Journal of Neuroimmunology 291 (2016) 96–100

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Differentiation of neuromyelitis optica spectrum disorders from ultra-longitudinally extensive transverse myelitis in a cohort of Chinese patients Weihe Zhang ⁎, Yujuan Jiao, Lei Cui, Jinsong Jiao ⁎ Department of Neurology, China–Japan Friendship Hospital, Beijing 100029, China

a r t i c l e

i n f o

Article history: Received 21 September 2015 Received in revised form 4 January 2016 Accepted 6 January 2016 Available online xxxx Keywords: Longitudinally extensive transverse myelitis, ultra Neuromyelitis optica spectrum disorders Causes Clinical Imaging

a b s t r a c t This study aimed to differentiate neuromyelitis optica spectrum disorders (NMOSD) from other causes in cases of ultra-longitudinally extensive transverse myelitis (uLETM). We retrospectively analyzed thirty-three Chinese patients with uLETM hospitalized in the China–Japan Friendship Hospital. The patients were divided into NMOSD (n = 21) and non-NMOSD (n = 12) groups. The NMOSD group exhibited significantly more comorbidity compared with the non-NMOSD group; moreover, the NMOSD group uniquely exhibited intractable vomiting and hiccups (IVH). The prevalence rates of cervicothoracic, area postrema (AP), and other circumventricular organ (CVO) lesions were significantly increased in the NMOSD group compared with the non-NMOSD group. Moreover, uLETM was strongly associated with NMOSD. These novel findings indicate that CVO lesions, including AP, and particularly when combined with clinical IVH, may represent a useful discriminator to differentiate NMOSD. © 2016 Elsevier B.V. All rights reserved.

1. Introduction Longitudinally extensive transverse myelitis (LETM) is a relatively rare spinal cord syndrome, which was included as a critical supportive criterion for neuromyelitis optica (NMO) by Wingerchuk (Wingerchuk et al., 2006). LETM was also characterized as a main type of the NMO spectrum disorders (NMOSD) with seropositive aquaporin 4 antibody (AQP4-IgG) in the following year (Wingerchuk et al., 2007). The Abbreviations: LETM, longitudinally extensive transverse myelitis; NMO, neuromyelitis optica; NMOSD, NMO spectrum disorders; AQP4-IgG, aquaporin 4 antibody; MS, multiple sclerosis; uLETM, ultra-LETM; IVH, intractable vomiting and hiccups; CSF, cerebrospinal fluid; CVO, circumventricular organs; ADEM, acute disseminated encephalomyelitis; SDAVF, spinal dural arteriovenous fistula; PM, paraneoplastic myelopathy; iLETM, isolated LETM; AP, area postrema; EDSS, expanded disability status scale; IST, immunosuppressive treatments; FU, follow up; LON, left optic neuritis; BON, bilateral optic neuritis; TM, transverse myelitis; SS, Sjogren's syndrome; HT, Hashimoto's thyroiditis; IVMP, intravenous methylprednisolone; IVIg, intravenous immunoglobin; TPE, therapeutic plasma exchange; AZA, azathioprine; MMF, Mycophenolate Mofetil; CTX, intravenous cyclophosphamide; CS, corticosteroids; IFN-β, interferon-β; N/A, not available. ⁎ Corresponding authors at: Department of Neurology, China–Japan Friendship Hospital, 2 Yinghua, Dongjie, Hepingli, Beijing 100029, China. E-mail addresses: [email protected] (W. Zhang), [email protected] (J. Jiao).

http://dx.doi.org/10.1016/j.jneuroim.2016.01.004 0165-5728/© 2016 Elsevier B.V. All rights reserved.

majority of LETM studies to date have focused on the lower limits of the spinal cord segments involved, using a cut-off point of three vertebrae to distinguish NMOSD from multiple sclerosis (MS) (Wingerchuk et al., 2006; Wingerchuk et al., 2007; Kitley et al., 2012; Kitley et al., 2013). However, to the best of our knowledge, few case reports have specifically discussed longer spinal cord lesions, and these cases are almost exclusively cases of LETM secondary to systemic lupus erythematosus and paraneoplastic myelopathy (Tellez-Zenteno et al., 2001; Flanagan et al., 2011). We have previously reported four cases of transverse myelitis with whole spinal cord injury; in these cases, one patient died and two patients had severe residual disability (Zhang et al., 2011). Thus, we termed the more severe form of transverse myelitis that we observed, with lesions in the spinal cord that extend over ten or more vertebrae, as ultra-LETM (uLETM) (Zhang et al., 2011). Although the four previously reported patients eventually developed NMOSD (Zhang et al., 2011), uLETM was not caused by NMOSD in all patients (Jiao et al., 2014; Wang and Li, 2015), which may obscure the diagnosis, particularly for patients who have limited forms of NMOSD, such as monophasic LETM, or the less common optic neuritis. The identification of the underlying etiology at the initial visit is critical to initiate appropriate therapy and optimize outcomes. The aim of this study was to determine the etiologic

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distribution of uLETM patients and to identify discriminators that differentiate NMOSD from other causes via a retrospective analysis of a series of Chinese uLETM patients. To the best of our knowledge, this is the first study to distinguish NMOSD from uLETM in a Chinese cohort.

whole segments). We also recorded the circumventricular organ (CVO) lesions and gadolinium contrast lesions, when available.

2. Methods

All statistical analyses were performed using SPSS 22.0 software (IBM Corp., Armonk, NY, USA). Statistical significance was set at p b 0.05. The median age of uLETM onset, nadir EDSS for uLETM, and involved segments (vertebrae number) were analyzed using Mann– Whitney U tests. Differences in the sex ratio and other clinical and imaging parameters between the NMOSD and non-NMOSD groups were analyzed using Fisher's exact tests.

2.1. Patients Thirty-three (22 women and 11 men) Chinese patients with uLETM, who were hospitalized at the China–Japan Friendship Hospital (Beijing, China) between January 2009 and April 2015, were consecutively enrolled in our study. Patients were divided into two groups based on the presence or absence of NMOSD (e.g., the NMOSD and non-NMOSD groups, respectively). The following parameters were retrospectively analyzed and compared between the two groups: demographic data (age and gender), etiologic classification, clinical features (e.g., onset form, intractable vomiting and hiccups (IVH), comorbidity, and AQP4IgG status), and imaging features (e.g., spinal cord segments involved, distribution and extent of spinal and brain lesions, and contrast lesions on MR images). The onset severity of uLETM in the NMOSD and nonNMOSD patients was assessed using the Expanded Disability Status Scale (EDSS, range 0–10). The study was approved by the Institutional Review Board of the China-Japan Friendship Hospital, and informed consent was waived by the committee. 2.2. Inclusion criteria Patients with clinical signs and symptoms of myelopathy, with at least one concurrent lesion in the spinal cord that extended over ten or more vertebrae on T2-weighted MRI scans, were included. The 2015 International Consensus Diagnostic Criteria were used for NMOSD with or without AQP4-IgG (Wingerchuk et al., 2015). 2.3. Laboratory data AQP4-IgG was analyzed using a cell-based assay (AQP4-IgG test kit; EUROIMMUN (China) Co., Beijing, China) by an independent medical inspection agency. Serum specimens were collected during the acute phase or clinical relapse in 27 cases, including 20 cases of NMOSD. All AQP4-IgG samples were collected before the attack or maintenance treatments, with the exception of two patients in the NMOSD group, who received interferon-β and low-dose corticosteroid therapy, respectively. Anti-myelin oligodendrocyte glycoprotein antibodies were not recorded for the cases who exhibited seronegative AQP4-IgG. The cerebrospinal fluid (CSF) cell count, glucose concentration, and protein levels were recorded. Serum and CSF antibodies against herpes simplex virus, adenovirus, cytomegalovirus, varicella-zoster virus, Epstein–Barr virus, and enterovirus were considered, when necessary. The serum of all patients with suspected sarcoidosis was tested for angiotensinconverting enzyme. We recorded well-recognized serum antibodies, as well as CSF onconeural antibodies [e.g., anti-Hu (ANNA-1), anti-Yo (PCA-1), anti-Ri (ANNA-2), anti-CV2 (CRMP5), anti-amphiphysin, and anti-Ta/Ma2] in cases of suspected paraneoplastic myelopathy. 2.4. Imaging data Spinal cord MRI was performed on a SignaHDX-3.0T (General Electric Co., Fairfield, CT, USA) or GYROSCAN-1.5T (PHILIPS Co., Amsterdam, Holland) nuclear magnetic resonance scanner. MRI scanning covered the cervical, thoracic, and lumbar spine. T1-weighted sequences with and without gadolinium were obtained. T2-weighted sequences were used to obtain sagittal and axial images. We delineated the affected area as transverse sections of complete and partial lesions, the spinal cord segments involved (number of vertebral segments), and their location in the sagittal image (cervicothoracic, thoracic or

2.5. Statistical analysis

3. Results 3.1. Etiological distribution across uLETM patients In our cohort, 21 of 33 cases fulfilled the diagnosis of NMOSD. The detailed clinical characteristics of the NMOSD patients are summarized in Table 1. One AQP4-IgG seronegative case exhibited concurrent multiple brain lesions after brain surgery. The patient was diagnosed with acute disseminated encephalomyelitis (ADEM), which was attributed to a monophasic course during the previous four-year follow-up. Three middle-aged men who presented with chronic progressive spastic paraplegia with mild sensory and sphincter disorders were diagnosed with spinal dural arteriovenous fistula (SDAVF); two patients received interventional embolization therapy and recovered gradually, whereas another patient was lost to follow-up. One 62-year-old woman was diagnosed with paraneoplastic myelopathy (PM) and manifested subacute myelopathy with breast cancer, which was identified before the onset of PM; the patient's ability to walk progressed slowly over three years of follow-up. One 32-year-old woman with leukemiarelated myelopathy secondary to acute myelocytic leukemia exhibited an acute onset paraplegia and serious sphincter disorders; despite the timely application of leukemia chemotherapy, the patient died within six months. One 18-year-old woman with infectious mononucleosis manifested with high fever, an enlarged liver, spleen, and lymph nodes, and a positive screen for EB virus antibodies in the serum and CSF; she obtained full recovery within one year after receiving antiviral therapy combined with five sessions of therapeutic plasma exchange (TPE). One 69-year-old woman was diagnosed with Arnold-Chiari malformation associated with syringomyelia. The manifestations of the remaining four uLETM patients could not be classified as belonging to any of these diseases and were referred to as isolated LETM (iLETM); these four patients received attack immunotherapies (i.e., intravenous methylprednisolone and/or TPE) and remained relapse-free for at least three years. 3.2. Comparison of clinical features between NMOSD and non-NMOSD patients The comparison of clinical features in the NMOSD and non-NMOSD groups is summarized in Table 2. In the NMOSD group, there were predominantly female patients (17/21 [81.7%]) who exhibited an acute or subacute onset (20/21[95.2%]) compared with the non-NMOSD patients (5/12 [41.7%] and 7/12 [58.3%], respectively, p b 0.05). Nine patients (42.9%) exhibited comorbid systemic diseases, which significantly increased compared with the non-NMOSD patients (1 [8.3%]; p b 0.05). Nine patients (42.9%) exhibited IVH, and 14/20 patients (70.0%) exhibited seropositive AQP4-IgG. The median age of uLETM onset was not significantly different between the NMOSD group (33.0 [23.0] years) and the non-NMOSD group (47.0 [20.5] years). The median nadir EDSS for uLETM in the NMOSD group (7.0 [3.5]) was similar to the non-NMOSD group (5.0 [3.7]). Furthermore, there were no

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Table 1 Clinical features of uLETM in the NMOSD group. Case

Age of onset/sex

Initial symptoms

Nadir EDSS for uLETM

AQP4 -IgG

Comorbidity

Attack therapies

IST since uLETM

FU since uLETM (year)

No of relapses since uLETM

EDSS with recoverya

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

32/F 33/F 35/F 26/F 33/F 24/F 25/F 32/F 50/F 60/F 78/F 29/F 57/F 36/F 27/F 27/F 24/F 42/M 75/M 35/M 68/M

IVH LON Encephalomyelitis IVH + TM TM TM TM Encephalopathy IVH BON TM TM TM TM TM TM IVH BON TM IVH + TM IVH

6.5 8.5 7.5 5 9 8.5 9 8 5.5 4.5 6.5 5 8.5 7 4.5 4 4.5 4 9 10 8.5

+ + + − + − + + + − + + + − + + + − + − N/A

SS SS SS + HT − − Hepatitis B − − SS Hepatitis B HT − − − − − SS − − HT −

IVMP + IVIg IVMP IVMP IVMP IVMP IVMP + IVIg TPE TPE IVMP IVMP + TPE IVMP IVMP IVMP IVMP IVMP IVMP IVMP IVMP TPE IVMP + IVIg IVMP

AZA, CTX CTX MMF CS + IFN-β IFN-β, MMF CS CS + Leflunomide MMF MMF MMF CS AZA N/A AZA MMF AZA MMF Fingolimod MMF N/A N/A

6 4 3 6 4 3 1 0.5 1 2 2 1 Withdrew 1 0.25 0.25 2 5 2 Dead Withdrew

2 1 2 10 2 1 0 0 0 0 0 0 N/A 0 0 0 1 2 1 N/A N/A

2 2.5 0 1 3 0 7.5 2.5 1.5 3 3.5 1.5 N/A 2.5 N/A N/A 1 1 7 N/A N/A

AQP4-IgG: aquaporin-4 antibody; AZA: azathioprine; BON: bilateral optic neuritis; CS: low dose oral corticosteroids; CTX: intravenous cyclophosphamide; EDSS: Expanded Disability Status Scale; FU: follow up; HT: Hashimoto's thyroiditis; IFN-β: Interferon-β; IST: immunosuppressive treatments; IVH: intractable vomiting and hiccups; IVIg: intravenous immunoglobin; IVMP: intravenous methylprednisolone; LON: left optic neuritis; MMF: Mycophenolate Mofetil; N/A: not available; NMOSD: neuromyelitis optica spectrum disorders; SS: Sjogren's syndrome; TM: transverse myelitis; TPE: therapeutic plasma exchange; uLETM: ultra-longitudinally extensive transverse myelitis. a Only patients with a follow-up duration of more than 6 months were included.

significant differences in the clinical features between the AQP4seropositive and AQP4-seronegative patients in the NMOSD group. 3.3. Comparison of imaging features between NMOSD and non-NMOSD patients (Fig 1 and Fig 2) As shown in Table 2, the median segments involved in the NMOSD patients was 19.00 (8.00), which was similar to the non-NMOSD group (15.00 [8.00]). The prevalence of cervicothoracic lesions was significantly increased in the NMOSD group (20 [95.2%]) compared with Table 2 Comparison of clinical and imaging features in NMOSD and non-NMOSD patients. NMOSD (n = 21) Sex (female, %) Median age at uLETM, year (IQR) Onset form Acute or subacute, n (%) Chronic, n (%) IVH, n (%) Comorbidity, n (%) AQP4-IgG +, n (%) Median nadir EDSS for uLETM (IQR) Median involved segments (IQR) Spinal cord lesions Cervicothoracic, n (%) Whole segments, n (%) T1 hypointense lesion, n (%) Complete lesion, n (%) Partial lesion, n (%) Brain lesions Area postrema, n (%) Other CVOs, n (%) Nonspecific white matter lesions, n (%) Contrast lesions Parenchyma enhancement, n (%) Meninges enhancement, n (%)

the non-NMOSD group (7 [58.9%], p b 0.05). Nine NMOSD patients (42.9%) exhibited an area postrema (AP) lesion, and 5/19 NMOSD patients (26.3%) exhibited other CVO lesions, which were both significantly more prevalent compared with the non-NMOSD group (1 [8.3%] and 0 [0], respectively, p b 0.05). Among the overall uLETM group, 15 patients suffered whole spinal cord lesions during their one clinical attack, which included 11 cases of NMOSD. Many of these cases exhibited one or more comorbid systemic diseases. Other parameters, such as T1 hypointense cord lesions, transverse affected cord lesions, nonspecific white matter lesions, and contrast lesions, were similar between the two groups. Furthermore, there were no significant differences in the spinal, brain, or contrast lesions between the AQP4-seropositive and AQP4-seronegative patients in the NMOSD group.

non-NMOSD (n = 12)

17 (81.0)a 33.0 (23.0)

5 (41.7) 47.00 (20.5)

20 (95.2)a 1 (4.8)a 9 (42.9)a 9 (42.9)a 14/20 (70.0)a 7.0 (3.5) 19.0 (8.0)

7 (58.3) 5 (41.7) 0 (0.0) 1 (8.3) 0 (0.0) 5.0 (3.7) 15.0 (8.0)

20 (95.2)a 11 (52.4) 15 (71.4) 21(100) 0(0)

7 (58.3) 4 (33.3) 7 (58.3) 10 (83.3) 2 (16.7)

9 (42.9)a 5/19 (26.3)a 5/19 (26.3)

1 (8.3) 0 (0) 2/8 (25.0)

4/8 (50.0) 1/8 (12.5)

2/8 (25.0) 2/8 (25.0)

AQP4-IgG: aquaporin-4 antibody; CVO: circumventricular organ; IVH: intractable vomiting and hiccups; NMOSD: neuromyelitis optica spectrum disorders; uLETM: ultralongitudinally extensive transverse myelitis. a p b 0.05 compared with non-NMOSD.

4. Discussion In our cohort, more than one-third of the uLETM patients manifested features suggestive of an alternative diagnosis, such as iLETM, ADEM, SDAVF, PM, infectious myelitis, or syringomyelia. In general, it is relatively easy to differentiate these diseases from NMOSD because of their stereotypical characteristics. However, neurologists should be aware of two issues. First, iLETM is characterized as a monophasic syndrome without AQP4-IgG and anti-MOG antibodies or an optic neuritis that cannot be classified as NMOSD. Although approximately 5–10% of contemporary NMOSD cases are described as monophasic, the optimal definition for monophasic NMOSD remains elusive. The International Panel for NMO Diagnosis has proposed the restricted condition that at least 5 years (preferably longer) without relapse is required to define a monophasic course (Wingerchuk et al., 2015). However, the conversion of iLETM to NMOSD may exist (Weinshenker et al., 2006), and long term follow-up, particularly a repeat AQP4-IgG test, is necessary. Second, some NMOSD patients, particularly children, may present with encephalomyelopathic symptoms that mimic ADEM (Lotze et al., 2008). One example is the patient in our cohort who was initially misdiagnosed as ADEM but eventually developed NMOSD due to a relapsing course with positive AQP4-IgG. We concluded that long-term follow-up of the clinical course over time and the reassessment of the

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Fig. 1. Representative MRI scans obtained from patients with NMOSD. A 33-year-old woman with AQP4-IgG (+). Spinal cord T2 image exhibiting a whole spinal cord lesion from the medulla to conus (a/b). A 50-year-old woman with AQP4-IgG (+) exhibiting an ultra-longitudinally extensive lesion from the medulla to T3; axial brain T2-weighted FLAIR indicating an area postrema lesion (c; arrow). A 35-year-old woman with AQP4-IgG (+) exhibiting a whole spinal cord lesion from C2-conus; axial brain T2-weighted FLAIR indicating bilateral cortical tract lesions and symmetrical splenium lesions (d; arrow).

AQP4-IgG status of some ADEM patients may be required to achieve a confident diagnosis. Nevertheless, a substantial proportion of uLETM patients fulfilled the diagnosis of NMOSD. These patients were predominantly female and had a preferential age of onset in their 40s, consistent with the overall population as previously reported (Wingerchuk et al., 2006; Wingerchuk et al., 2015). Seropositive AQP4-IgG was identified in 70.0% of the NMOSD patients, which is a significant increase compared with the entire NMOSD population (51.7%) in our clinical center (Zhang et al., 2015). This finding indicates an increased seropositive rate of AQP4-IgG along with the extension of involved segments. The relationship between NMOSD and systemic autoimmune diseases has long been debated (Zhang et al., 2015). The common genetic and/or environmental factors that predispose individuals to autoimmunity in these two conditions strongly indicate that they may coexist in a single patient (Wingerchuk and Weinshenker, 2012). Nine NMOSD patients in our cohort exhibited comorbidity with one or more systemic diseases; however, only one patient exhibited comorbidity in the nonNMOSD group. Thus, this finding may facilitate the diagnosis of NMOSD. AP, which is a CVO, expresses abundant AQP4 and is considered a vulnerable lesion location for NMOSD. Expectedly, the clinical

presentation of IVH further supports this neuroanatomical region (Misu et al., 2005; Pittock et al., 2006). A more recent neuropathological study demonstrated that AP is likely the selective target of NMO and is clinically compatible with IVH, which serves as the heralding symptom of NMO patients (Popescu et al., 2011). In our cohort, IVH presented as a unique preceding episode in NMOSD-related uLETM patients and was correlated with AP lesions. However, in one patient in the non-NMOSD subgroup, the myelitis associated with infectious mononucleosis involved whole spinal cord segments, including the AP; however, the patient did not clinically exhibit IVH similar to the NMOSD patients. Furthermore, spinal cord lesions of SDAVF may extend to the AP (Jiao et al., 2014), whereas the specific imaging appearance of “flow voids” on the caudal spinal cord surface, as well as a tortuous dilated vein-like “earth worm” on the contrast image may be helpful for diagnosis (Steiger et al., 2005). Syringomyelia should also be considered because the cervical lesion extends to the fourth ventricle, which may be confused with an AP lesion. However, both conditions rarely manifest IVH clinically. These findings indicate that AP may not be a distinctive lesion for NMOSD-related uLETM; however, if it is accompanied by IVH, it may optimize the diagnosis of NMOSD.

Fig. 2. Representative MRI scans obtained from patients with non-NMOSD. A 48-year-old man diagnosed with SDAVF exhibiting an extensive lesion on the thoracic T2 image from the T2 to conus; “flow voids” were present on the caudal spinal cord surface (a; arrow). A 60-year-old man diagnosed with ADEM exhibiting a whole spinal cord lesion on the T2 image from the C2 to conus (b). A 32-year-old woman diagnosed with leukemia-associated myelopathy exhibiting longitudinal transverse lesion across T1–T10. T6–T7 segment exhibiting a mass-like hypointense lesion on the T2 image (C; arrow). An 18-year-old girl diagnosed with infectious mononucleosis; spinal cord MRI indicating an ultra-longitudinally extensive lesion from the medulla to conus on the T2 image (d; arrow).

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In addition to AP lesions, periependymal lesions surrounding the ventricular system, which includes the thalamus, the hypothalamus, the anterior border of the midbrain, and the dorsal brainstem, have been reported in NMOSD (Kim et al., 2015). These specific sites also facilitated the differentiation of NMOSD from other causes in our cohort. Moreover, preferential cervicothoracic lesions may represent another predictor of NMOSD. In contrast to MS, T1 hypointensity is more common in NMO-related LETM because of the preferential involvement of cord gray matter and aggressive intrinsic cord damage, particularly in patients with seropositive AQP4-IgG (Downer et al., 2012). However, our data indicated that there were no significant differences in T1 hypointense cord lesions between the NMOSD and non-NMOSD patients. This finding indicates that cord T1 hypointensity cannot be considered a discriminator of NMOSD from uLETM from other causes. To date, few relevant reports of whole segment spinal cord involvement have been published (Zhang et al., 2011; Sekaric et al., 2013). Fifteen patients in our cohort exhibited the entire lesion within one clinical attack. More than two-thirds of these patients eventually evolved to NMOSD, and many patients exhibited one or more systemic diseases. These findings indicate that comorbid systemic diseases may cause a more severe spinal cord injury. Moreover, four NMOSD-related uLETM patients exhibited a concurrent AP lesion, which indicates that there is no upper limit for the length of cord lesion in NMOSD. In conclusion, uLETM is an etiologically heterogeneous spinal syndrome strongly correlated with NMOSD. The seropositive rate of AQP4-IgG exhibited a positive correlation with the extent of spinal cord involvement. CVO lesions, including AP and particularly when clinically combined with IVH, may represent a useful discriminator to differentiate NMOSD from other disorders. Moreover, other parameters, such as female predominance, acute or subacute onset form, comorbid systemic diseases, and cervicothoracic lesions, may contribute to the prediction of NMOSD-related uLETM. Despite these promising findings, several limitations should be considered in the interpretation of these results. For example, the patients in this study were evaluated from a single hospital, and a retrospective review was performed. Thus, a prospective, multi-center study that includes a larger sample of uLETM patients is warranted. Conflict of interest The authors declare that there are no potential conflicts of interest among the authors and/or other organizations. Acknowledgments This work was sponsored by the Youth Foundation of the China– Japan Friendship Hospital (2015-1-QN-12).

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Differentiation of neuromyelitis optica spectrum disorders from ultra-longitudinally extensive transverse myelitis in a cohort of Chinese patients.

This study aimed to differentiate neuromyelitis optica spectrum disorders (NMOSD) from other causes in cases of ultra-longitudinally extensive transve...
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