551454

research-article2014

MSJ0010.1177/1352458514551454Multiple Sclerosis JournalJW Hyun et al.

MULTIPLE SCLEROSIS MSJ JOURNAL

Research Paper

Idiopathic aquaporin-4 antibody negative longitudinally extensive transverse myelitis Jae-Won Hyun, Su-Hyun Kim, So-Young Huh, Woojun Kim, Junglim Yun, AeRan Joung, Douglas Kazutoshi Sato, Kazuo Fujihara and Ho Jin Kim

Multiple Sclerosis Journal 1­–8 DOI: 10.1177/ 1352458514551454 © The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav

Abstract Background: Longitudinally extensive transverse myelitis (LETM) is a characteristic manifestation of neuromyelitis optica (NMO). However, not all patients with LETM are positive for aquaporin-4 (AQP4) antibodies. We evaluated the characteristics of idiopathic isolated LETM negative for AQP4 antibodies. Methods: From the National Cancer Center registry of inflammatory diseases of the central nervous system, patients with LETM as an initial manifestation and follow-up for at least two years were enrolled. Their medical records and MRIs were reviewed retrospectively. AQP4 antibody was confirmed by three different validated methods at least three times. Cerebrospinal fluid (CSF) glial fibrillary acidic protein (GFAP) levels were measured to investigate astrocyte damage. Results: Among 108 patients with first-ever LETM, 55 were positive for AQP4 antibodies (P-LETM) and 53 were consistently negative. Of them, seven were later diagnosed with seronegative NMO, and four were positive for MOG antibodies. The remaining 42 patients (N-LETM) showed several features distinct from P-LETM: male predominance, older age of onset, milder clinical presentation, spinal cord confinement and absence of combined autoimmunity. CSF GFAP levels were not increased in N-LETM but were markedly elevated in P-LETM. Conclusions: Idiopathic isolated N-LETM is not that rare among first-ever LETM, and has many features distinct from P-LETM where astrocytic damage is evident.

Keywords:  Longitudinally extensive transverse myelitis, aquaporin-4 antibody, neuromyelitis optica, idiopathic Date received: 11 April 2014; accepted: 13 August 2014

Introduction Longitudinally extensive transverse myelitis (LETM), defined as a spinal cord inflammatory lesion that extends over three or more vertebral segments, is a syndrome that has various causes.1,2 After excluding vascular, compressive, metabolic, infectious, nutritional, rheumatological, paraneoplastic and radiationrelated disorders, most cases are considered to be immune mediated.1,2 LETM is at low risk of developing into multiple sclerosis (MS),3 while it is a characteristic feature of neuromyeitis optica (NMO),4 for which aquaporin-4 (AQP4) antibodies are a specific marker.5 Although NMO is a common underlying aetiology of LETM,4 not all patients with immune-mediated LETM are positive for AQP4 antibodies.6–9

In clinical practice, AQP4 antibody-negative isolated LETM without a determined cause poses a diagnostic and therapeutic challenge. Some of these patients develop optic neuritis and are diagnosed with seronegative NMO,10,11 and some are positive for myelinoligodendrocyte glycoprotein (MOG) antibodies.12–14 However, some of the patients are outside the context of the previously defined spectrum of immune-mediated inflammatory diseases of the central nervous system (CNS) and have not been well described. Previous studies have limitations in their investigations of the features of idiopathic AQP4 antibodynegative LETM because many of these studies were performed before the AQP4 antibody era or relied

Correspondence to: Ho Jin Kim Department of Neurology, Research Institute and Hospital of National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, Korea. [email protected] Jae-Won Hyun Su-Hyun Kim Junglim Yun AeRan Joung Ho Jin Kim Department of Neurology, Research Institute and Hospital of National Cancer Center, Goyang, Korea So-Young Huh Kosin University School of Medicine, Busan, Korea Woojun Kim Catholic University School of Medicine, Seoul, Korea Douglas Kazutoshi Sato Kazuo Fujihara Department of Neurology and Multiple Sclerosis Therapeutics, Tohoku University Graduate School of Medicine, Sendai, Japan

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Multiple Sclerosis Journal  on the serostatus of the AQP4 antibody that was determined by a single assay at a single time point.15–23 These factors may have caused the low frequency of seropositivity (10–18%) for AQP4 antibodies in previous reports on LETM,16,17,19 and thus patients with false-negative results may compromise the identification of the characteristics of true AQP4 antibody negative LETM. Recent studies have used more than one validated assay. However, they have focused mainly on seropositive LETM or included various causes of seronegative LETM, thus without focusing on ‘idiopathic’ AQP4 antibody negative LETM.8,9,24 In this study, we sought to establish a well-defined cohort who presented with isolated LETM without a determined cause and who were consistently negative for AQP4 antibodies after serial testing at different time points using three different validated assays, and to compare their characteristics to those of AQP4 antibody positive LETM. We also compared cerebrospinal fluid (CSF) levels of glial fibrillary acidic protein (GFAP) as a marker of astrocytic damage25 in order to investigate discriminative pathophysiological features.

serum MOG antibodies were tested using a CBA with live transfected cells with full-length MOG at Tohoku University.14 We analysed demographic, clinical, laboratory and MRI findings retrospectively and compared them between AQP4 antibody negative and positive patients. GFAP levels in CSF, obtained during acute attacks of LETM before administration of high-dose methylprednisolone, were measured using a human GFAP ELISA kit according to the manufacturer’s protocol (BioVendor, Minneapolis, MN). Patients with MS were also tested as a control. The Institutional Review Board of the NCC approved the study protocol and waived the need for informed consent due to de-identified data used. Statistical analysis Statistical analysis was performed using GraphPad Prism v4. We performed two-sample t-tests or Mann– Whitney U-tests for continuous data and chi-square or Fisher’s exact tests for categorical data for comparisons of patients with and without AQP4 antibodies. Two-sided p-values of

Idiopathic aquaporin-4 antibody negative longitudinally extensive transverse myelitis.

Longitudinally extensive transverse myelitis (LETM) is a characteristic manifestation of neuromyelitis optica (NMO). However, not all patients with LE...
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