclosed axons are also damaged, but several immune‐mediated, infectious and toxic insults cause selective disintegration of myelin sheaths with or without oligodendrocyte loss. This way the functionally vital oligodendrocyte/axon relationships are disturbed, and this process is termed demyelination. If such a perturbation occurs prior to the final developmental, perinatal process of myelination, it is termed hypomyelination. Some toxic and inherent disorders of oligodendrocytes result in disturbances of the myelin sheath, which are seen as vacuoles or fluid in the white matter, referred to as status spongiosus. Many of the disorders that affect myelin alone cause asynchrony of axonal conduction due to ephaptic coupling (short‐circuiting), seen clinically as congenital or delayed onset whole body tremor.

Remyelination of demyelinated CNS axons can occur under various conditions but is not consistent. Interestingly, remyelination in the superficial areas of the CNS is just as likely to be performed by resident and immigrant peripheral Schwann cells as by oligodendrocytes.

       Microglia

      These fixed histiocytes or tissue macrophages of the CNS respond quickly to any insult that results in necrosis and tissue debris, which they phagocytose. They thus can hypertrophy into macrophages. During proliferation, these histiocytes may form nodules or stars at sites of damage to CNS parenchyma and may also accumulate in perivascular cuffs along with monocytic and polymorphonucleated inflammatory cells. They are involved with removal of dead neurons in the process of neuronophagia. Focal or diffuse microgliosis often remains for years as the last recognizable change following lesions in the CNS.

      With prominent damage to CNS parenchyma,