Combatting the Myth of Neuropathology.

Abstract

The central nervous system (CNS) represents a highly complex immune-privileged organ with compartmentalization, regionspecific peculiarities and properties, as well as unusual cell types. It consists of highly specialized structures in various neuroanatomic regions, including gray and white matter areas, hippocampus, and circumventricular organs. Although gray and white matter can be easily distinguished in some areas, such as cerebrum, cerebellum, and spinal cord, this is not the case in other regions, such as the brainstem. In addition, CNS cells— such as astrocytes, neurons, oligodendrocytes, microglia, cerebellar external germinal cells, progenitor cells, and epiplexus cells—are present at varying quantities during embryogenesis and in the adult CNS as resident cells or during disease. Moreover, cellular plasticity during organogenesis and during disease initiation and progression represents a unique tissue-specific response. Furthermore, reaction patterns of cells—including chromatolysis of neurons, spheroid formation of axons, gemistocytic forms of astrocytes, and gitter cells of microglia/macrophages—will result in modified functions and morphology. This complexity of the CNS, with its neuroanatomic, neuropathologic, and neurologic implications, engenders the ‘‘myth of neuropathology,’’ in which the pathologic investigation of brain diseases is difficult, arcane, and frustrating. However, as with the skin and eye, the tissue-specific terminology should be considered a helpful manual to aid in precise thinking, instead of an insuperable hurdle. Most CNS structures and cell types can be identified with hematoxylin and eosin–stained sections, with assistance from a textbook on neuroanatomy and neuropathology. Factors causing CNS diseases include infectious pathogens, immune-mediated processes, gene defects, and noninfectious environmental factors resulting in inflammatory and degenerative changes. As for other body systems, pathologic evaluation often allows a morphologic diagnosis that, even if not indicating a specific diagnosis, suggests several causes or pathogeneses that form the basis for further investigation. This issue of Veterinary Pathology includes a series of 10 articles on degenerative and inflammatory CNS diseases due to various pathogens and noninfectious factors impressively displaying the plethora and diversity of causes, consequences, and reaction patterns of diseases of the nervous system.* This collection combats the myth of neuropathology by presenting a comprehensive insight into a range of morphologic CNS changes, including their interpretation, diagnosis, pathogenesis, and clinicopathologic correlation. The CNS is exposed to various environmental factors, including dietary imbalances, trauma, infectious pathogens, and toxins, or it may suffer from genetic conditions resulting in acute and chronic lesions. Most frequently, host cell– pathogen interaction is discussed under the assumption of a black-and-white response or, in other words, cell death or survival. However, especially in the CNS, cellular functions may remain impaired despite cell survival. A reduction of cellular ‘‘luxury functions,’’ defined as a loss of key elements that are essential to maintain organ homeostasis, may include reduced myelin production or disturbed axon formation. Although the overall stereotypic reaction pattern in the CNS allows a morphologic diagnosis, in most cases a definitive etiologic or pathogenetic interpretation may await further studies. In this respect, the study by Valberg et al on the pathogenesis of ‘‘shivers,’’ a progressive equine movement disorder, represents an excellent example of a thorough and successful analysis of a well-known but poorly understood disorder by combining neuropathology, immunohistochemistry, transmission microscopy, and neuroanatomy. This well-structured study sheds, for the first time, some light on the underlying mechanisms of this disease by revealing the existence of calretinin-negative, calbindin-positive, and glutamic acid decarboxylase–positive spheroids in Purkinje cell axons. The study by Ogawa et al on canine degenerative myelopathy—a progressive neurodegenerative disease frequently found in Pembroke Welsh Corgi dogs—and its clinical and pathologic similarities to human amyotrophic lateral sclerosis represents another example of modern and innovative neuropathology. The authors investigated abnormalities of autophagy, resulting in cell death through what is called type II programmed cell death, an important mechanism in this neurodegenerative disease. Their detailed study indicates that altered autophagosome degradation may result in LC3 and p62 accumulation in the degenerative myelopathy spinal cord. Both studies