NEUROPATHOLOGY FOR MEDICAL STUDENTS
Presented by William I. Rosenblum, MD
CHAPTER 1 PATHOLOGY OF THE NEURON AND ITS PROCESSES
PRETEST: Answers can be found in the text of this chapter or click on link at end of questions
The cellular elements of the central nervous system are neurons and glia. All of these cells have processes in addition to their cell bodies. The neuronal processes are called axons and dendrites. In the peripheral nervous system, there are no glia. There are Schwann cells which surround the axons and produce myelin in the same manner as the oligodendroglia of the CNS. Interestingly, the Schwann cells also become phagocytes, devouring the debris from injured peripheral nerves, and this property is not shared by the oligodendroglia.
PATHOLOGIC CHANGES IN NEURONAL CELL BODY
The image above is an example of a normal anterior horn nerve cell. The normal anterior horn cell serves as a good illustration of a normal neuron. The nucleus is centrally placed and contains a large, prominent nucleolus. In the cytoplasm, large clumps of blue-black material are seen which represent the prominent aggregates of ribonucleoprotein (RNA). This material is often called Nissl substance, after the man who devised special stains for staining it. One such stain, cresyl violet, has been used in this image.
The image above, with the more routine hematoxylin and eosin stain, also discloses Nissl substance, which is a shade of purple. Although the neurons illustrated in this image are typical of large neurons, please remember that neurons of all sizes exist in the central nervous system.
The image above illustrates central chromatolysis. In response to transection or destruction of the axons, whether by mechanical trauma or by other means, a characteristic change known as central chromatolysis occurs in the neuronal cell body. The nucleus moves to an eccentric position, the Nissl material is visible only peripherally, and the central area of the neuron is free of stainable material. This is a reversible change and electron microscopy shows that the ribonucleoprotein is dispersed rather than aggregated as in the normal neuron. The normal appearance of many neurons, especially in the brain stem, resembles that of central chromatolysis. The reversible movement of RNA within the cell body in response to axonal injury is apparently related to the call on the cell for increased protein synthesis - a demand arising as the cell attempts to regenerate a new axon. Regeneration can be completed in the peripheral nervous system, but is only abortive in the central nervous system. When the demand for increased protein synthesis is ended, the Nissl substance returns to its normal position. When the axon is injured very close to the cell body, or in instances of direct injury to the cell body, whatever the cause, the cell body may be irreversibly damaged and simply disappear. Disappearance is a frequent end result of ischemic and/or anoxic damage. Prior to disappearance, the cell body may show vascular degeneration or become surrounded by or covered by microglial cells (neuronophagia).
The image above is an example of neuronophagia. Neuronophagia is very common after viral infection of the CNS, but its occurrence is not restricted to viral diseases. The stain is H&E so the microglia are represented only by elongate , nuclei stained with hematoxylin.
Viral infection is often accompanied by the presence of inclusion bodies, either within the nucleus or the cytoplasm of the neuron. In this case the patient had rabies and the inclusions are called Negri bodies.Thesel cytoplasmic inclusions are illustrated by the red ovoids as seen in the image above (arrows).
Cytoplasmic inclusions are also characteristic of Parkinson's disease. They are called Lewy bodies. The large pink bodies seen here (image above) are illustrative of this condition. The pink centers of the inclusion bodies contain several substances including synuclein. The latter is a normally found at synapses and its function is unknown.
In storage disease, the neuronal cell body may become tremendously distended by the storage product. Some of the distended cell bodies on the image above are demarcated by arrows. When treated with special silver stains, elongate black neurofibrils can be demonstrated within the normal neurons as illustrated on this image. They extend down the entire length of the axon. The function of the fibrils is not known, but they may represent artifactually clumped tubules which, in turn, (hypothesis), may serve as conduits for the movement of intracellular materials from the cell body, or factory, down the axon to the synapse.
As we age, most of us will develop alterations of neurofibrils in at least some of our neurons. They will become clumped and twisted into odd shapes like tennis rackets or skeins of wool. In Alzheimer-type dementia, tremendous numbers of these neurofibrillary tangles are seen. In this image, arrows point to a neuron filled with such a tangle. Perhaps this leads to interruption of transport down the axon and this in turn is related to deteriorating intellectual function.
At the same time, the dendrites may degenerate to produce oval, haystack-like masses of silver-stained (argyrophilic) fibers. These masses are known as senile plaques or neuritic plaques, the adjective signifying the fact that the plaque is composed of degenerated "neurites".Another change accompanying aging is an increase in the amount of yellow-brown lipofuscin pigment in the neuronal cytoplasm.In addition to lipofuscin, some neurons contain neuromelanin. This material is an end product of catecholamine metabolism and is found in the neurons of the substantia nigra (images below), imparting a black appearance to this structure when seen in a sliced midbrain and presenting as dark brown granules in the neurons observed under the microscope.
IThe neurons of the substantia nigra degenerate and disappear in Parkinson's disease. Their pigment is phagocytosed by macrophages which carry it away. The substantia nigra then becomes pale, a morphologic tombstone representing a disease with disrupted catecholamine synthesis.
PATHOLOGIC CHANGES IN AXON
We will now progress to a discussion of injuries involving the extension of the cell body known as the axon. When the axon is severed or irreversibly injured, all of the axon degenerates distal to the site of injury. The entire axon degenerates at once, as does its myelin sheath. This form of degeneration is called Wallerian degeneration, after Waller, the man who first described it. Axonal injury is readily manifest by special silver stains and is indicated by axonal swelling, disintegration, and finally, disappearance. Myelin stains reveal degeneration and then loss of myelin all along the affected axon. Wallerian degeneration can occur in either the central nervous system or in the peripheral nerves. During the process of myelin degeneration in peripheral nerves, phagocytes engulf the myelin debris. Most of these phagocytes come from monocytes; some come from Schwann cells. You will remember that the Schwann cell is also the cell which has wrapped around the axon of the peripheral nerve to form the myelin. The analagous cell of the central nervous system is the oligodendroglia. Unlike the Schwann cell, the oligo does not become a phagocyte when myelin breaks down. Instead, in the central nervous system, phagocytosis of myelin debris is performed by mesodermal elements, like monocytes entering from the blood. In the peripheral nervous system, axons can successfully regenerate after Wallerian degeneration. In the CNS, regenerative sprouts may appear but will fail to continue growth and/or to make renewed functional connections with their original targets.
When Wallerian degeneration occurs in a large number of axons, running together in a compact "tract," tract degeneration is readily demonstrated on myelin stains. The image above displays a spinal cord stained with Luxol fast blue. Pallor of the lateral columns (pyramidal tracts) indicates lack of myelin in these columns or tracts. Wallerian degeneration has occurred.
In addition to Wallerian degeneration axons may undergo a different kind of breakdown. This is called "distal axonopathy" or "dying back". Here, for unknown reasons, the portions of the axon farthest from the cell body begin to die first. Then death proceeds up the axon, toward the cell body. The myelin will also degenerate along the affected segments of the axon. The changes occur in patchy fashion. They may be seen in the central nervous system or in the peripheral nervous syste. In the latter several metabolic diseases may cause dying back.