Various factors can cause myelin sheath defects, such as myelin loss. This includes secondary myelin sheath loss due to primary axonal destruction (e.g., degenerative diseases), primary myelin sheath destruction (e.g., demyelinating diseases), and simultaneous damage of the fiber itself (e.g., trauma). The myelin sheath largely consists of lipid components; therefore, when it is broken down, macrophages (lipid phagocytes) often infiltrate to digest the debris.
Primary destruction of the myelin sheath is called demyelination in the narrow sense and refers to demyelinating diseases such as multiple sclerosis and leukodystrophy. In the broader sense, secondary myelin sheath destruction is also called demyelination. Because the myelin sheath is primarily destroyed, the axons are relatively preserved. Demyelinated lesions are widespread and may exist in patchy forms; therefore, such lesions are called demyelinated plaques. Furthermore, regeneration of the myelin sheath (remyelination) is sometimes observed in the lesion site. Patchy demyelinated lesions (demyelinated plaque) form in typical demyelinating diseases, including multiple sclerosis, John Cunningham (JC) virus-induced progressive multifocal leukoencephalopathy, and methotrexate leukoencephalopathy, in which encephalopathy develops as a side effect of the anticancer agent methotrexate. In progressive multifocal leukoencephalopathy, demyelinated plaque patches gradually join to form large demyelinated lesions. The boundary of the demyelinated plaque caused by multiple sclerosis is characteristically very distinct. Demyelination, in general, is an unambiguous lesion in which the myelin sheath is destroyed; therefore, the axon tends to be relatively preserved; however, in general, as demyelination progresses, the axons also degenerate.
Myelinolysis refers to iatrogenic myelin sheath destruction as a result of sudden variations in serum electrolytes, in particular, sudden correction of hyponatremia, and it has low affinity for myelin sheath stains. It commonly develops in the pons part of the brainstem and is called central pontine myelinolysis (CPM). In addition, in the event of extrapontine lesion formation, it is referred to as extrapontine myelinolysis. The axons tend to be relatively preserved but break down as the condition progresses.
In leukodystrophy, the myelin sheath is broken down; however, it is thought that this is caused by incomplete formation as opposed to destruction of the myelin sheath. Therefore, dysmyelination should be distinguished from demyelination and myelinolysis, which are acquired.
Hypomyelination refers to poor congenital myelin sheath formation as a result of a brain malformation. For example, myelin sheath formation is poor in sites affected by focal cortical dysplasia or tuberous sclerosis, making the boundary between the white matter and cerebral cortex unclear. However, a brain malformation does not necessarily mean that there is hypoplasia of the myelin sheath, and in many instances, hypermyelination occurs as described below.
In the developmental stage of the nervous system, the myelin sheath systematically forms later than other constituents. Brains affected with a developmental disorder may have delayed or accelerated myelin sheath formation. Furthermore, hypermyelination can occur with tissue damage, e.g., in case of circulatory failure in development, and status marmoratus is characteristically seen on magnified images with myelin sheath staining. Furthermore, malformations have been found to cause aberrant myelin sheath bundles called aberrant fibers. In cerebral malformations such as lissencephaly and polymicrogyria myelin sheath bundles have been found to run parallel to the surface of the cerebrum, which is called superficial hypermyelination. In surgical findings of intractable epilepsy, these findings have been observed and are therefore thought to be a phenotype of microdysgenesis.
Myelin pallor occurs when cerebral deep white matter, particularly the centrum semiovale, shows reduced affinity for myelin sheath stains. In many instances, when reactive changes such as gliosis and macrophage invasion are absent, it is highly likely that there is an artificial change due to poor tissue fixation. Therefore, the term “myelin pallor” should be avoided when describing pathological findings.
