Abstract
Objectives: To report an association of myelin-oligodendrocyte glycoprotein (MOG) antibodies with aquaporin-4 (AQP4) antibody–seronegative neuromyelitis optica (NMO) and neuromyelitis optica spectrum disorder (NMOSD) in adults.
Methods: We describe the clinical and serologic features of 4 adult patients with an NMO/NMOSD phenotype who had antibodies to MOG.
Results: Twenty-seven adult AQP4-seronegative NMO/NMOSD patients were tested for MOG antibodies. Four patients (3 male, 1 female) with severe optic neuritis and/or longitudinally extensive transverse myelitis were positive. All 4 made good recoveries with steroids or plasma exchange. Two patients experienced recurrence of symptoms when corticosteroids were withdrawn quickly but none have experienced further relapses over a mean follow-up of 12 months, although 3 patients remain on treatment. Imaging abnormalities resolved fully following clinical recovery and MOG antibody titers fell in all 4 patients. MOG antibodies were not found in 44 AQP4 antibody–positive NMO/NMOSD patients, 75 adult patients with multiple sclerosis, or 47 healthy individuals.
Conclusions: MOG antibody–associated NMO/NMOSD could account for some cases thought previously to be AQP4-seronegative NMO/NMOSD. Our 4 patients appear to have more favorable clinical outcomes than those with typical AQP4 antibody–mediated disease. However, further studies of NMO/NMOSD and other demyelinating conditions are required to help clarify the diagnostic and prognostic relevance of MOG antibodies.
GLOSSARY
- ADEM=
- acute disseminated encephalomyelitis;
- AQP4 =
- aquaporin-4;
- AQP4-Abs =
- antibodies targeting aquaporin-4;
- MOG =
- myelin-oligodendrocyte glycoprotein;
- MOG-Abs =
- myelin-oligodendrocyte glycoprotein antibodies;
- MS =
- multiple sclerosis;
- NMO =
- neuromyelitis optica;
- NMOSD =
- neuromyelitis optica spectrum disorder;
- ON =
- optic neuritis;
- TM =
- transverse myelitis
Neuromyelitis optica (NMO), known traditionally as Devic disease, describes the association of inflammatory optic neuritis (ON) and longitudinally extensive transverse myelitis (TM). Limited forms of the disease are known as NMO spectrum disorder (NMOSD). Antibodies targeting the water channel aquaporin-4 (AQP4-Abs) are found in the sera of most patients with NMO1 and their presence predicts a high risk of further attacks2 with a need for long-term immunosuppression. It is unclear whether patients with an NMO/NMOSD phenotype without AQP4-Abs have the same disease with a similar requirement for aggressive treatment.
The original description of Devic disease, that of monophasic sequential TM and ON,3 is relatively rare in AQP4-Ab–seropositive NMO,4 but higher rates have been reported when AQP4-Ab–seronegative patients are included in cohorts.5,6 Such monophasic multifocal inflammation within the CNS is more reminiscent of acute disseminated encephalomyelitis (ADEM). Myelin-oligodendrocyte glycoprotein antibodies (MOG-Abs) have been described in pediatric ADEM and we wondered whether they may also occur in seronegative NMO/NMOSD, particularly in those with classic Devic disease. We found MOG-Abs in 4 adult patients within our AQP4-Ab–seronegative NMO/NMOSD cohort, 3 of whom had a classic Devic phenotype with simultaneous or sequential ON and TM.
METHODS
We identified 27 clinically well-characterized adult AQP4-Ab–seronegative NMO/NMOSD patients referred through our National Specialist NMO clinic in Oxford and tested them for MOG-Abs. We also tested 44 AQP4-Ab–positive adult NMO/NMOSD patients. Samples were tested at least twice using a cell-based assay as described previously7 (cDNA courtesy of Dr. K. O'Connor, Yale University, New Haven, CT). Immunofluorescence analysis was performed blinded by 2 independent observers using a semiquantitative scoring system.8 Serum samples scoring 1 or more by both observers at 1:20 dilution were classed as positive. MOG-Ab titers were obtained by endpoint dilution of the sera. The MOG-Ab assay was negative in healthy adults (n = 47) and patients with locally confirmed clinically definite adult multiple sclerosis (MS) (n = 75).
Standard protocol approvals, registrations, and patient consents.
The study was approved by the regional ethics committee and all patients provided written informed consent.
RESULTS
Of the 27 AQP4-Ab–seronegative NMO/NMOSD patients, 4 were positive for MOG-Abs, 3 of whom had a classic Devic syndrome with simultaneous or sequential ON and longitudinally extensive TM. The remaining AQP4-Ab–seronegative NMO/NMOSD patients, 14 of whom were monophasic (3 with a classic Devic syndrome), were negative for MOG-Abs. The 44 AQP4-Ab–positive patients all tested negative for MOG-Abs and none of them had a monophasic classic Devic phenotype. Typical antibody binding to MOG-transfected cells is shown in figure 1A. Serial dilutions showed that MOG-Ab titers decreased over time in all patients, with 1 patient becoming seronegative (figure 1B). The MOG-Ab positive patients are described below and their investigation results are summarized in the table.
(A) Binding of patients' serum immunoglobulin G (IgG) to MOG-expressing HEK cells. MOG-EGFP transfected HEK cells are shown in green, and detection of patients' IgG identified with red-antihuman IgG. Serum from a healthy control does not show any IgG binding to MOG-EGFP expressing cells. (B) MOG antibody (MOG-Ab) titers at presentation (patients 2–4) or when first tested (patient 1), and at last follow-up of all 4 patients plotted against duration from first presentation of disease. MOG-Ab levels were variable at presentation, and all decreased over time; patient 2 had the lowest MOG-Ab levels at disease onset, and was the only patient with undetectable Ab levels at 6 months of follow-up. The titers were measured by endpoint dilutions of the sera. Of note, no patients were treatment-naive prior to MOG-Ab testing.
Summary of investigations in MOG antibody–positive NMO/NMOSD patients
Case 1.
A 32-year-old Asian woman developed mild leg paresthesia following a coryzal illness, which settled spontaneously within 2 weeks. Two months later she developed painful unilateral visual loss to counting fingers in the right eye. She recovered fully following 2 weeks of oral corticosteroid treatment. One month later she developed acute leg weakness and paresthesia with urinary retention. There was severe pyramidal weakness in the legs with hyperreflexia and impaired sensation below T6. She was treated again with IV corticosteroids with substantial recovery over several weeks. Azathioprine was commenced for presumed seronegative NMO and she received oral prednisolone for 11 months. At follow-up 15 months after first symptom onset she has some urinary urgency but otherwise has no residual disability. She has remained on azathioprine.
Case 2.
A 27-year-old Asian man developed paresthesia in the hands and feet over 1 week followed by acute urinary retention and quadriparesis. There was no preceding illness and no ocular symptoms. On neurologic examination the legs were plegic and there was severe upper limb weakness. He was treated with IV methylprednisolone followed after 48 hours by plasma exchange, which led to a dramatic improvement. Oral prednisolone was commenced. Within 2 months the patient was independently mobile and neurologic examination was unremarkable except for brisk lower limb reflexes. At 12-month follow-up the patient remains well on tapering oral prednisolone (present dosage 25 mg alternate days).
Case 3.
A 34-year-old Caucasian man developed bilateral sequential visual loss over 1 week with paresthesia in both legs and hands and a band-like sensation around the trunk. There was no preceding illness. Visual acuities were decreased to 20/120 right and 20/60 left and both optic discs were swollen. Examination of the limbs was unremarkable. He was treated with IV steroids and recovered fully within 6 weeks. At 12-month follow-up he remains well off treatment.
Case 4.
A 16-year-old Caucasian boy developed painful visual loss followed after 48 hours by back pain and paresthesia in both legs. Examination revealed bilateral optic disc swelling and impaired vision to finger counting on the right and 20/80 left. Tone was increased in the legs with brisk reflexes and hyperesthesia but strength was preserved. He was treated with IV steroids with full recovery and then received a 1-month reducing course of oral dexamethasone. One week after stopping steroids, he developed visual loss in the right eye, which resolved promptly with reintroduction of oral dexamethasone, which was continued for a further month and then stopped. Two weeks after stopping steroids he developed back pain and sensory disturbance in the legs with impaired sensation below T4. He was treated again with IV steroids with quick and complete recovery. This was followed by oral prednisolone. By 4 months post initial presentation the patient was symptom-free and 10 months post presentation he remains well on tapering oral prednisolone (present dosage 20 mg daily).
DISCUSSION
We have described a MOG-Ab phenotype in adults, which appears to fit the original description of Devic disease3 and may account for some cases of AQP4-Ab–seronegative NMO/NMOSD.
MOG is a CNS-specific antigen that is expressed on the outer surface of myelin sheaths. Like AQP4, MOG is accessible to autoantibodies in the extracellular space, and MOG-Abs are potentially pathogenic. Antibodies to conformationally expressed MOG have previously been described in ADEM and variably in MS, usually childhood onset.9,–,13 Although we did not identify MOG-Abs in our locally characterized adult MS cohort (or in a further 300 patients with MS, unpublished data), in addition to the adult patients described here, we identified 3 MOG-Ab–positive pediatric patients, 2 with an ADEM-like illness and 1 with atypical MS. The phenotype of MOG-Ab–positive childhood ADEM has not been described in sufficient detail to establish if it is Devic-like or indistinguishable from classic ADEM.
Three of the 4 MOG-Ab–positive patients were male, ON and TM occurred simultaneously or sequentially in 3, and the clinical recovery was excellent. Moreover, MRI abnormalities resolved completely on follow-up imaging and evoked potentials normalized in 3/3 patients evaluated (figure 2). In addition, no patient has subsequently relapsed, although immunosuppressive therapy has been withdrawn in 1 and substantially tapered in 3. By contrast, AQP4-Ab–positive NMO/NMOSD is female predominant,4 the full syndrome of ON and TM at onset is unusual,4 as we have found in our patients, and relapse-related disability is common.14 In our experience, evoked potentials tend to remain abnormal and spinal cord imaging usually shows persistent abnormal signal change and atrophy. Thus, our results suggest that in adults MOG-Abs may be found in an apparently monophasic Devic-like phenotype, perhaps indicating overlap of this condition with ADEM.
(A–D) Coronal fluid-attenuated inversion recovery brain MRI during acute illness in patient 3 shows T2 hyperintensity in the right thalamus (A) and the right cerebellar hemisphere (B), with resolution of changes 1 year later (C, D). (E, F) T2 hyperintensity extending from T4/5 to T11 during acute illness in patient 4 (E), with complete lesion resolution at 10-month follow-up (F).
As noted in our patients, MOG-Ab titers in pediatric ADEM are reported to decrease over time.12,13 By contrast, MOG-Ab titers in pediatric MS tend to be lower and remain stable over time or even increase.12,13 As is well-recognized in ADEM, 2 of our patients experienced early recurrence of symptoms when corticosteroids were withdrawn quickly. None of our patients had encephalopathy, a requirement for pediatric ADEM, but generally this is rare in adult ADEM.15
Although the mean follow-up period in our patients is only 12 months, our findings suggest that MOG-Ab–positive NMO/NMOSD adults may have a more favorable prognosis than AQP4-Ab–positive patients. A recent study16 also found MOG-Abs in some adults with NMOSD but in contrast to our findings, some patients had relapsing disease; low titers of MOG-Abs were also found in a few adult patients with MS or other neurologic conditions. This may reflect differences in the assays used but it does appear that MOG-Abs, particularly at low titer, may lack specificity. However, the positive MOG-Ab results in some children and adults with ADEM or NMOSD, and the negative results in MS in our hands, suggest that MOG-Ab testing can have the sensitivity and specificity consistent with a useful role in the differential diagnoses of these conditions. Although MOG-Abs can produce inflammation and demyelination in animal models,17 a pathogenic role has not yet been proven in humans. Further studies are required to fully characterize MOG-Ab disease, optimize the assays, and determine the role of the antibodies.
AUTHOR CONTRIBUTIONS
J. Kitley: drafting/revising the manuscript for content, including medical writing for content, analysis or interpretation of data. M. Woodhall: drafting/revising the manuscript for content, including medical writing for content, analysis or interpretation of data, study concept or design. P. Waters: drafting/revising the manuscript for content, including medical writing for content, study concept or design, analysis or interpretation of data. M.I. Leite: drafting/revising the manuscript. E. Devenney: drafting/revising the manuscript for content, including medical writing for content. J. Craig: drafting/revising the manuscript for content, including medical writing for content. J. Palace: drafting/revising the manuscript for content, including medical writing for content, study concept or design, analysis or interpretation of data. A. Vincent: drafting/revising the manuscript for content, including medical writing for content, study concept or design, analysis or interpretation of data.
DISCLOSURE
J. Kitley has received support for scientific meetings from Biogen Idec and is supported by the NHS National Specialised Commissioning Group for Neuromyelitis Optica. M. Woodhall, P. Waters, and M.I. Leite are involved in AQP4 and MOG antibody testing, supported by the NHS National Specialised Commissioning Group for Neuromyelitis Optica and by the NIHR Oxford Biomedical Research Centre. E. Devenney reports no disclosures. J. Craig has received grants for research projects and honoraria for giving lectures from UCB-Pharma, Janssen-Cilag, Sanofi-Aventis, Pfizer, GSK, and Eisai. J. Palace has received unrestricted grants and support for scientific meetings and scientific advisory honorariums from Merck Serono, TEVA, Biogen, Bayer Schering, and Novartis, has held MS society grants, is a clinical lead for the UK DOH RSS, and is supported by the NHS National Specialised Commissioning Group for Neuromyelitis Optica. A. Vincent and the Nuffield Department of Clinical Neurosciences hold patents and receive royalties and payments for antibody tests. Go to Neurology.org for full disclosures.
- Received September 6, 2011.
- Accepted March 28, 2012.
- Copyright © 2012 by AAN Enterprises, Inc.
REFERENCES
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