Pathophysiology of NMOSD


Aaron Miller, MD, FAAN, reviews the pathophysiology of neuromyelitis optica spectrum disorder and the role of aquaporin-4 in the disease pathway.

Brian Weinshenker, MD: Dr Miller, we’re going to talk a little bit about NMOSD [neuromyelitis optica spectrum disorder] pathophysiology. Could you tell us a bit about the role of aquaporin-4 in the pathophysiology?

Aaron Miller, MD, FAAN: When aquaporin-4 was first discovered by your former colleague Von De-Linen it wasn’t so clear immediately whether this was pathogenic or if it was just an associated phenomenon. But now it’s become clear that aquaporin-4 is destructive to astrocytes. Aquaporin-4 is the major water channel in the central nervous system, particularly in astrocytes, and especially at the astrocytic footprint. The aquaporin-4 antibody attaches there. It’s an IgG1 [immunoglobulin G1] antibody, which is the most potent fixer of complement that comes in and through the membrane attack complex. There’s destruction of the astrocytic foot process and ultimate destruction of the astrocyte itself. It sounds like MS [multiple sclerosis], which is a disease primarily of myelin and secondary destruction of axons, but this is an astro-psychopathy with secondary destruction of myelin by all the other inflammatory cells that are brought into this picture.

Brian Weinshenker, MD: And another key feature of patients who have neuromyelitis optica spectrum disorder is they often have other autoimmune disease, which happens in about 25% to 35% of patients. And I think there is some recent evidence suggesting that B cells may not be appropriately deleted at various checkpoints.

Aaron Miller, MD, FAAN: Yeah, exactly. So, during the B-cell lineage, there are various checkpoints that stop autoreactive B cells from going on and maturing and exerting their damage. And there seems to be a failure of these checkpoints in the pathologic process in NMOSD.

Transcript edited for clarity

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