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NEUROPATHOLOGY FOR MEDICAL STUDENTS Presented by William I. Rosenblum, MD CHAPTER 2: CYTOPATHOLOGY OF THE NEUROGLIA PRETEST: Answers can be found in the text of this chapter or click on link at end of questions
INTRODUCTION There are three types of glia: astrocytes, oligodendroglia and microglia. Astrocytes and oligodendroglia are neuroectodermal derivatives. The astrocyte is the principle cell responding in a non-specific way to injuries of the nervous system. A major function of the oligodendroglia is to produce myelin. Microglia are members of the mononuclear phagocyte system (formerly called Reticulo Endothelial System). There is a fixed population which comes from bone marrow and seed the brain during fetal life. Additional monocytes enter the brain from the blood especially after various destructive insults. Generally the tissue macrophages come from these monocytes. The latter may present antigens. In some situations the fixed population of microglia can become macrophages. In addition to becoming macrophages there are other functions of microglia, e.g., cytokine release, antigen presentation. In the peripheral nervous system there are no glia. There are Schwann cells whose nature was discussed in the chapter on the neuron and its processes . They are mentioned only to remind you that they share one property in common with oligodendroglia, namely the production of myelin. The reactions of astrocytes, described in this chapter, occur over and over again in different disease settings. Thus, after reviewing this chapter, the student should be prepared to approach other chapters dealing with specific disease entities. ASTROCYTES This image illustrates several normal astrocytes stained with a special gold stain named after Cajal. This and other special stains disclose the starfish like processes of the normal astrocyte. Often, as is the case of several astrocytes in this image, the processes attach to very small blood vessels. Until recently it was thought that these foot process attached to capillaries. Now it has been shown that they do not, but attach instead to precapillary arterioles and post capillary venules. These processes are called foot processes or "sucker feet." The latter term implied that the foot processes serve as conduits for substances from the capillary lumen to the brain. In fact, this does NOT occur. Transport is through the capillary walls into the extracellular space. The true capillaries are wrapped by very fine astrocytic processes. The role of these fine wrappings in determining or controlling the passage of materials through the capillary wall or through the tight junctions between capillary endothelial cells is unclear.
If astrocytes do not act as conduits, what do they do? Their known and hypothesized functions are continually being expanded. They include: removal of potassium ion from vicinity of firing neurons; removal of glutamate, the principal excitatory transmitter, from vicinity of firing neurons; metabolism of glutamate to lactate which is then liberated from the astrocyte and may serve as partial energy source for neurons;synthesis of glutamine for transport to neurons which convert it to glutamate; production of diverse cytokines with diverse purposes; release of molecules that signal nearby vessels to express and translate structural and functional proteins required to produce and maintain barriers to proteins and other solutes [i.e. these make up a variety of so-called "blood brain barriers"]; release of dilators and constrictors of arterioles which may help couple the local vascular supply to the demand of nearby neurons. Not all astrocytes have long slender processes. Some, predominantly in grey matter, have shorter processes with more frequent thorn-like side branches. Considerable confusion has arisen because the latter type of astrocyte has been called "protoplasmic" while the former has been called "fibrous." These terms do not refer to the shape of the cell body or its processes. They refer instead to the presence, or relative absence of delicate fibrils within the cell body and processes. These are best seen with a different stain, phosphotungstic acid hematoxylin (PTAH). Normal fibrous astrocytes have large numbers of intracytoplasmic fibrils; normal protoplasmic astrocytes do not. The intracytoplasmic fibrils may represent bundles of intermediate filaments. In any case, such filaments, seen with the electron microscope, are characteristic of normal astrocytes, are more prevalent in fibrous astrocytes, increase in number when astrocytes react to injury, and contain an epitope that is stained by an antibody to glial fibrillary acid protein (GFAP). This antibody labels astrocytic cytoplasm for light microscopy. Now you may wonder why we have emphasized special stains for astrocytes. That is because when astrocytes are normal, their cytoplasm does not stain with ordinary stains like hematoxylin and eosin. Only the nucleus stains, and, in fact, the same is true for the other two types of glia. Thus, the normal astrocyte is recognized on routine stains by its oval, vesicular nucleus, while the oligodendroglia is distinguished by its smaller, more perfectly round, and very darkly staining nucleus. Some of the latter are indicated by arrows on the image shown later in this chapter.. The microglia has a small elongated or cigar-shaped nucleus. Now let us review the features and nomenclature of normal astrocytes: Astrocytes respond dramatically in response to injury of the nervous tissue. Astrocytic reaction is the most important evidence that "something is wrong" with the brain or cord. Astrocytes respond to injury by (1) multiplying, (2) increasing the length of their processes, and (3) changing their staining characteristics so that their cytoplasm, normally unstained by H&E, now becomes eosinophilic. Not all of these changes need occur. When the cytoplasm does become stainable with eosin, the nucleus is often displaced to the periphery and the cell looks plump or fat. Such a cell is often called gemistocytic or a gemistocyte from a German word implying "stuffed" as in after eating.. Do not apply the term protoplasmic to these plump, reactive astrocytes. Remember that the term "protoplasmic" is reserved for normal astrocytes with few intracytoplasmic fibrils. In fact, both protoplasmic astrocytes and fibrous astrocytes can react to tissue injury. When they do so, they both may show an increase in intracytoplasmic fibrils. THE FIGURE BELOW SHOWS REACTIVE ASTROCYTES STAINED WITH H&E. NOTE VESICULAR NUCLEI AND PINK CYTOPLASM. THE PINK MESH BETWEEN CELL BODIES IS REALLY PART OF THE CELL AND REPRESENTS CELL PROCESSES. THE FIGURE SHOWS GOLD STAINED REACTIVE ASTROCYTES WHICH ARE INCREASED IN NUMBER COMPARED TO NORMAL.
THE FIGURE BELOW SHOWS REACTIVE ASTROCYTOSIS WITH THE PTAH STAIN. THE PROCESSES ARE BLUE. This image shows the edge of a so called glial "scar." It is a dense tangle of delicate astrocytic processes stained, in this case, by PTAH. Please remember this so called "scar" does not consist of collagen, and unlike collagen, which is an extracellular material produced by fibroblasts, the glial processes or fibers are cytoplasmic extensions of the cells themselves. Also note that when CNS tissue dies, dense glial scars like that shown here, rarely fill in the resulting defect. Instead, the defect may remain a cyst, or contain only a loose mesh of glial fibers.
In hepatic failure, astrocytes proliferate without developing eosinophilia. Known as Alzheimer Type II astrocytes, they are characterized by irregularly shaped nuclei with exaggerated vesicular appearance. They may reflect the importance of astrocytes in ammonia metabolism. Ammonia is elevated in liver failure and can elicit formation of these astrocytes. OLIGODENDROGLIA Oligodendroglia are glial cells with few processes, hence the prefix "oligo." These processes may wrap around axons to form myelin like the Schwann cell of the peripheral nervous system. Thus, in diseases characterized by myelin loss, there may be a great diminution in the numbers of oligoglia. This will be especially noticeable in white matter as opposed to grey, since in the latter axons and their myelin sheath are normally separated by cell bodies of neighboring neurons and glia, while in the white matter there are no neuronal cell bodies, so that the myelinated axons form compact bundles which normally stain quite intensely.
THE ARROWS POINT TO OLIGODENDROGLIAL NUCLEI. CYTOPLASM REMAINS UNSTAINED WITH H&E
MACROPHAGES AND MICROGLIA The macrophage in the CNS looks like the round, foamy, or vacuolated macrophage found in any organ. In the CNS, the macrophage is sometimes called a "Gitter" cell. In many conditions these macrophages come from circulating monocytes. This is particularly true in destructive lesions of the brain such as traumatic lesions or in infarction. However in some circumstances macrophages may develop from resident microglia. Microglia are "cousins" of the macrophage/monocyte and share some CD sites with them. Microglia can be stained with a special silver stain and with antibodies directed against some lectins. . They arrive in the brain from bone marrow progenitors either during fetal/neonatal life or later. Thus, they represent a resident population of reticulo endothelial (mesenchymal) cells within the CNS. They may present antigen, release cytokines and have other functions identical to that of related RES cells in other organs. Sometimes the microglia simply proliferate and their cell bodies elongate. They are then called "rod cells". One form of tertiary syphillis--so called "general paresis" or "paralysis of the insane"-- is characterized by huge numbers of these rod cells throughout the brain. A few of these rod cells are illustrated in the silver stained image shown below. THE FIGURE SHOWS MICROGLIA STAINED WITH THE HORTEGA STAIN [SILVER CARBONATE]. THESE MICROGLIA HAVE THE ROD-LIKE FORM AND ARE SOMETIMES CALLED ROD CELLS. THEY CAN ALSO BE STAINED WITH A STAIN DIRECTED AGAINST ONE OF THE LECTINS. THE FIGURE BELOW IS A LOW POWER VIEW OF A BRAIN AFFLICTED WITH TERTIARY SYPHILIS AND SHOWS THE HUGE NUMBER OF PROLIFERATING ROD CELLS THAT MAY BE SEEN.
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