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Original Investigation |

Aquaporin 4 IgG Serostatus and Outcome in Recurrent Longitudinally Extensive Transverse Myelitis

Yujuan Jiao, MD1; James P. Fryer, MS1; Vanda A. Lennon, MD, PhD1,2,3; Andrew McKeon, MD1,2; Sarah M. Jenkins, MS4; Carin Y. Smith, BS4; Amy M. L. Quek, MBBS1; Brian G. Weinshenker, MD2; Dean M. Wingerchuk, MD5; Elizabeth A. Shuster, MD6; Claudia F. Lucchinetti, MD2; Sean J. Pittock, MD1,2
[+] Author Affiliations
1Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
2Department of Neurology, Mayo Clinic, Rochester, Minnesota
3Department of Immunology, Mayo Clinic, Rochester, Minnesota
4Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
5Department of Neurology, Mayo Clinic, Scottsdale, Arizona
6Department of Neurology, Mayo Clinic, Jacksonville, Florida
JAMA Neurol. 2014;71(1):48-54. doi:10.1001/jamaneurol.2013.5055.
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Importance  Studies focused on recurrent longitudinally extensive transverse myelitis (rLETM) are lacking.

Objectives  To determine the aquaporin 4 (AQP4) IgG detection rate using recombinant human APQ4-based assays in sequential serum specimens collected from patients with rLETM categorized as negative by first-generation tissue-based indirect immunofluorescence (IIF) assay and to define the clinical characteristics and motor disability outcomes in AQP4-IgG–positive rLETM.

Design, Setting, and Participants  A search of the Mayo Clinic computerized central diagnostic index (October 1, 2005, through November 30, 2011), cross-linked with the Neuroimmunology Laboratory database, identified 48 patients with rLETM, of whom 36 (75%) were positive and 12 (25%) negative for neuromyelitis optica (NMO) IgG (per IIF of serial serum specimens). Stored serum specimens from “seronegative” patients were retested with recombinant human AQP4-based assays, including enzyme-linked immunosorbent, transfected cell-based, and fluorescence-activated cell-sorting assays. Control patients included 140 AQP4-IgG–positive patients with NMO, of whom a subgroup of 20 initially presented with 2 attacks of transverse myelitis (rLETM-onset NMO).

Main Outcomes and Measures  AQP4-IgG serostatus, clinical characteristics, and Expanded Disability Status Scale score.

Results  Six patients with negative IIF results were reclassified as AQP4-IgG positive, yielding an overall AQP4-IgG seropositivity rate of 89%. Fluorescence-activated cell-sorting, cell-based, and enzyme-linked immunosorbent assays improved the detection rate to 89%, 85%, and 81%, respectively. The female to male ratio was 2:3 for AQP4-IgG–negative rLETM and 5:1 for AQP4-IgG–positive patients. The AQP4-IgG–positive patients with rLETM or rLETM-onset NMO were similar in age at onset, sex ratio, attack severity, relapse rate, and motor disability. From Kaplan-Meier analyses, 36% of AQP4-IgG–positive patients with rLETM are anticipated to need a cane to walk within 5 years after onset. For patients with rLETM-onset NMO, the median time from onset to first optic neuritis attack (54 months) was similar to the median disease duration for AQP4-IgG–positive patients with rLETM (59 months). The median number of attacks was 3 for AQP4-IgG–positive patients with rLETM (range, 2-22), and the first optic neuritis attack for those with rLETM-onset NMO followed a median of 3 myelitis attacks (range, 2-19). Immunosuppressant therapy reduced the relapse rate in both AQP4-IgG–positive and AQP4-IgG–negative patients with rLETM.

Conclusions and Relevance  Recombinant antigen–based assays significantly increase AQP4-IgG detection in patients with rLETM, and AQP4-IgG–negative adults with rLETM are rare. Evolution to NMO can be anticipated in AQP4-IgG–positive patients. Early initiation of immunotherapy may result in a more favorable motor outcome.

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Figure 1.
Flowchart for Recurrent Longitudinally Extensive Transverse Myelitis (rLETM) Cohort

Of 48 patients whose serum was tested (≥1 sequential specimen) with tissue-based indirect immunofluorescence (IIF), 12 were categorized as negative. Of 11 with available stored specimens, 6 (55%) were positive for aquaporin 4 (AQP4) IgG when retested with recombinant antigen–based assays. CBA indicates cell-based assay; ELISA, enzyme-linked immunosorbent assay; FACS, fluorescence-activated cell-sorting assay; NMO, neuromyelitis optica; and QNS, quantity not sufficient or no sample for further evaluation.

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Figure 2.
Clinical Course, Therapy, and Results of Aquaporin 4 (AQP4) IgG Testing by Multiple Assays in Serial Serum Samples From 2 Patients With Recurrent Longitudinally Extensive Transverse Myelitis

A, Retesting may increase the AQP4-IgG detection rate. Initial samples were negative at tissue-based indirect immunofluorescence (IIF), enzyme-linked immunosorbent assay (ELISA), and AQP4-transfected cell-based assay (CBA) but positive at fluorescence-activated cell-sorting (FACS) assay; subsequent samples converted to positive at CBA and ELISA but not IIF. The frequency of attacks decreased with immunosuppressant therapy. Numbers on the y-axis represent Expanded Disability Status Scale (EDSS) scores. B, Sensitivity improved with recombinant antigen–based assays; serial serum specimens were persistently classified as AQP4-IgG negative with IIF but reclassified as positive with use of multiple recombinant antigen–based assays. Serostatus commonly converts from positive to negative with immunotherapy. The frequency of attacks decreased with immunosuppressant therapy. Numbers on the y-axis represent EDSS scores. AZA indicates azathioprine; GA, glatiramer acetate; IFN-β, interferon beta; MP, methylprednisolone; PLEX, plasma exchange; +, positive; and −, negative.

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Figure 3.
Kaplan-Meier Estimates of Time to Motor Disability in Aquaporin 4 (AQP4) IgG–Positive Patients With Recurrent Longitudinally Extensive Transverse Myelitis (rLETM), rLETM-onset Neuromyelitis Optica (NMO), or NMO

Major disability outcomes were similar in AQP4-IgG–positive patients with rLETM and those with rLETM-onset NMO. At 5 years after onset, 36% of patients with rLETM and 41% with rLETM-onset NMO were expected to need a cane (Expanded Disability Status Scale [EDSS] score, 6; intermittent or unilateral assistance [canes, crutches, or braces] required to walk 100 m with or without resting) (P = .94); a lower frequency (22%) was expected for the total AQP4-IgG–positive NMO group. The rLETM-onset NMO group included AQP4-IgG–positive patients with NMO who initially presented with 2 attacks of transverse myelitis.

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