Extensive remyelination of the CNS leads to functional recovery

Abstract

Remyelination of the CNS in multiple sclerosis is thought to be important to restore conduction and protect axons against degeneration. Yet the role that remyelination plays in clinical recovery of function remains unproven. Here, we show that cats fed an irradiated diet during gestation developed a severe neurologic disease resulting from extensive myelin vacuolation and subsequent demyelination. Despite the severe myelin degeneration, axons remained essentially intact. There was a prompt endogenous response by cells of the oligodendrocyte lineage to the demyelination, with remyelination occurring simultaneously. Cats that were returned to a normal diet recovered slowly so that by 3-4 months they were neurologically normal. Histological examination of the CNS at this point showed extensive remyelination that was especially notable in the optic nerve where almost the entire nerve was remyelinated. Biochemical analysis of the diet and tissues from affected cats showed no dietary deficiencies or toxic accumulations. Thus, although the etiology of this remarkable disease remains unknown, it shows unequivocally that where axons are preserved remyelination is the default pathway in the CNS in nonimmune-mediated demyelinating disease. Most importantly, it confirms the clinical relevance of remyelination and its ability to restore function.

Fig. 1.

Demyelination and remyelination in the spinal cord. During acute disease, extensive changes are seen in the white matter of the spinal cord (A, B, D, and E). In the cervical cord, myelin vacuolation can be seen throughout the lateral and ventral columns (A and B) and on higher power (D). The deeper white matter and dorsal column is less affected (A). Vacuolation of myelin inevitably led to demyelination but with no loss of axons (D). In one myelinated axon, myelin debris is present next to an intact axon (*); other axons can be seen in adjacent fibers undergoing myelin vacuolization. There are numerous scattered remyelinated axons (thin myelin sheaths) and two demyelinated axons (D, arrows). In the dorsal column in a second cat, macrophages filled with myelin debris line the pia above numerous adjacent demyelinated axons. In marked contrast, a cat that had been fed a normal diet for 6 months showed almost complete myelin repair (C and F). Few vacuoles persisted, and the myelinated fiber density appeared normal (C). On higher power (F), it can be seen that many fibers of all diameters were remyelinated with only occasional demyelinated axons remaining (arrow). In 2 cats, although remyelination also was extensive in dorsal columns (G), numerous lipid-filled macrophages persisted adjacent to blood vessels, although many remyelinated axons were also present. There also appeared to be collections of capillaries adjacent to these macrophages (arrow). Toluidine blue. (Scale bars: A, 1.0 mm; B and C, 200 μm; D, 20 μm; E–G, 10 μm.)

Fig. 2.

Changes in the optic nerve during active disease (A–C), during recovery (D–F), and in controls (G–I). The center of the optic nerve (A) shows almost total myelin loss, representative of changes across the entire optic nerve from the subpial area (B) to the center of the nerve (A and C). Few myelinated fibers remain with many demyelinated axons (arrows) and frequent myelin-filled macrophages (B and C). In contrast, the optic nerve in the recovered cat appears to have an almost normal density of myelinated axons (D–F), although practically all myelin sheaths are thin, both subpial (E) and at the center of the nerve (F) compared with the control cat optic nerve (G–I) sampled at the same levels as the affected and recovered cats (A–F). A single fiber with an intact, thick myelin sheath (F, arrow) represents the only axon not remyelinated. Toluidine blue. (Scale bars: A, D, and G, 100 μm; B, C, E, F, H, and I, 10 μm.)

Fig. 3.

Myelin sheath thickness is reduced across the optic nerve. Plot of myelin sheath thickness against axon diameter demonstrates a significant difference at both the periphery and center of the nerve. The regression lines are y = 0.241x + 0.0648 (R² = 0.6926) for normal center; y = 0.2304x + 0.0376 (R² = 0.7428) for normal periphery; y = 0.0851x + 0.1088 (R² = 0.4111) for recovered center; and y = 0.0681x + 0.1096 (R² = 0.6018) for recovered periphery. The differences between wild-type and recovered cat g-ratio in both the center and periphery of the nerve were calculated as significant by the Mann–Whitney rank sum test (P < 0.001).