The diverse, structurally unrelated chemicals that cause toxic myelinopathies have been investigated and can be categorized into two types of primary demyelinators. Some demyelinating chemicals seem to leave intact the myeli-nating cells (oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system), while others damage the myelinating cells as well as the myelin. The significance between the two is that with the myelinating cells still in tact, repair of the myelin sheath can occur. However, if the myelinating cells are destroyed, repair and reversal of the neuropathy may not occur. Histologically, these chemicals produce an edema of the white matter of the brain, and in some cases the peripheral nervous system, that appears spongy by light microscopy. By electron microscopy, vacuoles can be seen in the myelin surrounding axons. These vacuoles are characterized as fluid-filled separations (splitting) of myelin lamellae at the intraperiod line. In some cases these vacuoles can degenerate further to full demyelination, affecting conduction through those axons. Regeneration of the myelin layers can occur, and in some cases occurs at the same time other axons are undergoing toxic demyelination. Several of these chemicals, however, have been shown to increase cerebrospinal fluid pressure in the brain, optic nerve, and spinal cord, and/or intraneuronal pressure in the perineurium surrounding the axons in the peripheral nervous system. This increased pressure has been correlated with decreased conduction capacity through the axon, ischemia to the neuronal tissue from decreased blood flow because of pressure against the blood vessels, and, if unrelieved, permanent axonal damage. Several of these chemicals havebeen shown to inhibit oxidative phosphorylation, while others uncouple oxidative phosphorylation. One chemical appears to inhibit an enzyme critical to cholesterol synthesis, thus destabilizing myelin. Another hypothesis for a mechanism of action may be in the ability of these compounds to alter membrane permeability.
Utilization in vivo of glucose and volatile fatty acids by sheep brain for the synthesis of acidic amino acids