Lesion development in Marburg's type of acute multiple sclerosis: from inflammation to demyelination

Abstract

We report a patient who suffered from acute inflammatory CNS demyelination and underwent two consecutive diagnostic stereotactic brain biopsies during the early disease course. The first lesion was drawn 33 days after the onset of disseminated neurological symptoms. Macrophages and T lymphocytes diffusely infiltrated small vessel walls and the white matter. mRNA for tumor necrosis factor alpha (TNFalpha) and inducible nitric oxide synthase (iNOS) was abundantly expressed. Myelin sheaths were entirely preserved. The second biopsy 76 days later showed confluent demyelinating lesions with a diffuse infiltration of macrophages that were positive for myelin debris, activation markers and TNFalpha and iNOS mRNA. IgG and C9neo deposits were found along myelin sheaths. The patient had received intravenous immunoglobulins (IVIG) prior to biopsy. Findings from this single patient affirm that demyelination follows the migration of inflammatory cells from the circulation into the white matter with subsequent inflammation and demyelination. Inflammation alone may be sufficient to cause significant clinical deficits without demyelination. Inflammatory mediators such as TNFalpha and NO are involved at very early stages in the pathogenetic process. IVIG treatment may lead to the deposition of immunoglobulins and to the activation of the complement cascade, but the clinical relevance of this particular finding remains uncertain.

Multiple Sclerosis: Molecular Mechanisms and Therapeutic Opportunities

“…Similar results were acquired in other studies, reporting that astrocytes and endothelial cells are positive for nitrotyrosine in active lesions (101,275). The authors have proposed that astrocyte-derived NO could be important for orchestrating further processes in MS. An abundant expression of iNOS in macrophages early in the course of the disease and before demyelization was also reported (49). The importance of iNOS expression in MS development is further substantiated by the fact that the injection of arginine [which acts both as an iNOS substrate and an up-regulator of iNOS mRNA (263)] into the rat brain provokes demyelination (248).…”

“…In some cases, such as in aggressive Marburg's type of acute MS, the inflammation develops very fast (49). On the other hand, Lucchinetti et al showed that, within an average of 27 days of potential MS symptom onset, at which point the biopsy samples were taken, around 50% of examined patients showed signs of cortex inflammation and/or demyelination, involving the activity of CD8 + T cells and myelin-laden macrophages.…”

Theiler's Virus Infection: a Model for Multiple Sclerosis

“…TNF-␣ is capable of inducing oligodendrocyte proliferation and remyelination (19,429). In one study where patient biopsy specimens were analyzed at 33 and 76 days after the onset of acute MS (42), it was shown that high TNF-␣ and inducible nitric oxide synthase (iNOS) expression was associated with demyelination (42).…”

Hypoxia-like tissue injury as a component of multiple sclerosis lesions

“…Another effector pathway of inflammation, which may directly impair mitochondrial energy metabolism, is the action of reactive oxygen species (ROS) and nitric oxide intermediates (RNI). In active MS lesions inducible nitric oxide synthase (i-NOS) is highly expressed mainly in macrophages and microglia [43 -45] and deposition of nitrothyrosine, a footprint for peroxynitrite formation, is present [46,47]. RNIs, mainly in cooperation with ROS, may play a prominent role in the pathogenesis of oligodendrocyte injury [48] as well as in functional and structural disturbance of axons [49,50].…”