title: Diagnostic utility of aquaporin-4 in the analysis of active demyelinating lesions.
abstract: OBJECTIVE
  To assess, in a surgical biopsy cohort of active demyelinating lesions, the diagnostic utility of aquaporin-4 (AQP4) immunohistochemistry in identifying neuromyelitis optica (NMO) or NMO spectrum disorder (NMOSD) and describe pathologic features that should prompt AQP4 immunohistochemical analysis and AQP4-immunoglobulin G (IgG) serologic testing.
  
  
  METHODS
  This was a neuropathologic cohort study of 20 surgical biopsies (19 patients; 11 cord/9 brain), performed because of diagnostic uncertainty, interpreted as active demyelinating disease and containing 2 or more of the following additional features: tissue vacuolation, granulocytic infiltrates, or astrocyte injury.
  
  
  RESULTS
  AQP4 immunoreactivity was lost in 18 biopsies and increased in 2. Immunopathologic features of the AQP4 loss cohort were myelin vacuolation (18), dystrophic astrocytes and granulocytes (17), vascular hyalinization (16), macrophages containing glial fibrillary acid protein (GFAP)-positive debris (14), and Creutzfeldt-Peters cells (0). All 14 cases with available serum tested positive for AQP4-IgG after biopsy. Diagnosis at last follow-up was NMO/NMOSD (15) and longitudinally extensive transverse myelitis (1 each relapsing and single). Immunopathologic features of the AQP4 increased cohort were macrophages containing GFAP-positive debris and granulocytes (2), myelin vacuolation (1), dystrophic astrocytes (1), Creutzfeldt-Peters cells (1), and vascular hyalinization (1). Diagnosis at last follow-up was multiple sclerosis (MS) and both tested AQP4-IgG seronegative after biopsy.
  
  
  CONCLUSIONS
  AQP4 immunohistochemistry with subsequent AQP4-IgG testing has diagnostic utility in identifying cases of NMO/NMOSD. This study highlights the importance of considering NMOSD in the differential diagnosis of tumefactive brain or spinal cord lesions. AQP4-IgG testing may avert biopsy and avoid ineffective therapies if these patients are erroneously treated for MS.
authors.affiliation: From the Department of Anatomy and Cell Biology and Cameco MS Neuroscience Research Center (B.F.G.P.), University of Saskatchewan, Saskatoon, Canada; the Departments of Neurology (Y.G., J.E.P., V.A.L., S.J.P., B.G.W., S.L.C., C.F.L.), Laboratory Medicine and Pathology (M.E.J., J.E.P., V.A.L., S.J.P., G.G.), and Immunology (V.A.L.), Mayo Clinic, Rochester, MN; the Department of Neurology (D.M.W., J.C.), Mayo Clinic, Scottsdale, AZ; the Department of Neuropathology (I.M., W.B.), University Medical Center, Georg August University, Göttingen, Germany; the Department of Neurology (E.A.S.), Mayo Clinic, Jacksonville, FL; the Department of Neurology (C.D.B.), Columbia University Medical Center, New York, NY; and the Department of Neurology (B.A.C.), Feinberg School of Medicine, Northwestern University, Evanston, IL.
authors.forename: Bogdan F G
authors.initials: BF
authors.lastname: Popescu
authors.affiliation: From the Department of Anatomy and Cell Biology and Cameco MS Neuroscience Research Center (B.F.G.P.), University of Saskatchewan, Saskatoon, Canada; the Departments of Neurology (Y.G., J.E.P., V.A.L., S.J.P., B.G.W., S.L.C., C.F.L.), Laboratory Medicine and Pathology (M.E.J., J.E.P., V.A.L., S.J.P., G.G.), and Immunology (V.A.L.), Mayo Clinic, Rochester, MN; the Department of Neurology (D.M.W., J.C.), Mayo Clinic, Scottsdale, AZ; the Department of Neuropathology (I.M., W.B.), University Medical Center, Georg August University, Göttingen, Germany; the Department of Neurology (E.A.S.), Mayo Clinic, Jacksonville, FL; the Department of Neurology (C.D.B.), Columbia University Medical Center, New York, NY; and the Department of Neurology (B.A.C.), Feinberg School of Medicine, Northwestern University, Evanston, IL.
authors.forename: Yong
authors.initials: Y
authors.lastname: Guo
authors.affiliation: From the Department of Anatomy and Cell Biology and Cameco MS Neuroscience Research Center (B.F.G.P.), University of Saskatchewan, Saskatoon, Canada; the Departments of Neurology (Y.G., J.E.P., V.A.L., S.J.P., B.G.W., S.L.C., C.F.L.), Laboratory Medicine and Pathology (M.E.J., J.E.P., V.A.L., S.J.P., G.G.), and Immunology (V.A.L.), Mayo Clinic, Rochester, MN; the Department of Neurology (D.M.W., J.C.), Mayo Clinic, Scottsdale, AZ; the Department of Neuropathology (I.M., W.B.), University Medical Center, Georg August University, Göttingen, Germany; the Department of Neurology (E.A.S.), Mayo Clinic, Jacksonville, FL; the Department of Neurology (C.D.B.), Columbia University Medical Center, New York, NY; and the Department of Neurology (B.A.C.), Feinberg School of Medicine, Northwestern University, Evanston, IL.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Jentoft
authors.affiliation: From the Department of Anatomy and Cell Biology and Cameco MS Neuroscience Research Center (B.F.G.P.), University of Saskatchewan, Saskatoon, Canada; the Departments of Neurology (Y.G., J.E.P., V.A.L., S.J.P., B.G.W., S.L.C., C.F.L.), Laboratory Medicine and Pathology (M.E.J., J.E.P., V.A.L., S.J.P., G.G.), and Immunology (V.A.L.), Mayo Clinic, Rochester, MN; the Department of Neurology (D.M.W., J.C.), Mayo Clinic, Scottsdale, AZ; the Department of Neuropathology (I.M., W.B.), University Medical Center, Georg August University, Göttingen, Germany; the Department of Neurology (E.A.S.), Mayo Clinic, Jacksonville, FL; the Department of Neurology (C.D.B.), Columbia University Medical Center, New York, NY; and the Department of Neurology (B.A.C.), Feinberg School of Medicine, Northwestern University, Evanston, IL.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Parisi
authors.affiliation: From the Department of Anatomy and Cell Biology and Cameco MS Neuroscience Research Center (B.F.G.P.), University of Saskatchewan, Saskatoon, Canada; the Departments of Neurology (Y.G., J.E.P., V.A.L., S.J.P., B.G.W., S.L.C., C.F.L.), Laboratory Medicine and Pathology (M.E.J., J.E.P., V.A.L., S.J.P., G.G.), and Immunology (V.A.L.), Mayo Clinic, Rochester, MN; the Department of Neurology (D.M.W., J.C.), Mayo Clinic, Scottsdale, AZ; the Department of Neuropathology (I.M., W.B.), University Medical Center, Georg August University, Göttingen, Germany; the Department of Neurology (E.A.S.), Mayo Clinic, Jacksonville, FL; the Department of Neurology (C.D.B.), Columbia University Medical Center, New York, NY; and the Department of Neurology (B.A.C.), Feinberg School of Medicine, Northwestern University, Evanston, IL.
authors.forename: Vanda A
authors.initials: VA
authors.lastname: Lennon
authors.affiliation: From the Department of Anatomy and Cell Biology and Cameco MS Neuroscience Research Center (B.F.G.P.), University of Saskatchewan, Saskatoon, Canada; the Departments of Neurology (Y.G., J.E.P., V.A.L., S.J.P., B.G.W., S.L.C., C.F.L.), Laboratory Medicine and Pathology (M.E.J., J.E.P., V.A.L., S.J.P., G.G.), and Immunology (V.A.L.), Mayo Clinic, Rochester, MN; the Department of Neurology (D.M.W., J.C.), Mayo Clinic, Scottsdale, AZ; the Department of Neuropathology (I.M., W.B.), University Medical Center, Georg August University, Göttingen, Germany; the Department of Neurology (E.A.S.), Mayo Clinic, Jacksonville, FL; the Department of Neurology (C.D.B.), Columbia University Medical Center, New York, NY; and the Department of Neurology (B.A.C.), Feinberg School of Medicine, Northwestern University, Evanston, IL.
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Pittock
authors.affiliation: From the Department of Anatomy and Cell Biology and Cameco MS Neuroscience Research Center (B.F.G.P.), University of Saskatchewan, Saskatoon, Canada; the Departments of Neurology (Y.G., J.E.P., V.A.L., S.J.P., B.G.W., S.L.C., C.F.L.), Laboratory Medicine and Pathology (M.E.J., J.E.P., V.A.L., S.J.P., G.G.), and Immunology (V.A.L.), Mayo Clinic, Rochester, MN; the Department of Neurology (D.M.W., J.C.), Mayo Clinic, Scottsdale, AZ; the Department of Neuropathology (I.M., W.B.), University Medical Center, Georg August University, Göttingen, Germany; the Department of Neurology (E.A.S.), Mayo Clinic, Jacksonville, FL; the Department of Neurology (C.D.B.), Columbia University Medical Center, New York, NY; and the Department of Neurology (B.A.C.), Feinberg School of Medicine, Northwestern University, Evanston, IL.
authors.forename: Brian G
authors.initials: BG
authors.lastname: Weinshenker
authors.affiliation: From the Department of Anatomy and Cell Biology and Cameco MS Neuroscience Research Center (B.F.G.P.), University of Saskatchewan, Saskatoon, Canada; the Departments of Neurology (Y.G., J.E.P., V.A.L., S.J.P., B.G.W., S.L.C., C.F.L.), Laboratory Medicine and Pathology (M.E.J., J.E.P., V.A.L., S.J.P., G.G.), and Immunology (V.A.L.), Mayo Clinic, Rochester, MN; the Department of Neurology (D.M.W., J.C.), Mayo Clinic, Scottsdale, AZ; the Department of Neuropathology (I.M., W.B.), University Medical Center, Georg August University, Göttingen, Germany; the Department of Neurology (E.A.S.), Mayo Clinic, Jacksonville, FL; the Department of Neurology (C.D.B.), Columbia University Medical Center, New York, NY; and the Department of Neurology (B.A.C.), Feinberg School of Medicine, Northwestern University, Evanston, IL.
authors.forename: Dean M
authors.initials: DM
authors.lastname: Wingerchuk
authors.affiliation: From the Department of Anatomy and Cell Biology and Cameco MS Neuroscience Research Center (B.F.G.P.), University of Saskatchewan, Saskatoon, Canada; the Departments of Neurology (Y.G., J.E.P., V.A.L., S.J.P., B.G.W., S.L.C., C.F.L.), Laboratory Medicine and Pathology (M.E.J., J.E.P., V.A.L., S.J.P., G.G.), and Immunology (V.A.L.), Mayo Clinic, Rochester, MN; the Department of Neurology (D.M.W., J.C.), Mayo Clinic, Scottsdale, AZ; the Department of Neuropathology (I.M., W.B.), University Medical Center, Georg August University, Göttingen, Germany; the Department of Neurology (E.A.S.), Mayo Clinic, Jacksonville, FL; the Department of Neurology (C.D.B.), Columbia University Medical Center, New York, NY; and the Department of Neurology (B.A.C.), Feinberg School of Medicine, Northwestern University, Evanston, IL.
authors.forename: Caterina
authors.initials: C
authors.lastname: Giannini
authors.affiliation: From the Department of Anatomy and Cell Biology and Cameco MS Neuroscience Research Center (B.F.G.P.), University of Saskatchewan, Saskatoon, Canada; the Departments of Neurology (Y.G., J.E.P., V.A.L., S.J.P., B.G.W., S.L.C., C.F.L.), Laboratory Medicine and Pathology (M.E.J., J.E.P., V.A.L., S.J.P., G.G.), and Immunology (V.A.L.), Mayo Clinic, Rochester, MN; the Department of Neurology (D.M.W., J.C.), Mayo Clinic, Scottsdale, AZ; the Department of Neuropathology (I.M., W.B.), University Medical Center, Georg August University, Göttingen, Germany; the Department of Neurology (E.A.S.), Mayo Clinic, Jacksonville, FL; the Department of Neurology (C.D.B.), Columbia University Medical Center, New York, NY; and the Department of Neurology (B.A.C.), Feinberg School of Medicine, Northwestern University, Evanston, IL.
authors.forename: Imke
authors.initials: I
authors.lastname: Metz
authors.affiliation: From the Department of Anatomy and Cell Biology and Cameco MS Neuroscience Research Center (B.F.G.P.), University of Saskatchewan, Saskatoon, Canada; the Departments of Neurology (Y.G., J.E.P., V.A.L., S.J.P., B.G.W., S.L.C., C.F.L.), Laboratory Medicine and Pathology (M.E.J., J.E.P., V.A.L., S.J.P., G.G.), and Immunology (V.A.L.), Mayo Clinic, Rochester, MN; the Department of Neurology (D.M.W., J.C.), Mayo Clinic, Scottsdale, AZ; the Department of Neuropathology (I.M., W.B.), University Medical Center, Georg August University, Göttingen, Germany; the Department of Neurology (E.A.S.), Mayo Clinic, Jacksonville, FL; the Department of Neurology (C.D.B.), Columbia University Medical Center, New York, NY; and the Department of Neurology (B.A.C.), Feinberg School of Medicine, Northwestern University, Evanston, IL.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Brück
authors.affiliation: From the Department of Anatomy and Cell Biology and Cameco MS Neuroscience Research Center (B.F.G.P.), University of Saskatchewan, Saskatoon, Canada; the Departments of Neurology (Y.G., J.E.P., V.A.L., S.J.P., B.G.W., S.L.C., C.F.L.), Laboratory Medicine and Pathology (M.E.J., J.E.P., V.A.L., S.J.P., G.G.), and Immunology (V.A.L.), Mayo Clinic, Rochester, MN; the Department of Neurology (D.M.W., J.C.), Mayo Clinic, Scottsdale, AZ; the Department of Neuropathology (I.M., W.B.), University Medical Center, Georg August University, Göttingen, Germany; the Department of Neurology (E.A.S.), Mayo Clinic, Jacksonville, FL; the Department of Neurology (C.D.B.), Columbia University Medical Center, New York, NY; and the Department of Neurology (B.A.C.), Feinberg School of Medicine, Northwestern University, Evanston, IL.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Shuster
authors.affiliation: From the Department of Anatomy and Cell Biology and Cameco MS Neuroscience Research Center (B.F.G.P.), University of Saskatchewan, Saskatoon, Canada; the Departments of Neurology (Y.G., J.E.P., V.A.L., S.J.P., B.G.W., S.L.C., C.F.L.), Laboratory Medicine and Pathology (M.E.J., J.E.P., V.A.L., S.J.P., G.G.), and Immunology (V.A.L.), Mayo Clinic, Rochester, MN; the Department of Neurology (D.M.W., J.C.), Mayo Clinic, Scottsdale, AZ; the Department of Neuropathology (I.M., W.B.), University Medical Center, Georg August University, Göttingen, Germany; the Department of Neurology (E.A.S.), Mayo Clinic, Jacksonville, FL; the Department of Neurology (C.D.B.), Columbia University Medical Center, New York, NY; and the Department of Neurology (B.A.C.), Feinberg School of Medicine, Northwestern University, Evanston, IL.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Carter
authors.affiliation: From the Department of Anatomy and Cell Biology and Cameco MS Neuroscience Research Center (B.F.G.P.), University of Saskatchewan, Saskatoon, Canada; the Departments of Neurology (Y.G., J.E.P., V.A.L., S.J.P., B.G.W., S.L.C., C.F.L.), Laboratory Medicine and Pathology (M.E.J., J.E.P., V.A.L., S.J.P., G.G.), and Immunology (V.A.L.), Mayo Clinic, Rochester, MN; the Department of Neurology (D.M.W., J.C.), Mayo Clinic, Scottsdale, AZ; the Department of Neuropathology (I.M., W.B.), University Medical Center, Georg August University, Göttingen, Germany; the Department of Neurology (E.A.S.), Mayo Clinic, Jacksonville, FL; the Department of Neurology (C.D.B.), Columbia University Medical Center, New York, NY; and the Department of Neurology (B.A.C.), Feinberg School of Medicine, Northwestern University, Evanston, IL.
authors.forename: Clara D
authors.initials: CD
authors.lastname: Boyd
authors.affiliation: From the Department of Anatomy and Cell Biology and Cameco MS Neuroscience Research Center (B.F.G.P.), University of Saskatchewan, Saskatoon, Canada; the Departments of Neurology (Y.G., J.E.P., V.A.L., S.J.P., B.G.W., S.L.C., C.F.L.), Laboratory Medicine and Pathology (M.E.J., J.E.P., V.A.L., S.J.P., G.G.), and Immunology (V.A.L.), Mayo Clinic, Rochester, MN; the Department of Neurology (D.M.W., J.C.), Mayo Clinic, Scottsdale, AZ; the Department of Neuropathology (I.M., W.B.), University Medical Center, Georg August University, Göttingen, Germany; the Department of Neurology (E.A.S.), Mayo Clinic, Jacksonville, FL; the Department of Neurology (C.D.B.), Columbia University Medical Center, New York, NY; and the Department of Neurology (B.A.C.), Feinberg School of Medicine, Northwestern University, Evanston, IL.
authors.forename: Stacey Lynn
authors.initials: SL
authors.lastname: Clardy
authors.affiliation: From the Department of Anatomy and Cell Biology and Cameco MS Neuroscience Research Center (B.F.G.P.), University of Saskatchewan, Saskatoon, Canada; the Departments of Neurology (Y.G., J.E.P., V.A.L., S.J.P., B.G.W., S.L.C., C.F.L.), Laboratory Medicine and Pathology (M.E.J., J.E.P., V.A.L., S.J.P., G.G.), and Immunology (V.A.L.), Mayo Clinic, Rochester, MN; the Department of Neurology (D.M.W., J.C.), Mayo Clinic, Scottsdale, AZ; the Department of Neuropathology (I.M., W.B.), University Medical Center, Georg August University, Göttingen, Germany; the Department of Neurology (E.A.S.), Mayo Clinic, Jacksonville, FL; the Department of Neurology (C.D.B.), Columbia University Medical Center, New York, NY; and the Department of Neurology (B.A.C.), Feinberg School of Medicine, Northwestern University, Evanston, IL.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Cohen
authors.affiliation: From the Department of Anatomy and Cell Biology and Cameco MS Neuroscience Research Center (B.F.G.P.), University of Saskatchewan, Saskatoon, Canada; the Departments of Neurology (Y.G., J.E.P., V.A.L., S.J.P., B.G.W., S.L.C., C.F.L.), Laboratory Medicine and Pathology (M.E.J., J.E.P., V.A.L., S.J.P., G.G.), and Immunology (V.A.L.), Mayo Clinic, Rochester, MN; the Department of Neurology (D.M.W., J.C.), Mayo Clinic, Scottsdale, AZ; the Department of Neuropathology (I.M., W.B.), University Medical Center, Georg August University, Göttingen, Germany; the Department of Neurology (E.A.S.), Mayo Clinic, Jacksonville, FL; the Department of Neurology (C.D.B.), Columbia University Medical Center, New York, NY; and the Department of Neurology (B.A.C.), Feinberg School of Medicine, Northwestern University, Evanston, IL. lucchinetti.claudia@mayo.edu.
authors.forename: Claudia F
authors.initials: CF
authors.lastname: Lucchinetti
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051401:Aquaporin 4 / Q000276:immunology*; D001253:Astrocytes / Q000473:pathology*; D001323:Autoantibodies / Q000276:immunology*; D001706:Biopsy; D001921:Brain / Q000276:immunology* / Q000473:pathology; D002648:Child; D015331:Cohort Studies; D020278:Demyelinating Autoimmune Diseases, CNS / Q000175:diagnosis / Q000276:immunology; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D007150:Immunohistochemistry; D007249:Inflammation; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000175:diagnosis* / Q000276:immunology; D009186:Myelin Sheath / Q000473:pathology*; D009471:Neuromyelitis Optica / Q000175:diagnosis* / Q000276:immunology; D013116:Spinal Cord / Q000276:immunology* / Q000473:pathology; D055815:Young Adult
chemical_list: C496030:AQP4 protein, human; D051401:Aquaporin 4; D001323:Autoantibodies; D007074:Immunoglobulin G