Aquaporin-4 antibody-positive cases beyond current diagnostic criteria for NMO spectrum disorders

and National Center for Neurology, Neurosurgery and Psychiatry (Y.I.), Tokyo, Japan.
Neurology (Impact Factor: 8.29). 05/2013; 80(24). DOI: 10.1212/WNL.0b013e318296ea08
Source: PubMed


To analyze aquaporin-4 (AQP4) antibody-positive patients who do not fulfill the current diagnostic criteria of neuromyelitis optica (NMO) and NMO spectrum disorders (NMOSD).

We used a cell-based assay (CBA) with AQP4-transfected cells to detect AQP4 antibody in 298 consecutive patients with inflammatory CNS disorders seen at Tohoku University Hospital from 2007 to 2012. The patients were diagnosed as NMO, NMOSD, multiple sclerosis, or others using the respective current diagnostic criteria. The seropositive samples by CBA were also tested using a commercial ELISA.

Seventy-two patients were AQP4 antibody positive. Among them, 18.1% (13/72) did not meet the NMO or NMOSD criteria (7 with monophasic optic neuritis, 2 with attacks restricted to the brainstem, and 4 with myelitis with less than 3 vertebral segments) and 84.6% (11/13) of these had only a single attack. The ELISA results were negative in 38.4% (5/13) of those patients, and they had lower antibody titers by CBA than patients with NMO/NMOSD. Although these patients had a shorter follow-up and few attacks, they shared some clinical features with NMO/NMOSD patients such as onset age, female predominance, presence of other autoantibodies, severe optic neuritis attacks, centrally located spinal cord lesions, persisting hiccups, and nausea or vomiting episodes.

AQP4 antibody-positive patients with single or recurrent attacks of optic neuritis, myelitis, or brain/brainstem disease not fulfilling the current criteria of NMO or NMOSD may not be uncommon, and they should also be included in the NMO spectrum.

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    • "Additionally , we did no retrieve enough studies to conduct a subgroup analysis for the different peptides used with the CBA (Mader et al., 2010; Pisani et al., 2013; Marignier et al., 2013) technique or the different tissues employed in the TBA (Fazio et al., 2009; Long et al., 2012a). Finally, we should emphasize that the studies included in our meta-analysis were those with patients diagnosed with definitive NMO; studies of patients with neuromyelitis optica spectrum disorder were intentionally excluded (Kang et al., 2012; Sato et al., 2013; S.-H. Kim et al., 2012 , , Kim et al., 2013). "
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    ABSTRACT: Antibodies against water channel protein aquaporin 4 (AQP4) in astrocytes play a role in the etiology and physiopathology of neuromyelitis optica (NMO); detection of this immunoglobulin in serum is highly suggestive of this diagnosis. There are several immunoassays to detect the antibody with different sensitivities and specificities. We conducted a meta-analysis to determine the overall diagnostic accuracy from these tests. We conducted a systematic review in five different electronic databases: Pubmed, Embase, The Cochrane Library, Scopus, Database of Abstracts of Reviews of Effect (DARE) and Lilacs. We included both case control and consecutive enrollment studies that evaluated the performance of the immunoassays in patients with suspected NMO in comparison with the 2006 Wingerchuk diagnostic criteria. Articles were assessed by two different reviewers, who also extracted data. 30 studies for three different immunoassays were included in the meta-analysis. To obtain a summary estimate for the sensitivity and specificity with 95% confidence interval a bivariate random effect model was used. The approximated sensitivity for the cell based assay (CBA), the tissue-based assay (TBA) and the ELISA test were 0.76(95% CI 0.67-0.82), 0.59(95% CI 0.50-0.67), and 0.65(95% CI 0.53-0.75) respectively. The mean specificity of the CBA was 0.99 (95% CI 0.97-0.99), TBA 0.98 (95% CI 0.97-0.99) and ELISA 0.97(95% CI 0.96-0.99). AQP4 detection in serum with immunoassay is a great tool for the diagnosis of patients with NMO, due to the high specificity, allowing the clinician to differentiate this disease from other neurological conditions that resemble NMO. Copyright © 2015 Elsevier B.V. All rights reserved.
    06/2015; 4(4). DOI:10.1016/j.msard.2015.06.003
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    • "However, AQP4 antibody titers in the serum did not correlate with GFAP levels in 1 study,8 and no study has evaluated AQP4 antibody titers in the CSF. In this pilot study, we evaluated AQP4 antibody levels measured directly in the CSF during attacks using our highly sensitive cell-based assay (CBA) for AQP4 antibodies,10 and correlated these levels with astrocyte damage and the cytokine profile. "
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    ABSTRACT: To elucidate immunopathogenetic roles of aquaporin-4 antibodies in the cerebrospinal fluid (CSF) of neuromyelitis optica spectrum disorders (NMOSD), we analyzed aquaporin-4 antibody titers, cellular and inflammatory markers in the CSF collected from eleven aquaporin-4 antibody seropositive patients. The CSF aquaporin-4 antibody levels during attacks (but not in sera) closely correlated with pleocytosis, inflammatory cytokines including interleukin-6 that can regulate antibody-producing plasmablasts, and glial fibrillary acidic protein levels in the CSF. The amount of aquaporin-4 antibodies present in the central nervous system may have therapeutic implications, as it is associated with astrocyte injury and inflammatory responses during NMOSD attacks. ANN NEUROL 2014. © 2014 American Neurological Association
    Annals of Neurology 08/2014; 76(2). DOI:10.1002/ana.24208 · 9.98 Impact Factor
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    • "2) A small number of patients (n = 2, 5.4% of our NMO group), who did not show these clinical features, still showed positive AQP4-Ab assay results (Figure 1). This result is in accord with recent studies evaluating the diagnostic utility of these clinical features [34,35]. Thus, despite the current diagnostic criteria and clinical features of NMOSD [2,3] seeming to be useful, they still appear to require further revisions, especially if they will be applied to Asians. "
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    ABSTRACT: The relative frequencies of demyelinating diseases among Korean patients with idiopathic inflammatory demyelinating disease of the central nervous system (IIDD) have not been sufficiently studied. We therefore describe a cohort of 203 patients with IIDD from three centers in Korea whose syndromes were identified precisely according to international clinical criteria and autoantibody to aquaporin 4 (AQP4-Ab) status. In total, 260 consecutive patients were screened and 203 were included from three hospitals in Korea. All were tested for AQP4-Ab by using a cell-based assay. Patients who met the criteria for definite neuromyelitis optica (NMO) or had a positive AQP4-Ab test result were defined as the NMO group. Among the others, patients were assessed if they had acute disseminated encephalomyelitis, multiple sclerosis (MS), acute transverse myelitis, optic neuritis, or other demyelinating disease as a clinically isolated syndrome of the brain. Eighteen percent of patients were classified as the NMO group, 2% as acute disseminated encephalomyelitis, 18% as MS, 41% as acute transverse myelitis, 11% as optic neuritis, and 8% as other clinically isolated syndrome of the brain. AQP4-Ab was positive in 18% of patients and the relative frequency of NMO to MS (NMO/MS ratio) was 1.06. The mean duration of follow up in our patients was 64 months. Among Korean patients with idiopathic inflammatory demyelinating diseases, the incidence of NMO may be similar to that of MS, and the overall positivity of AQP4-Ab could be lower than previously reported. In addition, acute transverse myelitis that is not associated with MS or NMO can be relatively common in these patients. Further population-based studies with AQP4-Ab are needed to determine the exact incidence of NMO and other idiopathic inflammatory demyelinating diseases in Korea.
    BMC Neurology 04/2014; 14(1):93. DOI:10.1186/1471-2377-14-93 · 2.04 Impact Factor
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