Posterior reversible encephalopathy syndrome in neuromyelitis optica spectrum disorders

Magaña, Setty M.; Matiello, Marcelo; Pittock, Sean J.; McKeon, Andrew; Lennon, Vanda A.; Rabinstein, Alejandro A.; Shuster, Elizabeth A.; Kantarci, Orhun H.; Lucchinetti, Claudia F.; Weinshenker, Brian G.

doi:10.1212/01.wnl.0000343001.36493.ae

Cited by 188 publications

(136 citation statements)

References 29 publications

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“…When complement is unavailable or inactivated by complement-regulatory proteins, the major anticipated pathophysiological outcome would be disruption of water homeostasis either by direct blockade of water flux and by AQP4 internalization. NMO-characteristic periventricular abnormalities that rapidly reverse with high-dose corticosteroid therapy have been documented by magnetic resonance imaging and are attributed to tissue water accumulation (21,22). The striking parenchymal edema that we observed in NMO histopathological lesions is consistent with these interpretations.…”

Section: Discussionsupporting

confidence: 88%

Molecular outcomes of neuromyelitis optica (NMO)-IgG binding to aquaporin-4 in astrocytes

Hinson¹,

Romero²,

Popescu³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

291

274

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The astrocytic aquaporin-4 (AQP4) water channel is the target of pathogenic antibodies in a spectrum of relapsing autoimmune inflammatory central nervous system disorders of varying severity that is unified by detection of the serum biomarker neuromyelitis optica (NMO)-IgG. Neuromyelitis optica is the most severe of these disorders. The two major AQP4 isoforms, M1 and M23, have identical extracellular residues. This report identifies two novel properties of NMO-IgG as determinants of pathogenicity. First, the binding of NMO-IgG to the ectodomain of astrocytic AQP4 has isoform-specific outcomes. M1 is completely internalized, but M23 resists internalization and is aggregated into larger-order orthogonal arrays of particles that activate complement more effectively than M1 when bound by NMO-IgG. Second, NMO-IgG binding to either isoform impairs water flux directly, independently of antigen down-regulation. We identified, in nondestructive central nervous system lesions of two NMO patients, two previously unappreciated histopathological correlates supporting the clinical relevance of our in vitro findings: (i) reactive astrocytes with persistent foci of surface AQP4 and (ii) vacuolation in adjacent myelin consistent with edema. The multiple molecular outcomes identified as a consequence of NMO-IgG interaction with AQP4 plausibly account for the diverse pathological features of NMO: edema, inflammation, demyelination, and necrosis. Differences in the nature and anatomical distribution of NMO lesions, and in the clinical and imaging manifestations of disease documented in pediatric and adult patients, may be influenced by regional and maturational differences in the ratio of M1 to M23 proteins in astrocytic membranes.T he most abundant water channel in the central nervous system (CNS) is aquaporin-4 (AQP4), which is confined to astrocytes and ependyma; is enriched at glial-pial and glialendothelial interfaces; and surrounds nodes of Ranvier and paranodes, adjacent oligodendroglial loops, and synapses (1). In 2005, we identified AQP4 as the target of pathogenic autoantibodies in a spectrum of inflammatory CNS disorders of varying severity that is unified by detection of the serum biomarker neuromyelitis optica (NMO)-IgG (2, 3). These disorders are now recognized collectively as IgG-mediated autoimmune astrocytopathies. Before discovery of this antibody, NMO spectrum disorders were misclassified as multiple sclerosis variants. NMOIgG is centrally involved in the pathogenesis of NMO spectrum disorders. Its detection predicts frequent relapses that cause cumulative neurological impairment. Lesions characteristically affect the spinal cord and optic nerve, but do not spare the brain. Independent laboratories have demonstrated that NMO-IgG binding initiates AQP4 down-regulation with accompanying endocytosis of its physically associated glutamate transporter, EAAT2, complement activation, impairment of blood-brain barrier integrity, inflammation, and astrocyte injury (4-8). Demyelination is a proposed consequence of both pa...

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Section: Discussionsupporting

confidence: 88%

Molecular outcomes of neuromyelitis optica (NMO)-IgG binding to aquaporin-4 in astrocytes

Hinson¹,

Romero²,

Popescu³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

291

274

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show abstract

“…There are some descriptions of the association of PRES with neuromyelitis optica spectrum disorders (NMOSD) 8 , and also linking NMOSD and SLE. Therefore we tested our patient for the aquaporin-4 specific antibodies, which were negative.…”

Section: Rheumatologymentioning

confidence: 99%

Atypical Posterior Reversible Encephalopathy Syndrome: A Flare of Systemic Lupus Erythematosus: Figure 1.

Monteiro¹,

Almeida²,

Dias³

et al. 2012

J Rheumatol

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“…Aquaporin-4 autoimmunity is considered to predispose to PRES in neuromyelitis optica 7 . Reports of PRES in normotensive patients with thrombotic thrombocytopenic purpura with severe renal involvement also point to endothelial dysfunction and altered cerebral autoregulation.…”

Section: To the Editormentioning

confidence: 99%

Dr. Varaprasad and Dr. Agrawal reply

Varaprasad¹,

Agrawal²

2012

J Rheumatol

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Posterior reversible encephalopathy syndrome in neuromyelitis optica spectrum disorders

Cited by 188 publications

References 29 publications

Molecular outcomes of neuromyelitis optica (NMO)-IgG binding to aquaporin-4 in astrocytes

Molecular outcomes of neuromyelitis optica (NMO)-IgG binding to aquaporin-4 in astrocytes

Atypical Posterior Reversible Encephalopathy Syndrome: A Flare of Systemic Lupus Erythematosus: Figure 1.

Dr. Varaprasad and Dr. Agrawal reply

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