Neuromyelitis optica and the evolving spectrum of autoimmune aquaporin‐4 channelopathies

Abstract

Water channels are a recognized "novel" target for central nervous system, inflammatory, autoimmune, demyelinating diseases, and represent an evolving spectrum of disorders termed neuromyelitis optica (NMO) spectrum disorders (SD). These disorders should now be considered under the umbrella term "autoimmune aquaporin-4 channelopathy". NMOSD represent the first multiple sclerosis (MS)-like disease for which a specific antigen has been identifiedthe astrocytic water channel aquaporin-4 (AQP4). MS lacks a distinguishing biomarker. This discovery represents a seismic shift from historic emphasis on the oligodendrocyte and myelin to the astrocyte. The NMO of today represents a relapsing spectrum of disease, not necessarily restricted to the optic nerves and spinal cord, that is different from the monophasic disorder in which near simultaneous bilateral optic neuritis and transverse myelitis occur, as was originally described by Devic. Recent clinical, radiological and pathological findings have documented brain involvement in NMO spectrum disorders, particularly in children. Most patients with NMOSD have brain abnormalities on magnetic resonance imaging, and these are consistent with MS in up to 10% of patients. Others have lesions in areas that highly express AQP4 including the circumventricular organs accounting for intractable nausea and vomiting, and the syndrome of inappropriate antidiuresis as presenting symptoms or heralds of relapse. Diencephalic involvement might explain recently recognized sleep disorders and endocrinopathies. Continued progress in our understanding of the immunobiology of AQP4 autoimmunity necessitates continuing revision of the clinical diagnostic criteria for NMO spectrum disorders. As the clinical spectrum broadens, the importance of highly specific assays that detect pathogenic AQP4-immunoglobulin G targeting extracellular epitopes of AQP4 cannot be overemphasized. (Clin. Exp. Neuroimmunol.

Neuromyelitis optica and the evolving spectrum of autoimmune aquaporin‐4 channelopathies: a decade later

“…11 This is supported by a significant difference in the prevalence of AQP4-IgG in relapsing (>9 0%) versus monophasic (<10%) disease. 11 We suspect that the duration of follow-up may not be long enough to accurately define monophasic in most published reports.…”

“…11 This is supported by a significant difference in the prevalence of AQP4-IgG in relapsing (>90%) versus monophasic (<10%) disease. 11 We suspect that the duration of follow-up may not be long enough to accurately define monophasic in most published reports. This is supported by a single case of AQP4-IgG-seropositive monophasic NMO (representing 12.5% of monophasic cases) reported by Banwell et al in 2008 who had a relapse subsequent to that publication (unpublished personal communications, Silvia Tenenbaum), thus indicating a 0% frequency of AQP4-IgG in monophasic pediatric NMO for that study.…”

“…11 NMOSDs encompass a broadening clinical spectrum and include NMO but also partial forms, such as longitudinally extensive transverse myelitis (LETM) and recurrent uni- or bilateral optic neuritis (Fig. 1).…”

“…9 Since then, a combination of clinical, pathological, radiological, and serological observations have clearly distinguished NMO and its partial or inaugural forms (constituting a spectrum of NMO-related disorders, NMO spectrum disorder (NMOSD)) from classical MS, for which no specific biomarkers are recognized. 10,11 The detection of AQP4-IgG predicts relapses with cumulative attack-related neurological disability, and justifies prompt initiation of immunosuppressive therapy. [12][13][14] AQP4 is highly expressed in astrocytic end feet at the blood-brain barrier, surrounding CNS synapses and nodes of Ranvier, and in areas involved in osmosensitivity and osmoregulation, including supraoptic and paraventricular nuclei of the hypothalamus and circumventricular organs (e.g., the subfornical organ, the organum vasculosum of the lamina terminalis, and the area postrema).…”

“…While a patient may be diagnosed clinically with NMO in the absence of AQP4-IgG positivity, 18 we consider NMOSD to be defined by the presence of AQP4-IgG. 11 NMOSDs encompass a broadening clinical spectrum and include NMO but also partial forms, such as longitudinally extensive transverse myelitis (LETM) and recurrent uni-or bilateral ON ( Fig. 1).…”