Autoimmune Aquaporin-4 Myopathy in Neuromyelitis Optica Spectrum

Guo, Yuxin; Lennon, Vanda A.; Popescu, Bogdan F. Gh.; Grouse, Carrie; Topel, Jordan L.; Milone, Margherita; Lassmann, Hans; Parisi, Joseph E.; Pittock, Sean J.; Stefoski, Dusan; Balabanov, Roumen; Lucchinetti, Claudia F.

doi:10.1001/jamaneurol.2014.775

Cited by 61 publications

(41 citation statements)

References 15 publications

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“…Thus, while NMO is certainly a primary astrocytopathy, the disease also has an important component of an “AQP4-opathy” that involves antibody-mediated injury to other CNS cell types that express the water channel. As with our previous report demonstrating that sarcolemmal AQP4 is a target of IgG in patients with NMO [19], these observations further expand the cellular repertoire of NMO IgG targets beyond the archetypal astrocyte.…”

Section: Discussionsupporting

confidence: 87%

Pathogenic implications of cerebrospinal fluid barrier pathology in neuromyelitis optica

et al. 2017

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Pathogenic autoantibodies associated with neuromyelitis optica (NMO) induce disease by targeting aquaporin-4 (AQP4) water channels enriched on astrocytic endfeet at blood–brain interfaces. AQP4 is also expressed at cerebrospinal fluid (CSF)–brain interfaces, such as the pial glia limitans and the ependyma and at the choroid plexus blood–CSF barrier. However, little is known regarding pathology at these sites in NMO. Therefore, we evaluated AQP4 expression, microglial reactivity, and complement deposition at pial and ependymal surfaces and in the fourth ventricle choroid plexus in 23 autopsy cases with clinically and/or pathologically confirmed NMO or NMO spectrum disorder. These findings were compared to five cases with multiple sclerosis, five cases of choroid plexus papilloma, and five control cases without central nervous system disease. In the NMO cases, AQP4 immunoreactivity was reduced relative to control levels in the pia (91%; 21/23), ependyma (56%; 9/16), and choroid plexus epithelium (100%; 12/12). AQP4 immunoreactivity was normal in MS cases in these regions. Compared to MS, NMO cases also showed a focal pattern of pial and ependymal complement deposition and more pronounced microglial reactivity. In addition, AQP4 loss, microglial reactivity, and complement deposition colocalized along the pia and ependyma only in NMO cases. Within the choroid plexus, AQP4 loss was coincident with C9neo immunoreactivity on epithelial cell membranes only in NMO cases. These observations demonstrate that NMO immunopathology extends beyond perivascular astrocytic foot processes to include the pia, ependyma, and choroid plexus, suggesting that NMO IgG-induced pathological alterations at CSF–brain and blood–CSF interfaces may contribute to the occurrence of ventriculitis, leptomeningitis, and hydrocephalus observed among NMO patients. Moreover, disruption of the blood–CSF barrier induced by binding of NMO IgG to AQP4 on the basolateral surface of choroid plexus epithelial cells may provide a unique portal for entry of the pathogenic antibody into the central nervous system.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-017-1682-1) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 87%

Pathogenic implications of cerebrospinal fluid barrier pathology in neuromyelitis optica

et al. 2017

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“…The binding of AQP4-ab to AQP4 on the sarcolemma of muscle fibers can lead to muscle injury and leakage of creatine kinase by complement-mediated cytotoxicity. [21, 22] However, myopathy or muscle fatigue during the disease course was not observed in our patients. More interestingly, both muscular fatigue and central fatigue exist after spinal cord injury, as in post-polio syndrome.…”

Section: Discussionmentioning

confidence: 58%

Fatigue in patients with neuromyelitis optica spectrum disorder and its impact on quality of life

et al. 2017

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Fatigue is a prevalent symptom and major burden in neuroimmunological diseases. In neuromyelitis optica spectrum disorder (NMOSD), a severe autoimmune central nervous system (CNS) inflammatory disease with autoantibodies reactive to aquaporin-4, there are few reports about fatigue and quality of life (QOL). We aimed to evaluate the severity of fatigue and its relationship with QOL in patients with NMOSD. We prospectively studied patients with NMOSD who were in remission and seropositive for anti-aquaporin-4 antibody, and they were divided into 2 groups based on the presence of fatigue assessed using the Functional Assessment of Chronic Illness Therapy-fatigue score. Sleep quality, depression, pain, and QOL were also evaluated. A total of 35 patients were enrolled (mean age, 46.5 ± 14.1 years; female: male = 29:6), and the median Expanded Disability Status Scale (EDSS) score was 2.0 (range, 0 to 8.0). The patients with fatigue (N = 25, 71.4%) had poorer sleep quality and more severe depression than those without fatigue (p = 0.009 and p = 0.001). Both the physical and mental QOL scores were lower in patients with fatigue than in those without fatigue (p = 0.033 and p = 0.004). Multiple linear regression analyses showed that the degree of fatigue with EDSS score and pain were independent predictors of physical aspects of QOL (B = 0.382, p = 0.001), whereas depression was the only predictor of the mental components of QOL (B = -0.845, p = <0.001). Fatigue is a common symptom and an important predictor of QOL in patients with NMOSD.

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“…9 A recent mouse passive transfer study showed that intraperitoneal injection of both AQP4-IgG and human complement resulted in placental inflammation with increased fetal death, 10 reproducing key histologic features seen in NMO lesions of the CNS, as well as in placental lesions in a case report of a miscarriage at 20 weeks in a patient with NMO. 8 This adds to the growing clinical 8,21,22 and experimental 10,23 evidence of AQP4-IgG-mediated organ involvement beyond the CNS.…”

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Pregnancy outcomes in aquaporin-4–positive neuromyelitis optica spectrum disorder

et al. 2016

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Objective: To investigate the association between neuromyelitis optica spectrum disorder (NMOSD) and pregnancy outcome.Methods: An international cohort of women with aquaporin-4 antibody-positive NMOSD and $1 pregnancy was studied retrospectively. Multivariate logistic regression was used to investigate whether pregnancy after NMOSD onset was associated with an increased risk of miscarriage (cohort of 40 women) or preeclampsia (cohort of 57 women).Results: Miscarriage rate was higher in pregnancies after NMOSD onset (42.9% [95% confidence interval 17.7%-71.1%] vs 7.04% [2.33%-15.7%]). Pregnancies conceived after, or up to 3 years before, NMOSD onset had an increased odds ratio of miscarriage (7.28 [1.03-51.6] and 11.6 [1. , respectively), independent of maternal age or history of miscarriage. Pregnancies after, or up to 1 year before, NMOSD onset ending in miscarriage were associated with increased disease activity from 9 months before conception to the end of pregnancy, compared to viable pregnancies (mean annualized relapse rate 0.707 vs 0.100). The preeclampsia rate (11.5% [6.27%-18.9%]) was significantly higher than reported in population studies. The odds of preeclampsia were greater in women with multiple other autoimmune disorders or miscarriage in the most recent previous pregnancy, but NMOSD onset was not a risk factor.Conclusions: Pregnancy after NMOSD onset is an independent risk factor for miscarriage, and pregnancies conceived at times of high disease activity may be at increased risk of miscarriage. Women who develop NMOSD and have multiple other autoimmune disorders have greater odds of preeclampsia, independent of NMOSD onset timing. Neurology ® 2016;86:79-87 GLOSSARY AQP4 5 aquaporin-4; ARR 5 annualized relapse rate; CI 5 confidence interval; IgG 5 immunoglobulin G; NMO 5 neuromyelitis optica; NMOSD 5 neuromyelitis optica spectrum disorder; ON 5 optic neuritis; OR 5 odds ratio.Neuromyelitis optica spectrum disorder (NMOSD) is a severe recurrent antibody-mediated inflammatory disorder of the CNS, mainly characterized by optic neuritis (ON) and longitudinally extensive transverse myelitis, 1 but also affecting other areas in the CNS (e.g., brainstem and hypothalamus). The presence of immunoglobulin G (IgG) that binds to aquaporin-4 (AQP4), 2,3 known to be key in the pathogenic process of this disorder, distinguishes NMOSD from other CNS inflammatory disorders.1 NMOSD is up to 8 times more prevalent in women, 4 many of whom have active disease during childbearing years. [5][6][7] Recently, experimental and clinical reports have demonstrated the presence of AQP4 in human and animal placenta, and have linked AQP4-mediated placental inflammation to fetal death. [8][9][10] It is clear that the annualized relapse rate (ARR) of NMOSD is significantly increased in the 0-to 3-month postpartum period, 11-13 but there is a lack of information on the influence of NMOSD on the course of pregnancy.We investigated the effect of NMOSD on miscarriage and preeclampsia rates using multivariate logistic regre...

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Autoimmune Aquaporin-4 Myopathy in Neuromyelitis Optica Spectrum

Cited by 61 publications

References 15 publications

Pathogenic implications of cerebrospinal fluid barrier pathology in neuromyelitis optica

Pathogenic implications of cerebrospinal fluid barrier pathology in neuromyelitis optica

Fatigue in patients with neuromyelitis optica spectrum disorder and its impact on quality of life

Pregnancy outcomes in aquaporin-4–positive neuromyelitis optica spectrum disorder

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