Compromised blood-nerve barrier, astrogliosis, and myelin disruption in optic nerves during fatal murine cerebral malaria.

We examined the optic nerve, as an analogous tissue to brain white matter, to assess possible relationships between changes in the blood-nerve barrier, axonal integrity, and astrocyte morphology in the central nervous system during fatal murine cerebral malaria (FMCM). In the FMCM model, namely, CBA mice infected with Plasmodium berghei ANKA, neurological symptoms begin around day 5 post-inoculation (p.i.) and mice become increasingly ill by day 7 p.i., at which time they lapse into coma and die. Using intravascular perfusion with horseradish peroxidase combined with light and electron microscopy, and GFAP immunohistochemistry, the optic nerves in malaria-infected mice were found to display i) breakdown of the blood-nerve barrier, detectable as early as day 3 p.i. (about 2 days before the onset of neurological symptoms) increasing to peak severity by day 7 p.i.; ii) monocytosis, vascular congestion, and monocyte adherence to the endothelium in the microvasculature during the later stages of the disease process; iii) an increased incidence of patchy axonal demyelination and degeneration, mostly associated with vascular changes and astrogliosis, beginning at day 5 p.i. and more evident by day 7 p.i.; and iv) an increased intensity of GFAP immunostaining, detectable from day 3 p.i. and peaking at day 7 p.i. These optic nerve changes were always seen in the infected individuals, though they varied in intensity. The temporal and anatomical coincidence between the compromised blood-nerve barrier, monocyte adherence to the vascular endothelium, astrocyte changes, neuronal degeneration, and demyelination in the optic nerve in FMCM suggests that these factors are mechanistically inter-related. These findings are consistent with the proposed immunopathological nature of FMCM and provide further evidence for the pivotal role of the CNS microvasculature in the disease process. This is the first investigation of involvement of the optic nerve in FMCM and the first demonstration, to our knowledge, of loss of axonal viability in this condition in any CNS tissue. The observed demyelination is consistent with reports by other workers on such changes in the brain in human cerebral malaria.