Oct 23, 2012 - by severe optic neuritis and transverse myelitis. Since the discovery of anti-aquaporin-4 (AQP4) anti- body,1,2 an NMO-specific autoantibody, ...
Yoshiki Takai, MD Tatsuro Misu, MD, PhD Ichiro Nakashima, MD, PhD Toshiyuki Takahashi, MD, PhD Yasuto Itoyama, MD, PhD Kazuo Fujihara, MD, PhD Masashi Aoki, MD, PhD
Supplemental data at www.neurology.org Supplemental Data
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TWO CASES OF LUMBOSACRAL MYELORADICULITIS WITH ANTI-AQUAPORIN-4 ANTIBODY
Neuromyelitis optica (NMO) is an inflammatory disease of the CNS which is typically characterized by severe optic neuritis and transverse myelitis. Since the discovery of anti-aquaporin-4 (AQP4) antibody,1,2 an NMO-specific autoantibody, other unique features of NMO have been clarified. NMO lesions tend to be localized in site of AQP4 expression, such as dorsomedial medulla lesions or hypothalamic lesions.3–5 Here we report 2 cases of NMO spectrum disorders (NMOSD) with lumbosacral myeloradiculitis. Case reports. Case 1. A 79-year-old woman was admitted to our hospital in May 2007. Because of her previous history of longitudinally extensive myelitis at age 72 and left frontal lesion at age 78 with antiAQP4 antibody, she was diagnosed with NMOSD. One week before admission, she had gait disturbance because of her right leg weakness. Neurologic examination revealed mild muscle weakness in the right leg, vibratory sense disturbance in both legs, and right Achilles tendon hyporeflexia. MRI demonstrated a T2 high-intense lesion with gadolinium enhancement at conus medullaris. Moreover, the enhancement was also observed in spinal roots and cauda equina (figure, A–C). CSF examination showed increased immunoglobulin G (IgG) index (1.86) and positive oligoclonal IgG bands without pleocytosis or elevated protein concentration. Her symptoms did not respond to the initial 2 courses of IV methylprednisolone, but improved by 4 times of plasma exchanges. She had no further relapse after the treatment with low-dose prednisolone until she suddenly died at age 81. Pathologically, chronic inactive demyelinating lesions and complete loss of myelinated fibers with few macrophage infiltrations were seen at right ventral portion of the lumbar cord (Th12 to L3 level). Most parts of the lesion showed loss of glial fibrillary acidic protein (GFAP) and AQP4, which was compatible with the previously reported histopathologic findings in NMO.6 In addition, right anterior root at Th12 level contiguous with the spinal cord lesion was demyelinated (figure, J). A part of cauda equina at Th12 and L1 levels close to the cord was also demyelinated, especially at the inner half area of myelin sheaths suggesting transitional zone (normal pattern is shown in the figure, K–N). This work was approved by the ethical committee and informed consent was performed. Case 2. A 67-year-old woman without any previous history of neurologic disorder was admitted to Neurology 79
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our hospital in September 1997 because of the rapid progression of muscle weakness of both legs, initially diagnosed as Guillain-Barre´ syndrome. Neurologic examination showed distal dominant flaccid paraparesis, sensory disturbance below L2 level, areflexia of lower extremities, dysuria, and constipation. CSF examination revealed high protein concentration (113 mg/dL) without pleocytosis. Spinal MRI demonstrated diffuse high-intense lesion extending from Th11 to the conus medullaris on T2-weighted image (figure, D–G). Axial image showed the T2 high-intense lesion mainly located in the central gray matter, and right side of the cord and cauda equina were diffusely enhanced. She was treated with 6 plasma exchanges with good recovery. She did not show further exacerbations without any immunosuppressive treatment. In 2006, the anti-AQP4 antibody was revealed as positive with 1:64 titer. Discussion. The lesions in the conus medullaris were rare in anti-AQP4 antibody positive cases: only 5 out of 316 acute exacerbations in 52 patients with anti-AQP4 antibody in our hospital. There were 2 cases with extensive longitudinally transverse myelitis from cervical or upper thoracic levels to conus medullaris, and 1 case with an isolated conus lesion, but none of these cases had involvement of nerve roots. Thus only the present 2 cases developed myeloradiculitis. We confirmed histopathologically the existence of demyelinating lesions at anterior root and cauda equina, especially observed at the inner half of spinal root. Schwann cell can penetrate to the CNS via spinal root causing remyelination, which was recognized as the damage sign of the glial limitans in spinal cord lesions of NMO.6 In addition, it is known that CNS structures discriminated by glial limitance stained by GFAP were partially protruding into radial root of peripheral nervous system (PNS).7 Furthermore, we could find expression of AQP4 at the transitional zone in normal controls, especially inner part of cauda equina adjacent to the spinal cord (figure, K–N). These facts could explain the interesting demyelinating pattern seen at cauda equina and we consider this CNS-PNS transitional zone could be the target of radiculitis in NMOSD. The possibility cannot be excluded that these 2 cases have complication of other diseases. However, careful diagnostic workup (appendix e-1 on the Neurology ® Web site at www.neurology.org) could exclude alternative diagnoses such as malignancy, infections, and other systemic autoimmune diseases. Taken together, we
Figure
Spinal cord MRI and pathologic features of myeloradiculitis in neuromyelitis optica
(A–C) Spinal cord MRI in case 1. T2 high-intense lesion was seen at conus medullaris (A, allows). Axial image showed the gadolinium-enhanced lesions in right ventral side, anterior root, and right side of cauda equina. (D–G) Spinal cord MRI in case 2. Sagittal T2-weighted image showed longitudinally extensive lesion from Th10 to L4 level (D). Axial image showed T2 high-intense lesion completely located at gray matter of the spinal cord (E). Right side of the spinal cord (F) and large number of cauda equina (G) was enhanced with gadolinium. (H–J) Histopathologic findings of the spinal cord (Th12 level) of case 1. Klu ¨ver-Barrera (KB) staining showed the mostly complete loss of myelin sheaths at right ventral side of the spinal cord (H). Anterior root connecting to the cord lesion showed demyelination (KB), where aquaporin 4 (AQP4) (pink) staining was completely lost (I). High magnification of selected box area (H) showed the partial demyelinating lesion especially at the inner half of the cauda equina (J) (KB, ⫻200). (K–N) Normal expression pattern of AQP4 at spinal root and cauda equina. AQP4 was expressed at inner part of the anterior (K) or posterior (L) root and cauda equina adjacent to spinal cord; in contrast, Schwann cell existed mainly at outer part (M), suggesting the transitional zone of the CNS (K: AQP4 staining, pink; L: AQP4 staining, brown; M: P0 staining, blue). (N) An illustration of a typical structure of transitional zone (L, M) shows the special location of CNS (brown) at the inner part of cauda equina separated from peripheral nervous system (blue), especially at the axial view of the line adjacent to the spinal cord.
consider the myeloradiculitis seen in the present cases were caused by anti-AQP4 antibody.
Center Hospital (Y.I.), National Center of Neurology and Psychiatry, Kodaira, Japan.
From the Departments of Neurology (Y.T., T.M., I.N., K.F., M.A.) and Multiple Sclerosis Therapeutics (T.M., K.F.), Tohoku University Graduate School of Medicine, Sendai; Department of Neurology (T.T.), National Yonezawa Hospital, Yonezawa; and National
Author contributions: Study design and conceptualization: Y.T., T.M. Drafting of manuscript: Y.T., T.M., K.F. Acquisition, analysis, and interpretation of data: Y.T., T.T. Critical revision of the manuscript: T.M., I.N., Y.I., K.F., M.A. Neurology 79
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Study funding: Supported by grants-in-aid for scientific research (20390241, 21790828, 22229008) of The Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, and by the Health and Labour Sciences Research Grant on Intractable Diseases (Neuroimmunological Diseases) from the Ministry of Health, Labour and Welfare of Japan. Disclosure: Y. Takai reports no disclosures. T. Misu has received speaker honoraria from Bayer Schering Pharma and Asteras Pharma Inc. and has received research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Kuraray Medical Co., The Chemo-Sero-Therapeutic Research Institute, Teva Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, Teijin Pharma, and Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Technology, and the Ministry of Health, Labor and Welfare of Japan. I. Nakashima has received funding for travel and received speaker honoraria from Bayer Schering Pharma and Biogen Idec, has received research funding from Mitsubishi Chemical Medience Corporation, and has received Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Technology. T. Takahashi reports no disclosures. Y. Itoyama has received speaker honoraria from Bayer Schering Pharma and has received research support from Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Technology, and the Ministry of Health, Labor and Welfare of Japan. K. Fujihara serves on scientific advisory boards for Bayer Schering Pharma, Biogen Idec, and Merck Serono; has received funding for travel and received speaker honoraria from Bayer Schering Pharma, Biogen Idec, Eisai Inc., Mitsubishi Tanabe Pharma Corporation, Astellas Pharma Inc., Takeda Pharmaceutical Company Limited, and Asahi Kasei Kuraray Medical Co., Ltd.; has received research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Kuraray Medical Co., The Chemo-Sero-Therapeutic Research Institute, Teva Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, Teijin Pharma, Eisai Inc., and Kowa Pharmaceuticals America, Inc.; and has received Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Technology of Japan. M. Aoki has received research grants by Research on Measures for Intractable Diseases and Research on Psychiatric and Neurological Diseases and
Mental Health from the Japanese Ministry of Health Labor and Welfare, Grants-in-Aid for Scientific Research, an Intramural Research Grant for Neurological Psychiatric Disorders from NCNP, and a Grant-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology. Go to Neurology.org for full disclosures. Received February 13, 2012. Accepted in final form June 22, 2012. Correspondence & reprint requests to Dr. Misu: misu@med. tohoku.ac.jp Copyright © 2012 by AAN Enterprises, Inc. 1.
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Editor’s Note to Authors and Readers: Levels of Evidence in Neurology® Effective January 15, 2009, authors submitting Articles or Clinical/Scientific Notes to Neurology® that report on clinical therapeutic studies must state the study type, the primary research question(s), and the classification of level of evidence assigned to each question based on the AAN classification scheme requirements. While the authors will initially assign a level of evidence, the final level will be adjudicated by an independent team prior to publication. Ultimately, these levels can be translated into classes of recommendations for clinical care. For more information, please access the articles and the editorial on the use of classification of levels of evidence published in Neurology.1-3 1. French J, Gronseth G. Lost in a jungle of evidence: we need a compass. Neurology 2008;71:1634 –1638. 2. Gronseth G, French J. Practice parameters and technology assessments: what they are, what they are not, and why you should care. Neurology 2008;71:1639 –1643. 3. Gross RA, Johnston KC. Levels of evidence: taking Neurology® to the next level. Neurology 2009;72:8 –10.
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