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Neurology. 2013 Oct 1;81(14):1197-204. doi: 10.1212/WNL.0b013e3182a6cb5c. Epub 2013 Aug 30.

Updated estimate of AQP4-IgG serostatus and disability outcome in neuromyelitis optica.

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From the Departments of Laboratory Medicine and Pathology (Y.J., J.P.F., V.A.L., A.M.L.Q., A.M., R.I., S.J.P.), Neurology (V.A.L., A.M., C.C., B.G.W., C.F.L., S.J.P.), Immunology (V.A.L.), and Health Sciences Research (S.M.J., C.Y.S.), College of Medicine, Mayo Clinic, Rochester, MN; Department of Neurology (D.M.W.), College of Medicine, Mayo Clinic, Scottsdale, AZ; and Department of Neurology (E.A.S.), College of Medicine, Mayo Clinic, Jacksonville, FL.



To 1) determine, using contemporary recombinant antigen-based assays, the aquaporin-4 (AQP4)-immunoglobulin G (IgG) detection rate in sequential sera of patients assigned a clinical diagnosis of neuromyelitis optica (NMO) but initially scored negative by tissue-based indirect immunofluorescence (IIF) assay; and 2) evaluate the impact of serostatus on phenotype and outcome.


From Mayo Clinic records (2005-2011), we identified 163 patients with NMO; 110 (67%) were seropositive by IIF and 53 (33%) were scored seronegative. Available stored sera from 49 "seronegative" patients were tested by ELISA, AQP4-transfected cell-based assay, and in-house fluorescence-activated cell sorting assay. Clinical characteristics were compared based on final serostatus.


Thirty of the 49 IIF-negative patients (61%) were reclassified as seropositive, yielding an overall AQP4-IgG seropositivity rate of 88% (i.e., 12% seronegative). The fluorescence-activated cell sorting assay improved the detection rate to 87%, cell-based assay to 84%, and ELISA to 79%. The sex ratio (female to male) was 1:1 for seronegatives and 9:1 for seropositives (p < 0.0001). Simultaneous optic neuritis and transverse myelitis as onset attack type (i.e., within 30 days of each other) occurred in 32% of seronegatives and in 3.6% of seropositives (p < 0.0001). Relapse rate, disability outcome, and other clinical characteristics did not differ significantly.


Serological tests using recombinant AQP4 antigen are significantly more sensitive than tissue-based IIF for detecting AQP4-IgG. Testing should precede immunotherapy; if negative, later-drawn specimens should be tested. AQP4-IgG-seronegative NMO is less frequent than previously reported and is clinically similar to AQP4-IgG-seropositive NMO.

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