Arthritis & Rheumatism (Arthritis Care & Research)
Vol. 57, No. 2, March 15, 2007, pp 347351
DOI 10.1002/art.22540
2007, American College of Rheumatology
CONTRIBUTION FROM THE FIELD
Devics Syndrome in a Woman With Systemic
Lupus Erythematosus: Diagnostic and Therapeutic
Implications of Testing for the Neuromyelitis
Optica IgG Autoantibody
JULIUS BIRNBAUM AND DOUGLAS KERR
Introduction
Although neurologic complications of lupus may occur in
up to 75% of patients, transverse myelitis (TM) is uncom-
mon, occurring in only 2% of patients (1). The myelitis
occurring in lupus can be difcult to distinguish from that
occurring in multiple sclerosis (MS). This distinction is
crucial, because some treatments for MS, such as interfer-
on-, can cause ares of lupus disease (2). Neuromyelitis
optica (NMO), or Devics disease, is an inammatory syn-
drome characterized by sequential or concomitant attacks
of transverse myelitis and optic neuritis, with signicant
disease usually restricted to the spinal cord and optic
nerves. Lennon et al have recently reported an NMO IgG
autoantibody with a high specicity for NMO (3), which
might facilitate discrimination of the TM occurring in
NMO from that occurring in MS, even before emergence of
optic neuritis.
We report the rst example in the literature where the
NMO IgG autoantibody was used to conrm the diagnosis
of Devics syndrome in a lupus patient. In our patient,
recurrent episodes of myelitis were characterized by even-
tual longitudinal extension from the lower medulla to the
sacrum. Interestingly, NMO IgG autoantibody positivity
was documented during evaluation of recurrent myelopa-
thy, but before occurrence of optic neuritis. Much evi-
dence exists supporting a pathogenic role of the NMO IgG
antibody in mediating a humorally mediated spinal cord
microangiopathy (4). Treatment of severe neurologic man-
Julius Birnbaum, MD, Douglas Kerr, MD, PhD: The Johns
Hopkins University School of Medicine, Baltimore, Mary-
land.
Address correspondence to Julius Birnbaum, MD, Divi-
sion of Rheumatology, Russell H. Morgan Building at Good
Samaritan Hospital, 5601 Loch Raven Boulevard, Suite 508,
Baltimore, MD 21239. E-mail: jbirnba2@jhmi.edu.
Submitted for publication June 8, 2006; accepted in re-
vised form October 4, 2006.
ifestations of lupus often involves steroids with pulse cy-
clophosphamide therapy (5). However, earlier diagnosis of
NMO disease in patients with lupus, facilitated by testing
for NMO antibodies, might allow for earlier and more
specic use of B celltargeted therapies. Such earlier in-
tervention might help mitigate the grim prognostic fea-
tures of this devastating syndrome, which is otherwise
associated with either monocular blindness or loss of am-
bulatory capacity in more than 50% of patients within 5
years (6).
Case Report
A 31-year-old African American, right-handed woman
with a history of lupus was transferred to our institution
for evaluation and management of recurrent episodes of
paraparesis. The patients lupus was diagnosed in 1997
when she presented with polyarthralgias; an antinuclear
antibody (ANA) titer of 1:320 dilution; anti double-
stranded DNA (anti-dsDNA), anti-Smith, and anti-RNP
positivity; and Coombs-negative anemia and thrombocyto-
penia. Between 1997 and 2004, the patient was maintained
on hydroxychloroquine 400 mg by mouth per day (every
day); her lupus remained mostly quiescent, with pred-
nisone doses ranging from 5 mg to 20 mg periodically
instituted for ares of polyarthritis.
The patient presented to an outside hospital with the
rst TM attack (temporally referenced as month 0), report-
ing dysesthesias of the left upper and lower extremity,
with evolution of left lower-extremity weakness over 1
week. Magnetic resonance imaging (MRI) of the spine re-
portedly revealed an enhancing signal from C3 to C5 and a
distinct, nonenhancing lesion from T2 to T7. A lumbar
puncture revealed 41 white blood cells, 97% neutrophils,
normal protein and glucose, no oligoclonal bands, and
normal IgG index. The patient received pulse treatment
with 1 gram of methylprednisolone, with complete resto-
ration to her premorbid state.
In month 2 and month 3 after the rst TM attack, the
patient was hospitalized twice for recurrent episodes of
paraparesis, each respective episode worsening over days,
347
348 Birnbaum and Kerr

with functional nadir leaving the patient bedbound and

requiring Foley catheterization. She received a second and
third course of pulse steroids, and was started on intrave-
nous (IV) cyclophosphamide 750 mg/m2. From the time of
maximal impairment, her paraparesis incompletely re-
solved over a period of weeks, with a self-estimated im-
provement to 30% of premorbid baseline. The patient
required the use of a walker for independent ambulation.
In month 5, shortly after receiving her third course of IV
cyclophosphamide, the patient was again admitted to an
outside hospital for recurrent paraparesis, this time occur-
ring in the context of painless, gradually decreasing visual
acuity of the left eye. There had been no previous history
of ocular symptoms. An ophthalmologic evaluation re-
vealed no evidence of optic neuritis. The patient received
a fourth course of IV steroids, and reported full recovery of
visual acuity within 10 days. However, her paraparesis
responded minimally, and she was unable to ambulate
independently. She was transferred to our institution for
further evaluation.
On initial physical examination, the optic disc was
sharp, there was no color desaturation to red and no affer-
ent papillary defect, and visual acuity was full. The rest of
the cranial nerve examination was normal. Motor exami-
nation revealed a left-lateralizing pyramidal pattern of
weakness in the lower extremities, with Medical Research
Council (MRC) scale showing the iliopsoas (4/5) affected
more than the gluteus maximus (4/5) and increased tone
bilaterally. There were pathologic reexes with spread
more in the left lower extremities than the right lower
extremities, with bilateral Babinski signs. There was dim-
inution to large-ber modalities in the right upper and
lower extremity, with no denite cord level. The patients
stance was broad based and unsteady, and she was only
able to initiate 12 strides with 2-person assistance.
There were no reports of rash, oral ulcers, alopecia,
Raynauds symptoms or serositis, hematuria, sicca symp-
toms, or arthralgias. Initial serologies were remarkable
only for an ANA of 1:320 dilution, with negative anti-
dsDNA and extractable nuclear antigens. A comprehen-
sive antiphospholipid panel was negative, and comple-
ments were normal. A lumbar puncture revealed no
pleocytosis, normal protein and glucose, no oligoclonal
bands, and normal IgG synthetic rate. A formal ophthal-
mologic consult concurred that there was no evidence of
optic neuritis. NMO IgG antibody was positive. An MRI of
the spine (Figure 1A) revealed patchy signal abnormality
on T2-weighted sequences within the cord, extending
Figure 1. A, Sagittal T2-weighted magnetic resonance image
from the cervical-medullary junction to the T8 level, with- (MRI) of the spine demonstrating patchy signal abnormality
out any enhancement on gadolinium sequences, consis- within the cord, extending from the cervical-medullary junction
tent with a history of longitudinal myelitis. to the lower thoracic spine. B, Sagittal T2-weighted MRI of the
The patient was treated with 5 rounds of plasmaphere- spine showing radiographic progression of longitudinal myelitis,
with the patchy signal seen in A becoming more conuent and
sis. Within 10 days, she demonstrated signicant improve-
extensive.
ment in paraparesis, easily mobilizing proximal antigrav-
ity muscles. Within days, she was able to transfer and
stand without assistance, and after 2 weeks she was able to
ambulate 30 steps with assistance of a cane. The patient day, and was discharged to home. Over the ensuing weeks,
received a fourth course of IV cyclophosphamide, was the mycophenolate mofetil dosage was increased to 3
started on mycophenolate mofetil 1,000 by mouth twice a grams/day, and the prednisone was correspondingly ti-
day, continued taking prednisone 60 mg by mouth every trated to lower doses.
Devics Syndrome in SLE
In month 7, the patient was readmitted with her fth
episode of paraparesis, and neurologic examination re-
vealed MRC grade 2 out of 5 strength in the lower extrem-
ities. She received 5 rounds of plasmapheresis, with para-
paresis improving so that after 2 weeks she was able to
transfer independently, but still required 2-person assis-
tance for limited ambulation.
In month 9, the patient was rehospitalized for complete
paraplegia of the lower extremities, in the context of fever,
leukocytosis, crampy lower abdominal pain, and episodic
loose bowel movements. An infectious disease workup
demonstrated Clostridium difcile in stools and vancomy-
cin-resistant enterococcus in the urine, and she was
treated for the infections with metronidazole and lin-
ezolid, respectively. Over the following week, the patient
initially reported decreased left visual acuity, with bilat-
eral retroorbital pain. As left visual acuity was improving,
the patient developed severe deterioration in her right
visual acuity, progressing over 2 days. Formal ophthalmo-
logic evaluation revealed that she could barely discrimi-
nate gross hand movements in the right eye, and acuity
was 20/200 in the left eye. Both eyes demonstrated an
afferent papillary defect, red color desaturation was dem-
onstrated in the left eye, and there were no acute optic disc
abnormalities. With objective evidence of bilateral optic
neuritis, the patient now formally met denite diagnostic
criteria for NMO.
Over the ensuing days, the patient developed complete
weakness of her right arm, with MRC grade 2 out of 5
proximally and grade 4 out of 5 in intrinsic hand muscles.
MRI of the cervical and thoracic spine (Figure 1B) revealed
that increased signal previously seen on T2 sequences had
become more extensive and conuent, with expansion of
the cord demonstrating patchy, increased signal extending
from upper aspect of the dens into the conus. For acute
treatment of optic neuritis, the patient received methyl-
prednisolone 200 mg IV every day for 3 days, and then was
maintained on prednisone 60 mg by mouth every day. Due
to worsening clinical and radiographic progression of lon-
gitudinal myelitis, she received an additional dose of IV
cyclophosphamide. More intensive immunomodulatory
therapy was limited by concomitant infections with epi-
sodes of leukocytosis and hypotension.
Over the ensuing months, the patient has recovered
sufcient proximal lower strength so that she can initiate
transfers (MRC grade 23 out of 5), but is unable to ambu-
late independently. She recovered nearly full strength in
her right upper extremity, and she can now read ne print
with either eye. She has been re-admitted several times for
bilateral pneumonia and pulmonary emboli.
DISCUSSION
We described a case of NMO occurring in a patient with
lupus. Seropositivity for NMO IgG antibody was recently
incorporated as a major criterion in the revised diagnostic
criteria for NMO (7). To our knowledge, this is the rst
published case in which the recently described NMO IgG
antibody was used to conrm the diagnosis of NMO in a
349
patient with lupus. In an abstract presented at the 2006
American Academy of Neurology, Weinshenker et al iden-
tied 3 patients with clinical evidence of lupus or
Sjogrens syndrome and Devics disease with NMO IgG
positivity (8). Our case is unique because we demonstrate
seropositivity of NMO IgG before progression to clinically
denite NMO. Interestingly, seropositivity of NMO IgG
was documented before the patient had progressed to clin-
ically denite NMO. Given the inclusion of NMO antibod-
ies as part of the revised diagnostic criteria in Devics
syndrome, this case report emphasizes that American Col-
lege of Rheumatology classication criteria (9) should be
amended to include the evaluation of NMO autoantibodies
as part of the evaluation for lupus myelopathy, especially
in high-risk cases of longitudinal myelitis.
At the time of NMO IgG positivity, our patient had only
presented with recurrent episodes of a longitudinal myeli-
tis, with symptoms of transient monocular visual loss, but
with no corroborating physical ndings of an optic neuri-
tis. Although initially promulgated as a monophasic dis-
ease, a polyphasic course is now appreciated in up to 80%
of patients (4). Our patient developed evidence of optic
neuritis 9 months after development of myelopathy. Al-
though earlier diagnostic criteria placed restriction on the
time elapsed between optic and spinal cord disease, cur-
rent diagnostic criteria allow for signicant temporal seg-
regation of optic neuritis and myelitis.
When myelitis secondary to NMO occurs in a patient
with lupus, diagnostic distinction from multiple sclerosis
is crucial because interferon beta-1b treatments for MS can
cause lupus ares (2) and are ineffective in NMO (6). A
recent case report describing NMO occurring in a patient
with lupus (10) was criticized by Chan and Liu for not
clearly distinguishing features of lupus TM from MS (11);
Chan and Liu suggested that the presence or absence of
NMO IgG autoantibody might have claried this distinc-
tion.
The NMO antibody has recently been shown to bind to
aquaporin 4 (12), which is a water-pump channel associ-
ated with cerebral microvessels and endothelial foot pro-
cesses. Lennon et al noted that the presence of NMO IgG
antibody had a high specicity for NMO, occurring in
75% of patients with clinically denite NMO, as op-
posed to only 9% of patients with MS (3). Similarly, in our
patient, we documented NMO IgG positivity after recur-
rent episodes of longitudinal myelitis, but before there was
objective evidence of optic neuritis. Therefore, aside from
serving as a biomarker for the diagnosis of NMO, we pro-
pose that the NMO IgG autoantibody might serve as a
valuable prognostic tool in patients with lupus who
present with myelitis without optic neuritis, but who are
at increased risk to develop Devics syndrome. Such high-
risk features include recurrent episodes of myelitis; clini-
cal or radiographic evidence of longitudinal myelitis; and
spinal uid demonstrating a neutrophilic pleocytosis,
without evidence of intrathecal antibody production.
Identication of such high-risk features not only has obvi-
ous nosologic and prognostic implications, but suggests
different therapeutic strategies.
Early recognition that the myelopathy of NMO is being
350
mediated by a humorally mediated microangiopathy could
lead to earlier and mechanistic-based treatment while
there is a remediable inammatory phase, before progres-
sion to gray and white matter cylindrical necrosis. When
NMO presents monosymptomatically as a longitudinal
myelitis, plasmapheresis is often delayed until the inau-
gural myelopathic symptoms become coupled with optic
neuritis. Our case demonstrates that in patients with lupus
and TM, a polyphasic course, a longitudinal myelitis, and
a neutrophilic pleocytosis are features that warrant suspi-
cion for progression to NMO and should lead to testing for
the NMO IgG autoantibody. Our case further highlights the
difculty of treating NMO once there has been signicant
disease progression. Our patient was not referred to our
institution until she had experienced her fourth course of
recurrent myelitis, with evidence of worsening interictal
level of functioning.
This case report emphasizes that in patients with lupus
and myelopathy, recognition of Devics syndrome as a
distinct diagnostic entity is important not only because of
nosologic classication, but also because it augurs a para-
digm shift in the way such patients are evaluated and
treated. Despite the lack of evidence from controlled clin-
ical trials, the current standard of care in treating patients
with lupus with serious or life-threatening neurologic dis-
ease is intravenous cyclophosphamide, extrapolating from
the National Institutes of Health protocol used in manage-
ment of lupus nephritis (5). Luchinetti et al (13) have
shown that thickened spinal cord vessels of patients with
NMO feature deposition of immunoglobulins and comple-
ment C9 neoantigen, with vasculocentric and meningeal
inltration by neutrophil and eosinophils. With increasing
evidence that the myelitis in NMO is characterized by
antibody-mediated neutrophilic degranulation and che-
motactic damage (4), we believe that antibody and B cell
targeted therapy, such as intravenous immunoglobulin,
rituximab, and plasmapheresis, should be used earlier
and, in the absence of clinical trials, should be considered
with cyclophosphamide as the standard of care in patients
with lupus and NMO.
Although NMO is rarely described in patients with lu-
pus, we believe that this is due to unfamiliarity with NMO
as a distinct diagnostic entity. Throughout the past de-
cades, it is likely that many reports of lupus myelitis have
represented undiagnosed cases of NMO. Kovacs et al (14)
reviewed 105 case reports of TM in patients with lupus in
the English and German literature; although the subject of
optic neuritis was only addressed in 55 patients, 27 pa-
tients (48%) also had optic neuritis. Weinshenker et al (15)
have advocated broadening the NMO spectrum to include
syndromes restricted to the spinal cord but that have clin-
ical, radiographic, and serologic characteristics suggestive
of NMO, i.e., a longitudinal myelitis occurring in the NMO
IgG positivity. Other reports have noted longitudinal my-
elitis as a distinguishing radiographic feature in patients
with lupus (16,17), and it is likely that complementary use
of the NMO IgG autoantibody would now identify some of
these cases within the NMO spectrum of disease. In-
creased familiarity with the NMO syndrome, as well as
more widespread use of the NMO autoantibody, will lead
Birnbaum and Kerr
to increased diagnosis of NMO in patients otherwise diag-
nosed with an uncharacterized lupus myelitis.
In summary, we reported the rst published case of
NMO IgG positivity used to support the diagnosis of De-
vics syndrome occurring in a patient with lupus. Interest-
ingly, NMO IgG seropositivity was documented after re-
current episodes of longitudinal myelitis, but before
denitive diagnosis of optic neuritis. Earlier testing for
NMO IgG autoantibodies in patients with lupus and my-
elitis allows for anticipation of progression to NMO dis-
ease and will facilitate prompt institution of plasmaphere-
sis or other B celltargeted treatments before waiting for
episodes of optic neuritis or recurrent episodes of myelitis.
AUTHOR CONTRIBUTIONS
Dr. Birnbaum had full access to all of the data in the study and
takes responsibility for the integrity of the data.
Study design. Birnbaum.
Acquisition of data. Birnbaum.
Analysis and interpretation of data. Birnbaum, Kerr.
Manuscript preparation. Birnbaum, Kerr.
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