NMO-IgG predicts the outcome of
recurrent optic neuritis
M. Matiello, MD
V.A. Lennon, MD,
A. Jacob, MD
S.J. Pittock, MD
C.F. Lucchinetti, MD
Objective: To determine the prognostic value of neuromyelitis optica (NMO)–immunoglobulin G
(IgG) in patients with recurrent optic neuritis (ON). The aquaporin-4-specific serum autoantibody,
NMO-IgG, is a biomarker for NMO and relapsing transverse myelitis. Recurrent ON may herald
multiple sclerosis (MS) or NMO, or it may occur as an isolated syndrome. The prognosis and re-
sponse to therapy differs in each of these contexts.
Methods: We evaluated 34 patients who were tested for NMO-IgG between 2000 and 2007 and
who had two or more episodes of ON without satisfying a diagnosis of MS or NMO prior to sero-
logic testing. Clinical data were available for 25 Mayo Clinic patients (5 NMO-IgG positive and 20
NMO-IgG negative) and for an additional 9 seropositive patients whose serum was referred to the
Mayo Clinic Neuroimmunology laboratory for testing.
Results: Twenty percent of the patients with recurrent ON seen at Mayo Clinic were seropositive.
All NMO-IgG-positive patients (vs 65% NMO-IgG-negative patients) had at least one attack with
visual acuity in the affected eye worse than 20/200 (p ? 0.05). In seropositive patients for whom
long-term follow-up was possible (median 8.9 years after the initial ON), 6 of 12 (50%) experi-
enced an episode of myelitis and fulfilled criteria for NMO. In contrast, 1 of 15 seronegative
patients (6.7%) fulfilled McDonald criteria for MS (p ? 0.03). Seropositive patients had a final
visual score which was worse than that of seronegative patients (p ? 0.02).
Conclusions: Neuromyelitis optica (NMO)–immunoglobulin G seropositivity predicts poor visual
outcome and development of NMO. Seropositive recurrent optic neuritis is a limited form of NMO.
IgG ? immunoglobulin G; LETM ? longitudinally extensive transverse myelitis; MS ? multiple sclerosis; NMO ? neuromyelitis
optica; ON ? optic neuritis; RON ? recurrent ON; TM ? transverse myelitis; VA ? visual acuity.
Optic neuritis (ON) is an acute inflammatory demyelinating syndrome of the CNS that
may occur in isolation or may herald multiple sclerosis (MS), neuromyelitis optica
(NMO), or recurrences of ON without other CNS manifestation (idiopathic recurrent
ON [RON]).1The diagnosis of NMO, rather than MS, in a patient with a history of ON
and myelitis is largely dependent on documentation of longitudinally extensive spinal
cord lesions, which are common in NMO and rare in MS. The prognosis for NMO is
treatments for MS are ineffective for NMO.3-6Therefore, early distinction between
NMO (and its related spectrum of disorders) from MS is clinically important.
e-Pub ahead of print on April 23, 2008, at www.neurology.org.
From the Departments of Neurology (M.M., V.A.L., A.J., S.J.P., C.F.L., B.G.W.) and Laboratory Medicine and Pathology (V.A.L., S.J.P.),
Mayo Clinic College of Medicine, Rochester, MN; and Department of Neurology (D.M.W.), Mayo Clinic College of Medicine, Scottsdale,
Dr. Matiello is supported by a du Pre ´ fellowship grant provided by the Multiple Sclerosis International Federation (www.msif.org). This
research is sponsored in part by a grant to Dr. Weinshenker from the Olson Foundation.
Disclosure: Drs. Marcelo Matiello, Anu Jacob, and Sean Pittock have nothing to disclose. Drs. Brian Weinshenker, Vanda Lennon, and
Claudia Lucchinetti have intellectual property associated with the discovery of NMO-IgG, which has been licensed to a commercial entity.
The NMO-IgG test is offered on a service basis by Mayo Collaborative Service Inc., an agency of Mayo Foundation. Dean Wingerchuk and
Brian Weinshenker have served as consultants for Genentech for development of a clinical trial for neuromyelitis optica. Dr. Wingerchuk has
consulted for Teva pharmaceuticals. Drs. Weinshenker and Wingerchuk have also been investigators in clinical trials for MS.
Address correspondence and
reprint requests to Dr. Brian
Weinshenker, Department of
Neurology, Mayo Clinic
College of Medicine, 200 First
St SW, Rochester, MN 55905
Editorial, page 2192
Copyright © 2008 by AAN Enterprises, Inc.
The serum autoantibody, NMO-IgG, de-
tected by indirect immunofluorescence,2
binds to the CNS-dominant water channel,
aquaporin-4, and has high sensitivity and
of NMO-IgG seropositivity as a diagnostic
criterion for NMO8has been validated in-
dependently.9Detection of NMO-IgG in
patients with idiopathic longitudinally ex-
tensive transverse myelitis (LETM) pre-
dicts recurrence or development of ON
within 1 year in 55% of cases.10The goal of
the current study was to evaluate the diag-
nostic and prognostic value of NMO-IgG
in patients with RON.
METHODS The study was approved by the Mayo Clinic
Institutional Review Board (IRB# 1036-04). Eligible patients
fulfilled the following inclusion criteria: 1) tested for NMO-
IgG between 2000 and 2007 in the Mayo Clinic Neuroimmu-
nology Laboratory; 2) at least two clinical episodes of ON
separated by 30 days or more and documented before NMO-
IgG testing; 3) no other neurologic signs or symptoms prior
to the NMO-IgG test that suggested a diagnosis of MS or
Blinded indirect immunofluorescence testing for NMO-
IgG was performed on a service basis.2We reviewed medical
records for patients evaluated at Mayo Clinic (5 NMO-IgG
positive and 20 NMO-IgG negative) and abstracted data
Mayo Clinic. Data for patients evaluated elsewhere were as-
certained only for seropositive RON patients (identified se-
Laboratory [n ? 9], in the course of contacting physicians of
NMO-IgG-positive patients in routine laboratory physician-
initiated consultative and quality assurance activities). Thus,
only patients evaluated at Mayo Clinic were informative re-
garding the seroprevalence of NMO-IgG in RON. Data for
both groups were used to evaluate demographic characteris-
tics and outcome data associated with NMO-IgG seroposi-
Visual acuity (VA) was assessed in each eye by an ordinal
scale: 0 ? 20/20; 1 ? scotoma but better than 20/30; 2 ?
20/30 to 20/59; 3 ? 20/60 to 20/199; 4 ? 20/200 to 20/800; 5 ?
count fingers only; 6 ? light perception; 7 ? no light percep-
tion.11The final visual outcome was the sum of the last as-
signed visual score for each eye.
Follow-up information included additional relapses of
ON, development of transverse myelitis (TM) or other neu-
rologic manifestations, and the patient’s most recent visual
and motor status.
We determined whether the patients satisfied criteria for
MS or NMO.8,12We used the statistical package JMP 6.0
(SAS Institute, Cary, NC, 2005) to analyze the significance of
differences between the seropositive and seronegative groups
using ?2or Fisher exact test for frequency data, and Wil-
coxon or t test for continuous data, as appropriate. We used
a Kaplan-Meier analysis to evaluate differences in incidence
of TM in the seropositive and seronegative groups following
the first episode of ON.
RESULTS Five of the 25 patients (20%) evaluated
at Mayo Clinic were NMO-IgG-positive. Sero-
positivity was not associated with sex, age at on-
set, number of ON episodes prior to serologic
testing, interval between the first and the second
episodes, or occurrence of bilateral episodes of
ON. Among patients for whom ethnicity infor-
mation was available, non-Caucasian ancestry
was more common in the seropositives (5 of 12;
41.7%) than in the seronegatives (2 of 19; 10.5%,
p ? 0.07).
The initial ON episode was more severe in se-
ropositive patients (p ? 0.05) and VA in the af-
fected eye was worse than 20/200 at the nadir in
all seropositive patients (one or more ON epi-
sodes) compared to 64.7% in seronegative pa-
tients (p ? 0.05). Thirty-one patients had a brain
MRI after the first ON; none fulfilled MRI crite-
ria for MS,126 of 11 seropositive patients (55%)
and 12 of 19 seronegative patients (63%) had nor-
mal brain MRI or changes restricted to the optic
nerve. The remainder had nonspecific MRI signal
Follow-up data were available for 12 seroposi-
tive and 15 seronegative patients, representing
79.4% of the population studied. The interval
was similar in the two groups: 8.95 ? 2.0 years
for seropositive vs 8.02 ? 5.1 years (mean ? SD)
for seronegative patients (p ? 0.73). Four sero-
positive and 7 seronegative patients had ON re-
lapses after NMO-IgG testing (p ? 0.69). The
final visual status score was worse in the seropos-
itive group: 10.22 ? 9.0 (mean ? SD) vs 6.38 ?
1.0 in the seronegative group (p ? 0.02) (table).
One seronegative patient (6.6%) and 6 sero-
positive patients (50%) experienced TM epi-
sodes during the follow-up period (p ? 0.03)
(figure). The seronegative patient experienced a
band-like sensation around her chest accompa-
nied by paresthesia of the lower extremities;
MRI of thoracic spine revealed two small le-
sions adjacent to vertebra T11 each measuring
about 3 mm, likely unrelated to her symptoms
considering the dermatome level of sensory dis-
turbance. Minor sensory disturbances accom-
panied by small spinal cord MRI lesions also
occurred in one seropositive patient while she
was receiving monthly IVIg therapy. The other
five seropositive patients experienced severe
TM, leading either to quadriplegia or paraple-
gia, accompanied by severe sensory and sphinc-
ter deficits. Spinal cord lesions longer than
three vertebral segments were present in the
four patients on whom we had information
about their MRI scans. Two seropositive pa-
Neurology 70June 3, 2008
tients died shortly after developing TM, one
from a pulmonary embolism and the other from
NMO-IgG titers among seropositive cases
were higher in those who developed myelitis than
in those who did not. TM developed in 5 of 7
patients (71.4%) whose NMO-IgG was positive
at a serum dilution greater than 1:480, but in only
1 of 5 patients (20%) whose serum was positive at
a dilution of 1:480 or lower (p ? 0.07).
DISCUSSION The 20% seroprevalence of
NMO-IgG among patients presenting with
RON was similar to the frequency we origi-
nally reported for NMO-IgG among patients
with RON. In the original report, 2 of 8 pa-
tients (25%) with simultaneous or sequential
RON were NMO-IgG positive.2
The visual disability recorded for patients in
this report is consistent with previous reports for
patients with NMO. In a study conducted before
the advent of NMO-IgG testing, the initial ON
episode and final visual outcome of patients with
RON were worse in the NMO-conversion group
than in those who did not convert to NMO.1Sim-
ilarly, in comparing visual status immediately af-
ter an ON episode and then 6 months later in
Afro-Caribbean patients with NMO or MS, the
number of attacks in the first 2 years (2.0 ? 1.3 vs
0.97 ? 0.7), the annual relapse rate (0.39 ? 0.33
vs 0.27 ? 0.29), and the final visual acuity impair-
ment (20/50 vs 20/25) were greater in NMO than
NMO-IgG is not restricted to patients fulfill-
ing all criteria for a definite diagnosis of
NMO.10,14-16The seropositivity rate in patients
with recurrent LETM was 52%2and 40% in pa-
Patient demographic, clinical, and MRI characteristics and outcome information stratified by
neuromyelitis optica (NMO)–immunoglobulin G (IgG) serologic status
Baseline characteristics (prior to NMO-IgG testing)Seronegative (n ? 20)Seropositive (n ? 14)
Age at onset, y, median (IQR)
28.9 (14.8–43.7)31.0 (23.7–42.3) 0.45*
Ethnicity, n (%)
17 (89.5)7 (58.3)
2 (10.5) 5 (41.7)
No. of ON episodes, mean ? SD
3.05 ? 1.65 4.14 ? 2.950.14*
Interval between first and second episodes, d, median (IQR)
131 (50.5–912.3)258 (70.75–1,255) 0.19†
First ON visual score at nadir, mean ? SD
4.53 ? 2.26 6.12 ? 1.120.07‡
ON event with visual acuity worse than 20/200, n (%)
11/17 (64.7) 10/10 (100)0.05†
No. of patients with bilateral episodes of ON
At least one episode with no light perception, n (%)
7/17 (41.2)7/10 (70) 0.14§
Follow-up outcomesSeronegative (n ? 15)Seropositive (n ? 12)
No. of patients with ON episodes after NMO-IgG serologic
testing, n (%)
7 (46.7) 4 (33.3)0.69†
Visual score at last follow-up, sum of both eyes, mean ? SD
6.38 ? 3.42 10.22 ? 3.89 0.02‡
Transverse myelitis episodes, n (%)
1 (6.6)6 (50)0.03¶
†Fisher exact test.
IQR ? interquartile range; ON ? optic neuritis.
Kaplan-Meier analysis for the occurrence
of transverse myelitis stratified by
serologic status for neuromyelitis
Neurology 70 June 3, 2008
tients with a single episode of LETM.10This study Download full-text
provides support for RON being a limited or in-
augural symptom of NMO in at least 20% of pa-
No clinical trial has established the most effica-
cious treatment for preventing relapses in NMO.
However, case series strongly supports the use of
immunosuppressant drugs rather than interferon
beta.3-6Patients with RON who are seropositive for
NMO-IgG are at high risk for development of TM
patients with RON for NMO-IgG and favor use of
immunosuppressive therapy in treating NMO-IgG-
seropositive patients with RON, as we also recom-
mend for patients with LETM who are NMO-IgG
The authors thank Denice Bredlow for editing the manuscript.
Received August 2, 2007. Accepted in final form October 18,
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