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Abstract

Background:

Interferon-β-1b (IFNβ-1b) has been used to prevent exacerbation of relapsing-remitting multiple sclerosis (RRMS) including optic-spinal multiple sclerosis (OSMS) in Japan. We encountered 2 patients with OSMS with unexpectedly severe exacerbation soon after the initiation of IFNβ-1b therapy. The experience urged us to retrospectively review the patients with RRMS who had been treated with IFNβ-1b to identify similar cases.

Methods:

At neurologic departments of 9 hospitals, the medical records of 56 patients with RRMS were reviewed to identify those who showed severe exacerbation soon after the initiation of IFNβ-1b therapy.

Results:

Of 56 patients with RRMS, we identified 7 who experienced severe exacerbation (exacerbation with increased scores of Expanded Disability Status Scale ≧7.0) within 90 days of the initiation of IFNβ-1b therapy. In all 7 patients, the exacerbations after the initiation of IFNβ-1b therapy were more severe than those experienced by the individual patients before the use of IFNβ-1b, and seemed to have occurred unexpectedly in a short time after the initiation of INFβ-1b therapy. A retrospective analysis revealed that all 7 patients had antibodies toward aquaporin 4, and the clinical features of all 7 patients after the exacerbation were consistent with those of neuromyelitis optica (NMO) spectrum.

Conclusions:

Our study suggests that IFNβ-1b may trigger severe exacerbation in patients with the NMO spectrum. In INFβ-1b therapy, cases in NMO spectrum should be carefully excluded.

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Supplementary Material

File (appendix_e-1.doc)
File (appendix_e-2.doc)
File (figure_e-1.pdf)
File (figure_e-2.pdf)
File (table_e-1.pdf)

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Letters to the Editor
17 February 2011
IFNβ-1b may severely exacerbate Japanese optic-spinal MS in neuromyelitis optica spectrum
Roberto Bomprezzi, Barrow Neurological Institute
J. Michael Powers, MD

Shimizu et al. report increased demyelination and inflammation following interferon- beta-1b (IFNB-1b)therapy in patients with optico-spinal multiple sclerosis (OSMS) and neuromyelitis optica (NMO). [1] In the accompanying editorial, Drs. Weinshenker and Wingerchuk [2] discuss whether a shift of immune response secondary to treatment with IFNB-1b may account for the unpredictable response. We contend that the offset of immune response capable of unpredictable demyelinating attacks is unknown and not necessarily confined to B-cell activity or Th2 shift.

A 42-year-old Caucasian female had, over the course of six months, two episodes of optic neuritis-one in each eye- and two attacks to the spinal cord consistent with acute recurrent myelitis. The MRI brain showed no signs of demyelination and, despite negative NMO-IgG, the patient was started on rituximab. Within two weeks, she developed a left hemispheric brain lesion similar to the one shown in Figure 1A. [1].

The brain lesion continued to expand and after six courses of monthly cyclophosphamide the active process was suppressed. The pathology obtained via brain biopsy revealed reactive hyper-cellularity with large perivascular macrophage accumulation, numerous CD3 positive T-cells, and rare CD20 positive B lymphocytes. Staining for aquaporin-4 was preserved.

Similar to the case described by Shimizu et al. [1], we suspect that the brain lesion developed unexpectedly but not secondary to IFNB-1b treatment. In addition, it was not driven by B-cells. The B-cell depletion following rituximab treatment could have prompted an unbalanced immune response that perpetrated the progressive inflammation.

Our patient description confirms that cases of OSMS can be seen in Caucasians [3] and IFNB-1b and B-cells do not play a major role in unusually large tumefactive lesions. The pathogenetic mechanisms in seronegative NMO and OSMS patients are still unclear.

References

1. Shimizu J, Hatanaka Y, Hasegawa M, et al. IFN beta-1b may severely exacerbate Japanese optic-spinal MS in neuromyelitis optica spectrum. Neurology 2010:75:1423-1427

2. Weinshenker BG, Wingerchuk DM. Japanese optic-spinal MS: Is it MS or neuromyelitis optica and does the answer dictate treatment? Neurology 2010;75:1404-1405.

3. Sheremata WA, Brown AD, Bedi G, Delgado S. NMO associated with destructive brain lesions in 3 cases. Neurology 2009;72(suppl 3). Abstract.

Disclosures:

R. Bomprezzi has served as a consultant for Teva Pharmaceutical Industries Ltd., EMD Serono and Biogen Idec; received research support from Genzyme Corporation, Novartis, Merck Serono, Biogen Idec, Genentech Inc., and UCB. Dr. Powers has given expert testimony and acted as an expert witness and consultant involving commercial entities.

17 February 2011
Reply from the authors
Jun Shimizu MD, PhD, Graduate School of Medicine
Shoji Tsuji MD PhD

We thank Drs. Bomprezzi and Powers for their interest in our article [1] and for describing their case.

The correspondents state that IFB1-b and B-cells do not play a role in unusually large tumefactive lesions. In addition, they contend that the clinical course of their patient and the development of unexpected tumefactive hemispheric lesions appear similar to our case 4. [1]

The suspected factor that triggered exacerbations, the positivity of NMO-IgG/anti-aquaporin 4 (AQP 4) antibody, and the response to treatment are different than our experience. In our patient, the anti-AQP 4 antibody was positive, whereas NMO-IgG was negative in their patient. In addition, our patient's brain lesion responded well to high-dose methylprednisolone therapy. Demyelinating disease with tumefactive lesions has been described as Marburg's disease, fulminant MS, Balo's concentric sclerosis, or tumefactive MS. Due to the rarity of these cases, the clinical features and pathological mechanisms of this type of demyelinating disease are still unclear.

It was recently shown that the final diagnosis in 70 percent of cases with tumefactive lesions was MS [4] and several patients with tumefactive brain lesions associated with NMO have also been reported. [5] In a recent report on Balo's concentric sclerosis, the AQP 4 loss without vasculocentric deposition of complement or immunoglobulin was seen. [6] Demyelinating disease with tumefactive lesions is probably heterogeneous regarding the positivity of NMO-IgG/anti-AQP 4 antibody as Kira et al. proposed. [7]

NMO-IgG was negative in the correspondents' patient despite the presentation of tumefactive lesions similar to our patient so the immune conditions underlying the tumefactive lesions in their patient should be different.

Further studies are necessary to determine if rituximab treatment induces unpredictable attacks with tumefactive lesions in demyelinating disease with negative NMO-IgG/anti-AQP 4 antibodies.

References

4. Lucchinetti CF, Gavrilova RH, Metz I, et al. Clinical and radiographic spectrum of pathologically confirmed tumefactive multiple sclerosis. Brain. 2008 Jul;131(Pt 7):1759-1775.

5. Saiki S, Ueno Y, Moritani T, et al. Extensive hemispheric lesions with radiological evidence of blood-brain barrier integrity in a patient with neuromyelitis optica. J Neurol Sci. 2009;284:217-219.

6. Matsuoka T, Suzuki SO, Iwaki T, et al. Aquaporin-4 astrocytopathy in Balo's disease. Acta Neuropathol. 2010;120:651-660.

7. Matsuoka T, Matsushita T, Osoegawa M, et al. Heterogeneity and continuum of multiple sclerosis in Japanese according to magnetic resonance imaging findings. J Neurol Sci. 2008;266:115-125.

See original articles for disclosures.
17 February 2011
Reply from the Editorialists
Brian G. Weinshenker, Department of Neurology
Dean M. Wingerchuk

Drs. Bomprezzi and Powers raise several issues based on their experience with a single patient. Shimizu et al. [1] based their findings on a consecutive series of patients who developed severe brain lesions after interferon treatment, all of whom had aquaporin-4 autoantibody seropositive neuromyelitis optica (NMO). A single patient with a poor response to therapy is rarely as informative as a consecutive series; it would be difficult to conclude that rituximab was responsible for the deterioration of Drs. Bomprezzi and Power's patient, although it is possible.

It was recently reported that treatment with rituximab can be associated with a short term increase in NMO relapse frequency. [8] Drs. Bomprezzi and Power's NMO patient was seronegative but it is difficult to determine whether these patients have seronegative NMO or another demyelinating condition due to imperfect sensitivity of current generation tests for aquaporin-4 autoantibodies. That stainable aquaporin-4 was present in the acute lesion further calls into question the diagnosis of NMO although the role of immunopathology in this diagnosis is not adequately defined.

Drs. Bomprezzi and Powers do not mention the length of the spinal cord lesion in this patient. Selective optic nerve and spinal cord inflammatory disease alone are not adequate for a diagnosis of NMO unless additional specificity characteristics are satisfied. [9]

We agree that the mechanism(s) underlying the immunological effects of any of the drugs to treat and of drugs that apparently exacerbate NMO are poorly understood and the quest for understanding should continue.

References

8. Permal J, Kister I, Howard J, Herbert J. Paradoxical response after first rituximab infusion in patients with neuromyelitis optica. Mult Scler 2010;16:S300.

9. Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG. Revised diagnostic criteria for neuromyelitis optica. Neurology 2006;66:1485-1489.

For original disclosures, please see editorial.

Information & Authors

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Published In

Neurology®
Volume 75Number 16October 19, 2010
Pages: 1423-1427
PubMed: 20826711

Publication History

Received: January 10, 2010
Accepted: June 7, 2010
Published online: September 8, 2010
Published in print: October 19, 2010

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Disclosure

Dr. Shimizu has received research support from Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. Dr. Hatanaka and Dr. Hasegawa report no disclosures. Dr. Iwata serves as a consultant for Pfizer Inc. and receives research support from Janssen, the Japanese Society for Promotion of Science, Mochida Memorial Foundation for Medical and Pharmaceutical Research, Sankyo Foundation for Life Science, and the Brain Science Foundation. Dr. Sugimoto, Dr. Date, Dr. Goto, Dr. Shimizu, Dr. Takatsu, Dr. Sakurai, Dr. Nakase, Dr. Uesaka, Dr. Hashida, and Dr. Komiya report no disclosures. Dr. Tsuji receives research support from Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

Authors

Affiliations & Disclosures

J. Shimizu, MD, PhD
From the Department of Neurology (J.S., M.H., A.I., I.S., H.D., J.G., S.T.), Graduate School of Medicine, University of Tokyo; Department of Neurology (Y.H., T.S.), University of Teikyo; Department of Neurology (M.T.), Tokyo Postal Services Agency Hospital; Department of Neurology (Y.S.), Mitsui Memorial Hospital; Department of Neurology (H.N.), Toranomon Hospital; Department of Neurology (Y.U.), International Medical Center; Department of Neurology (H.H.), Japanese Red Cross Medical Center; Department of Neurology (K.H.), Toshiba General Hospital; and Department of Neurology (T.K.), Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan.
Y. Hatanaka, MD, PhD
From the Department of Neurology (J.S., M.H., A.I., I.S., H.D., J.G., S.T.), Graduate School of Medicine, University of Tokyo; Department of Neurology (Y.H., T.S.), University of Teikyo; Department of Neurology (M.T.), Tokyo Postal Services Agency Hospital; Department of Neurology (Y.S.), Mitsui Memorial Hospital; Department of Neurology (H.N.), Toranomon Hospital; Department of Neurology (Y.U.), International Medical Center; Department of Neurology (H.H.), Japanese Red Cross Medical Center; Department of Neurology (K.H.), Toshiba General Hospital; and Department of Neurology (T.K.), Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan.
M. Hasegawa, MD
From the Department of Neurology (J.S., M.H., A.I., I.S., H.D., J.G., S.T.), Graduate School of Medicine, University of Tokyo; Department of Neurology (Y.H., T.S.), University of Teikyo; Department of Neurology (M.T.), Tokyo Postal Services Agency Hospital; Department of Neurology (Y.S.), Mitsui Memorial Hospital; Department of Neurology (H.N.), Toranomon Hospital; Department of Neurology (Y.U.), International Medical Center; Department of Neurology (H.H.), Japanese Red Cross Medical Center; Department of Neurology (K.H.), Toshiba General Hospital; and Department of Neurology (T.K.), Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan.
A. Iwata, MD, PhD
From the Department of Neurology (J.S., M.H., A.I., I.S., H.D., J.G., S.T.), Graduate School of Medicine, University of Tokyo; Department of Neurology (Y.H., T.S.), University of Teikyo; Department of Neurology (M.T.), Tokyo Postal Services Agency Hospital; Department of Neurology (Y.S.), Mitsui Memorial Hospital; Department of Neurology (H.N.), Toranomon Hospital; Department of Neurology (Y.U.), International Medical Center; Department of Neurology (H.H.), Japanese Red Cross Medical Center; Department of Neurology (K.H.), Toshiba General Hospital; and Department of Neurology (T.K.), Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan.
I. Sugimoto, MD
From the Department of Neurology (J.S., M.H., A.I., I.S., H.D., J.G., S.T.), Graduate School of Medicine, University of Tokyo; Department of Neurology (Y.H., T.S.), University of Teikyo; Department of Neurology (M.T.), Tokyo Postal Services Agency Hospital; Department of Neurology (Y.S.), Mitsui Memorial Hospital; Department of Neurology (H.N.), Toranomon Hospital; Department of Neurology (Y.U.), International Medical Center; Department of Neurology (H.H.), Japanese Red Cross Medical Center; Department of Neurology (K.H.), Toshiba General Hospital; and Department of Neurology (T.K.), Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan.
H. Date, PhD
From the Department of Neurology (J.S., M.H., A.I., I.S., H.D., J.G., S.T.), Graduate School of Medicine, University of Tokyo; Department of Neurology (Y.H., T.S.), University of Teikyo; Department of Neurology (M.T.), Tokyo Postal Services Agency Hospital; Department of Neurology (Y.S.), Mitsui Memorial Hospital; Department of Neurology (H.N.), Toranomon Hospital; Department of Neurology (Y.U.), International Medical Center; Department of Neurology (H.H.), Japanese Red Cross Medical Center; Department of Neurology (K.H.), Toshiba General Hospital; and Department of Neurology (T.K.), Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan.
J. Goto, MD, PhD
From the Department of Neurology (J.S., M.H., A.I., I.S., H.D., J.G., S.T.), Graduate School of Medicine, University of Tokyo; Department of Neurology (Y.H., T.S.), University of Teikyo; Department of Neurology (M.T.), Tokyo Postal Services Agency Hospital; Department of Neurology (Y.S.), Mitsui Memorial Hospital; Department of Neurology (H.N.), Toranomon Hospital; Department of Neurology (Y.U.), International Medical Center; Department of Neurology (H.H.), Japanese Red Cross Medical Center; Department of Neurology (K.H.), Toshiba General Hospital; and Department of Neurology (T.K.), Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan.
T. Shimizu, MD, PhD
From the Department of Neurology (J.S., M.H., A.I., I.S., H.D., J.G., S.T.), Graduate School of Medicine, University of Tokyo; Department of Neurology (Y.H., T.S.), University of Teikyo; Department of Neurology (M.T.), Tokyo Postal Services Agency Hospital; Department of Neurology (Y.S.), Mitsui Memorial Hospital; Department of Neurology (H.N.), Toranomon Hospital; Department of Neurology (Y.U.), International Medical Center; Department of Neurology (H.H.), Japanese Red Cross Medical Center; Department of Neurology (K.H.), Toshiba General Hospital; and Department of Neurology (T.K.), Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan.
M. Takatsu, MD, PhD
From the Department of Neurology (J.S., M.H., A.I., I.S., H.D., J.G., S.T.), Graduate School of Medicine, University of Tokyo; Department of Neurology (Y.H., T.S.), University of Teikyo; Department of Neurology (M.T.), Tokyo Postal Services Agency Hospital; Department of Neurology (Y.S.), Mitsui Memorial Hospital; Department of Neurology (H.N.), Toranomon Hospital; Department of Neurology (Y.U.), International Medical Center; Department of Neurology (H.H.), Japanese Red Cross Medical Center; Department of Neurology (K.H.), Toshiba General Hospital; and Department of Neurology (T.K.), Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan.
Y. Sakurai, MD, PhD
From the Department of Neurology (J.S., M.H., A.I., I.S., H.D., J.G., S.T.), Graduate School of Medicine, University of Tokyo; Department of Neurology (Y.H., T.S.), University of Teikyo; Department of Neurology (M.T.), Tokyo Postal Services Agency Hospital; Department of Neurology (Y.S.), Mitsui Memorial Hospital; Department of Neurology (H.N.), Toranomon Hospital; Department of Neurology (Y.U.), International Medical Center; Department of Neurology (H.H.), Japanese Red Cross Medical Center; Department of Neurology (K.H.), Toshiba General Hospital; and Department of Neurology (T.K.), Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan.
H. Nakase, MD, PhD
From the Department of Neurology (J.S., M.H., A.I., I.S., H.D., J.G., S.T.), Graduate School of Medicine, University of Tokyo; Department of Neurology (Y.H., T.S.), University of Teikyo; Department of Neurology (M.T.), Tokyo Postal Services Agency Hospital; Department of Neurology (Y.S.), Mitsui Memorial Hospital; Department of Neurology (H.N.), Toranomon Hospital; Department of Neurology (Y.U.), International Medical Center; Department of Neurology (H.H.), Japanese Red Cross Medical Center; Department of Neurology (K.H.), Toshiba General Hospital; and Department of Neurology (T.K.), Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan.
Y. Uesaka, MD, PhD
From the Department of Neurology (J.S., M.H., A.I., I.S., H.D., J.G., S.T.), Graduate School of Medicine, University of Tokyo; Department of Neurology (Y.H., T.S.), University of Teikyo; Department of Neurology (M.T.), Tokyo Postal Services Agency Hospital; Department of Neurology (Y.S.), Mitsui Memorial Hospital; Department of Neurology (H.N.), Toranomon Hospital; Department of Neurology (Y.U.), International Medical Center; Department of Neurology (H.H.), Japanese Red Cross Medical Center; Department of Neurology (K.H.), Toshiba General Hospital; and Department of Neurology (T.K.), Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan.
H. Hashida, MD, PhD
From the Department of Neurology (J.S., M.H., A.I., I.S., H.D., J.G., S.T.), Graduate School of Medicine, University of Tokyo; Department of Neurology (Y.H., T.S.), University of Teikyo; Department of Neurology (M.T.), Tokyo Postal Services Agency Hospital; Department of Neurology (Y.S.), Mitsui Memorial Hospital; Department of Neurology (H.N.), Toranomon Hospital; Department of Neurology (Y.U.), International Medical Center; Department of Neurology (H.H.), Japanese Red Cross Medical Center; Department of Neurology (K.H.), Toshiba General Hospital; and Department of Neurology (T.K.), Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan.
K. Hashimoto, MD, PhD
From the Department of Neurology (J.S., M.H., A.I., I.S., H.D., J.G., S.T.), Graduate School of Medicine, University of Tokyo; Department of Neurology (Y.H., T.S.), University of Teikyo; Department of Neurology (M.T.), Tokyo Postal Services Agency Hospital; Department of Neurology (Y.S.), Mitsui Memorial Hospital; Department of Neurology (H.N.), Toranomon Hospital; Department of Neurology (Y.U.), International Medical Center; Department of Neurology (H.H.), Japanese Red Cross Medical Center; Department of Neurology (K.H.), Toshiba General Hospital; and Department of Neurology (T.K.), Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan.
Deceased.
T. Komiya, MD, PhD
From the Department of Neurology (J.S., M.H., A.I., I.S., H.D., J.G., S.T.), Graduate School of Medicine, University of Tokyo; Department of Neurology (Y.H., T.S.), University of Teikyo; Department of Neurology (M.T.), Tokyo Postal Services Agency Hospital; Department of Neurology (Y.S.), Mitsui Memorial Hospital; Department of Neurology (H.N.), Toranomon Hospital; Department of Neurology (Y.U.), International Medical Center; Department of Neurology (H.H.), Japanese Red Cross Medical Center; Department of Neurology (K.H.), Toshiba General Hospital; and Department of Neurology (T.K.), Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan.
S. Tsuji, MD, PhD
From the Department of Neurology (J.S., M.H., A.I., I.S., H.D., J.G., S.T.), Graduate School of Medicine, University of Tokyo; Department of Neurology (Y.H., T.S.), University of Teikyo; Department of Neurology (M.T.), Tokyo Postal Services Agency Hospital; Department of Neurology (Y.S.), Mitsui Memorial Hospital; Department of Neurology (H.N.), Toranomon Hospital; Department of Neurology (Y.U.), International Medical Center; Department of Neurology (H.H.), Japanese Red Cross Medical Center; Department of Neurology (K.H.), Toshiba General Hospital; and Department of Neurology (T.K.), Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan.

Notes

Address correspondence and reprint requests to Dr. Jun Shimizu, Department of Neurology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan [email protected]
Study funding: Supported by Grants-in-Aid for Scientific Research and Health and Labour Sciences Research Grants for Research on Intractable Diseases from the Ministry of Health, Labour and Welfare of Japan.

Author Contributions

J.S. was involved in the study design and wrote the report. All the authors reviewed and validated data and final analyses. J.S. had full access to the complete set of data. J.S., Y.H., M.H., I.S., Y.S., H.N., Y.U., H.H., K.H., and T.K. contributed to the analysis of the data. A.I., M.H., and H.D. contributed to the assay of the anti-AQP4 antibody. J.G., T.S., M.T., and S.T. were involved in and contributed to the writing and review of the manuscript. All the authors have seen and approved the final version of the manuscript.

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