Wallerian Degeneration and Myelin Loss Secondary to Neuronal and Axonal Degeneration

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1 Chapter 105 Wallerian Degeneration and Myelin Loss Secondary to Neuronal and Axonal Degeneration Introduction There are basically two causes of wallerian degeneration in our definition: neuronal cell death and axonal lesions. It should be noted that our definition is wider than usual and includes not only acute axonal lesions, but neuronal and axonal lesions of any kind. Degeneration of the entire arborization of a neuron with its axon and axonal branches inevitably follows necrosis of the neuronal cell body. Examples are degenerative diseases affecting neuronal cell bodies and axons, such as amyotrophic lateral sclerosis, Friedreich ataxia, olivopontocerebellar atrophy, and neuronal ceroid lipofuscinosis. A lesion of the axon that leads to an interruption of its continuity gives rise to degeneration of the distal part, whereas the proximal portion as a rule survives. The myelin in the distal portion undergoes dissolution as a consequence of the axonal degeneration, as the integrity of the myelin sheaths depends on continued contact with a viable axon. The changes in the distal part of the interrupted nerve are called wallerian degeneration in a narrower sense, following Waller s original description of the changes that he observed after cutting the glossopharyngeal and hypoglossal nerves in the frog in Any lesion of axons that leads to an interruption and any lesion of nerve cell bodies that leads to cell death are followed by wallerian degeneration. In all white matter disorders, wallerian degeneration eventually plays a role, as myelin loss is followed by secondary axonal degeneration, which in turn is followed by wallerian degeneration of the distal parts of the axons and their myelin sheaths. Wallerian degeneration as such cannot be considered a condition that primarily affects myelin. Nevertheless, wallerian degeneration with myelin loss secondary to neuronal and axonal degeneration are discussed here as a component of all disorders and because the MRI appearance may be mistaken for primary white matter affection. This is especially the case when the cortex and the neuronal cell bodies are unaffected. An example is the traumatic shearing of nerve fibers, which may lead to bilateral extensive white matter degeneration, whereas the cortex is remarkably normal Pathology Characteristic of wallerian degeneration is the fact that the sequence and timing of its changes are highly stereotyped. The cascade of events is similar in the PNS and CNS, but much slower in the CNS. Most experimental studies of wallerian degeneration in the CNS have been carried out in the optic nerve, degenerating as a result of enucleation of the eye. Tract degeneration in the dorsal column of animals has also been studied after myelotomy. Human studies mainly concern wallerian degeneration after hemorrhage, stroke, tumors, and traumatic lesions. Abnormalities in axons severed from their neuronal perikarya precede changes in the myelin sheath. There is no spatiotemporal gradient of degradation: abnormalities appear over the whole length of the axons simultaneously. About 8 15 days after the event, the axons have disintegrated, whereas the myelin still appears normal. Most axonal debris disappears from degenerating tracts within about 1 month. In the process of wallerian degeneration, degradation of myelin sheaths becomes apparent after days and the myelin sheaths disintegrate. The breakdown of myelin into simpler lipids does not start until after about 100 days and takes place in the cytoplasm of phagocytic cells. The pivotal process of wallerian degeneration is granular disintegration of the cytoskeleton, in which the normal cytoskeletal elements of the axon, the neurofilaments and microtubules, are abruptly depredated to granular and amorphous debris. This change occurs throughout the distal stump in the first 48 h after dissection. Granular disintegration of the cytoskeleton is the result of the activation of ion-sensitive proteases within the distal stump. A rise in intra-axonal calcium to critical levels initiates the proteolysis of the axoplasm.the reason for the rise in calcium is still unclear. Some evidence suggests that macrophages may also participate in the granular disintegration of the cytoskeleton: anti-macrophagic antibodies appear to delay axonal breakdown. The proteases, however, appear to be intrinsic to the axon. Granular disintegration of the cytoskeleton is associated with loss of the axolemma as well as the axoplasm, so that the myelin sheath surrounds an apparently empty cylinder formerly occupied by the axon. The granular debris still contains some axonal residua, as shown by the ability to stain the degenerating

2 105.4 Pathogenetic Considerations 833 fibers by silver impregnation for long periods after axotomy, and by the staining with some anti-neurofilament antibodies,even in the absence of surviving filamentous organelles. Following granular disintegration of the cytoskeleton, the myelin sheaths lose their regular smooth outline and undergo segmentation into short portions with closed ends, termed ovoids, which break down into smaller globules. The myelin collapses radially upon itself, the lamellae become loose, and the periodicity of myelin is gradually lost. Clearing of the debris is performed by macrophages. Without macrophages there is no efficient clearing. In the PNS this is achieved by circulating macrophages; in the CNS the process is much slower and not completely understood. Electron microscopy reveals the degenerating axons and axonal debris to be surrounded by myelin sheaths, occasionally irregularly folded. The myelin sheaths initially show a regular structure with major and minor dense lines and a periodicity of 105 Å. Splitting of myelin lamellae is noted. The structure of myelin lamellae continues to change with time, developing into uniformly layered structures with a periodicity of Å. At this stage, the myelin degradation products become smaller and are phagocytosed. Unstructured lipid droplets as well as complex lamellar inclusions are typically found in phagocytic cells during the later stages of degeneration. Inclusions of unstructured lipid crystals are sometimes seen. In the final stages, numerous different inclusions are seen. The role of oligodendrocytes in wallerian degeneration in the CNS is not clear. It is probable but not certain that oligodendrocytes do not participate, or participate only to a minor extent. Macrophages, astrocytes, and multipotent glial cells have been observed to contain myelin debris. Histological evidence indicates that wallerian degeneration takes place at different rates depending on a number of variables. The most important factor in determining the course of the wallerian degeneration is whether the axonal or neuronal lesion is acute and monophasic or chronically progressive Chemical Pathology Biochemical analysis of CNS myelin undergoing wallerian degeneration shows a gradual decrease in all myelin constituents but otherwise a remarkable normality in the composition of the remaining myelin. Only an increase in cholesterol esters and a slight decrease of ethanolamine phosphoglycerides have been demonstrated. Neither are any major abnormalities found in the protein constituents. Basic protein is lost from the myelin sheath relatively early in the process of myelin degradation, due to an increase in proteinase activity. This occurs before phagocytosis of myelin by macrophages and astrocytes and results in transformation of myelin sheaths into uniformly layered lipid structures. Cholesterol esters are the major constituents of the lipid droplets and the crystal inclusions of phagocytic cells. The change in biochemical composition of whole white matter depends on the extent of myelin loss. Cholesterol esters are relatively elevated Pathogenetic Considerations Wallerian degeneration entails both breakdown of the axon and clearance of myelin from the distal stump of the transected nerve fibers as described in the previous paragraph. Wallerian degeneration is one of the most prevalent types of cellular pathology in nervous system disease. The pathogenesis of wallerian degeneration depends largely upon the type of initial injury. The time schedule differs according to whether the lesion occurs acutely (as in stroke, intracerebral hemorrhage, and traumatic diffuse axonal injury), more slowly (as in progressive neurodegenerative disorders such as amyotrophic lateral sclerosis, Friedreich ataxia, neuronal ceroid lipofuscinosis, and Alzheimer disease), or is accompanied by an inflammatory reaction (in infectious or inflammatory disease, such as multiple sclerosis and HIV encephalopathy). The isolation of myelin retaining an almost normal protein and lipid composition despite wallerian degeneration as late as 90 days after the injury is consistent with the morphological evidence that in wallerian degeneration in the CNS the breakdown of myelin occurs mainly within the cytoplasm of phagocytic cells. It would seem that the myelin sheath is degraded as a unit, with nonselective digestion of myelin constituents, cholesterol esters being the only residual constituents. A model of four stages of myelin degradation in wallerian degeneration has been proposed (Lassman et al. 1978a, b): 1. The stage of mechanical deterioration of myelin sheaths, showing normal myelin periodicity under the electron microscope. 2. The stage of degradation of digestible proteins, resulting in the transformation of myelin sheaths into uniformly layered structures. 3. The stage of lipid degradation, accompanied by the occurrence of unstructured lipid droplets and crystals in phagocytic cells. 4. The stage of deposition of poorly digestible lipids or lipoproteins, resulting in numerous different electron microscopic inclusion types in phagocytic cells. Resolution of tissue debris and atrophy are the final stage in the process. These four stages are reflected in MRI.

3 834 Chapter 105 Wallerian Degeneration and Myelin Loss Secondary to Neuronal and Axonal Degeneration Fig A patient with subacute meningoencephalitis involving the leptomeninges over the left hemisphere and the cortex in the occipital region. On the T 2 -weighted images (first row) the white matter underneath the affected cortex has a lower signal intensity than the white matter elsewhere.this represents the second stage of wallerian degeneration.the second row shows T 1 -weighted images after contrast with occipital cortical enhancement Magnetic Resonance Imaging In the CNS, wallerian degeneration of long tracts can usually be well depicted. As a multiplanar modality, the MR plane can be chosen to depict the signal changes over their full length. Depending on the location of the primary lesion or lesions, wallerian tract degeneration can be unilateral or bilateral, and, if bilateral, symmetrical or asymmetrical. Normally the long tracts of densely packed white matter have somewhat lower signal intensity on proton density and T 2 -weighted images than the remainder of the white matter. In wallerian degeneration the signal in the tract is lower or higher than usual compared to the normal white matter tracts, depending on the stage of degeneration. In fact MRI can help to distinguish the four stages of wallerian degeneration, each resulting from a rather well-defined phase in the process of degeneration: 1. Physical degeneration of the axon occurs first, with only mild biochemical changes. This happens in the first 2 4 weeks after the incident. This stage is not visible on conventional MR images. 2. The first stage is followed by myelin protein breakdown without myelin lipid breakdown. The resulting material with high lipid content is considered to be hydrophobic, causing low signal intensity on proton density and T 2 -weighted images. This occurs between 4 and 14 weeks after the incident (Fig ). 3. Next, myelin lipid breakdown starts to take place, with gliosis and increased water content, leading to a higher signal intensity of the involved tracts on proton density and T 2 -weighted images (Figs and 105.3). 4. Finally, after a number of months to years, the abnormal tissue constituents are removed and atrophy results (Fig ). Conventional MRI is able to depict stages 2 4. Although there is considerable overlap in time, each phase has been recognized. There is a crossover of contrast between the degenerating tract and the surrounding tissue between stages 2 and 3, fogging the MR depiction of wallerian degeneration. Most attention has been paid to local wallerian degeneration following acute focal lesions and involving single tracts, most often sensorimotor tracts. Acute diffuse wallerian degeneration occurs in cases of diffuse axonal injury, with disruption of corticomedullary connections. The wallerian degeneration leads to diffuse white matter degeneration in the

4 105.5 Magnetic Resonance Imaging 835 Fig The third phase of wallerian degeneration is clearly displayed on these T 2 -weighted images, showing the initial lesion and the corticospinal tracts undergoing wallerian degeneration all the way down into the brain stem. From Waragai et al. (1994), with permission Fig Prototype of wallerian degeneration late in the third phase. The T 2 -weighted image shows a hemorrhagic lesion in the corona radiata on the left.wallerian degeneration is seen in the corticospinal tract with high signal intensity. Atrophy is setting in course of weeks (see Chap. 104). The subcortical and deep white matter have a low density on CT images and remarkably low signal intensity on proton density and T 2 -weighted MR images. This occurs in a phase where protein degradation is most prominent and lipid degradation still absent. In the next phase the involved area shows higher signal intensity on T 2 - weighted and FLAIR images. Finally, atrophy with focal gliosis results. In addition, focal or diffuse, low-grade wallerian degeneration occurs in neurodegenerative disorders with loss of neurons, such as in amyotrophic lateral sclerosis, neuronal ceroid lipofuscinosis, Niemann Pick disease type C, Friedreich ataxia, Alzheimer disease, and in slowly developing inflammatory disorders. Neurons and axons disappear gradually and not all at the same time. That means that stages of wallerian degeneration overlap and that there are no stages to be visualized separately. In these disorders, MRI shows cortical atrophy and often, in addition, a slight to moderate increase of signal intensity in the cerebral hemispheric white matter (Fig ). The changes in normal-appearing white matter in relapsing remitting and secondary progressive forms of multiple sclerosis are probably also, at least in part, the result of wallerian degeneration. Wallerian degeneration has also been reported in the spinal cord, in particular in the posterior columns. This occurs after trauma of the spinal cord or in the course of a myelopathy, either caused by degenerative changes of the vertebral column, or by infectious or inflammatory lesions. From the lesion in the spinal cord wallerian degeneration occurs in two directions: downwards in the motor tracts, and upwards in the sensory tracts. In some degenerative cases there is a gap between the location of the original myelopathic lesions and the wallerian degeneration, the latter becoming visible several segments higher in the afferent tracts. Given time, the parts in between also show signal intensity changes in the affected tracts. To improve the detection of wallerian degeneration on MR, special techniques, such as diffusionweighted imaging and magnetization transfer ratio (MTR) measurements can be used. The most important advantage is that with these techniques changes can be detected in an earlier phase than with conventional MRI. In the first stage of wallerian degenera-

5 836 Chapter 105 Wallerian Degeneration and Myelin Loss Secondary to Neuronal and Axonal Degeneration Fig T 2 -weighted transverse series show a left opercular infarction. In the fourth stage of wallerian degeneration, atrophy results, as is shown in the brain stem (arrows) tion following an acute lesion, diffusion-weighted imaging reveals a decreased apparent diffusion coefficient in the tracts involved in the degenerative process (Figs and 105.7), whereas the MTR in these tracts is increased, and anisotropic diffusionweighted imaging or diffusion tensor imaging reveals loss of anisotropy in the affected tracts. The subsequent changes are more gradual and are progressive over time. From the second stage of wallerian degeneration onwards and continuing in the subsequent stages, the ADC is increased, MTR is decreased, and further loss of anisotropy occurs. Long-term follow-up studies with diffusion tensor imaging in patients with more slowly progressive tract degeneration, such as in amyotrophic lateral sclerosis, show loss of anisotropy, decreased ADC values, and a decreased MTR in the tracts involved. The MTR shows changes in the affected tracts before there are abnormalities in T 2 that lead to signal changes on conventional images (including FLAIR). Follow-up studies show increasingly abnormal values over time. In contrast with wallerian degeneration following an acute incident, there is no transition from one phase of degeneration to the other. MRS allows detection of changes in concentration of N-acetylaspartate in regions with loss of neurons or axons. Follow-up studies with MRS in patients with amyotrophic lateral sclerosis demonstrate that a marked decrease in the N-acetylaspartate/choline ratio is associated with the development of signs of upper motor neuron disease, and may even precede the appearance of pyramidal signs.

6 105.5 Magnetic Resonance Imaging 837 Fig In this 10-year-old boy with Niemann Pick disease type C, wallerian degeneration is seen in the white matter, secondary to cortical neuronal loss. There is a diffuse increase in signal intensity of the cerebral white matter on T 2 -weighted images and loss of distinction between gray and white matter. Note the cerebral atrophy. A combination of atrophy and subtle white matter signal abnormalities is suggestive of primary neuronal or axonal degeneration rather than a primary myelinopathy Fig A 5-week-old female infant with onset of seizures 3 days before the MRI. Neurological examination revealed right arm impairment. MRI reveals a left middle cerebral artery infarction. The images at the level of the midbrain are shown. The T 2 -weighted image (left) reveals no abnormalities. The Trace diffusion-weighted image (middle) reveals a high signal in the left cerebral peduncle, whereas the ADC map (right) reveals a decreased ADC in that area. From Mazumdar et al. (2003), with permission

7 838 Chapter 105 Wallerian Degeneration and Myelin Loss Secondary to Neuronal and Axonal Degeneration Fig A 4-day-old neonate with right middle cerebral artery infarction. The two images in the first row are T 2 -weighted fast spin echo images (left transverse, right coronal). Increased signal intensity is present in the white matter of the right temporal lobe and insular region; the overlying cortex has a high signal in some parts, a low signal in others. A focus of hemorrhage is seen in the corona radiata and putamen.the images show abnormally high signal in the right corticospinal tract (arrowheads). Diffusion-weighted images (second row left transverse, right coronal) show increased signal intensity in the territorial infarct and the right cerebral peduncle (arrowheads). The corresponding ADC maps (third row left transverse, right coronal) show reduced ADC values in the infarcted region and the right cerebral peduncle (arrowheads). Images of the fourth row containing the transverse diffusion-weighted image (left) and corresponding ADC map (right) show involvement of the splenium of the corpus callosum with decreased diffusion. From Mazumdar et al. (2003), with permission