Mechanism underlying pruritus in recessive dystrophic epidermolysis bullosa: Role of interleukin-31 from mast cells and macrophages.

BACKGROUND: Pruritus is a highly burdensome symptom in patients with epidermolysis bullosa, especially recessive dystrophic epidermolysis bullosa (RDEB); however, only a few studies have assessed the molecular pathogenesis of RDEB-associated pruritus. Interleukin (IL)-31 is a key cytokine implicated in pruritus associated with dermatologic diseases such as atopic dermatitis and prurigo nodularis. OBJECTIVE: To investigate the role and cellular source of IL-31 in RDEB-associated pruritus. METHODS: Serum and skin samples were obtained from 11 RDEB patients and 11 healthy controls. Pruritus visual analogue scale scores were determined. Serum levels of IL-31 and thymic stromal lymphopoietin (TSLP) were examined by enzyme-linked immunosorbent assay (ELISA). The expression of IL-31 and other pruritus mediators in the skin were examined through immunofluorescence staining, and their correlation with pruritus severity was analysed. RESULTS: Serum IL-31 and TSLP were elevated in RDEB patients. IL-31 expression was increased in RDEB skin and positively correlated with pruritus severity. Most of the IL-31-expressing cells were mast cells, and some were CD206(+) M2-like macrophages. The number of substance P(+) cells was also increased in the patients' skin, and most of them were mast cells. The number of substance P(+) mast cells was correlated with the number of IL-31(+) dermal infiltrates. The number of IL-4Rα- and IL-13-expressing cells and expression of TSLP and periostin increased in RDEB skin, but without a correlation to pruritus score. CONCLUSION: The increased production of skin IL-31 from mast cells and M2-like macrophages may be the mechanism underlying pruritus in RDEB.

Evaluation of Normal-Appearing White Matter in Multiple Sclerosis Using Direct Visualization of Short Transverse Relaxation Time Component (ViSTa) Myelin Water Imaging and Gradient Echo and Spin Echo (GRASE) Myelin Water Imaging.

BACKGROUND: In multiple sclerosis (MS), not only lesions but also normal MRI-appearing white matter (NAWM) may undergo demyelination. PURPOSE: To demonstrate the detection of NAWM demyelination using direct visualization of short transverse relaxation time component myelin water imaging (ViSTa-MWI) and to compare the results with those of conventional gradient echo and spin echo (GRASE)-MWI. STUDY TYPE: Control/cohort. POPULATION: Twenty-five MS patients and 18 healthy controls (HC). FIELD STRENGTH/SEQUENCE: 3T/ViSTa and GRASE-MWI. ASSESSMENT: Using ViSTa and GRASE-MWI, myelin water fraction (MWF) of NAWM or normal WM was compared between MS (all patients or early-stage MS patients) and HC. The comparison was performed for a global WM mask and five regional WM masks. STATISTICAL TESTS: A general linear model was applied for the comparison. A statistical power and a minimum sample size for the significant difference were obtained. Spearman's correlation coefficient was calculated between MWF and clinical measures and between ViSTa-MWF and GRASE-MWF for the global WM mask. RESULTS: MWFs of ViSTa were significantly lower in the MS patients than those in the HC in all masks (P < 0.001). GRASE-MWI results revealed reduced MWFs only in global WM, genu, and optic radiation. ViSTa-MWI had higher statistical powers than that of GRASE-MWI (power: ViSTa = 99.2 ± 1.6% and GRASE = 75.5 ± 31.0%; sample size: ViSTa = 18 ± 9 and GRASE = 78 ± 75). In early-stage MS, MWFs of ViSTa were significantly lower than those of the HC in all masks except for centrum semiovale; however, MWFs of GRASE MWI were significantly lower only in optic radiation. Disease duration was correlated with both MWIs (ViSTa; r = -0.437 and GRASE; r = -0.445). ViSTa and GRASE MWFs were significantly correlated in the HC (r = 0.664) and MS (r = 0.768). DATA CONCLUSION: ViSTa-MWI may detect a reduction of MWF in NAWM of MS. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;49:1091-1098.

Longitudinal analysis of myelin oligodendrocyte glycoprotein antibodies in CNS inflammatory diseases.

BACKGROUND: We evaluated the seroprevalence of myelin oligodendrocyte glycoprotein immunoglobulin G1 (MOG-IgG) and associated clinical features of patients from a large adult-dominant unselected cohort with mainly relapsing central nervous system (CNS) inflammatory diseases. We also investigate the clinical relevance of MOG-IgG through a longitudinal analysis of serological status over a 2-year follow-up period. METHODS: Serum samples from 505 patients with CNS inflammatory diseases at the National Cancer Center were analysed using cell-based assays for MOG-IgG and aquaporin-4 immunoglobulin G (AQP4-IgG). MOG-IgG serostatus was longitudinally assessed in seropositive patients with available serum samples and at least 2 years follow-up. RESULTS: Twenty-two of 505 (4.4%) patients with CNS inflammatory diseases were positive for MOG-IgG. Patients with MOG-IgG had neuromyelitis optica spectrum disorder (NMOSD, n=10), idiopathic AQP4-IgG-negative myelitis (n=4), idiopathic AQP4-IgG-negative optic neuritis (n=4), other demyelinating syndromes (n=3) and multiple sclerosis (n=1). No relapses were seen in patients when they became MOG-IgG seronegative, whereas a persistent positive serological status was observed in patients with clinical relapses despite immunotherapy. CONCLUSIONS: In a large adult-predominant unselected cohort of mainly relapsing CNS inflammatory diseases, we confirmed that NMOSD phenotype was most commonly observed in patients with MOG-IgG. A longitudinal analysis with 2-year follow-up suggested that persistence of MOG-IgG is associated with relapses.

Short segment myelitis as a first manifestation of neuromyelitis optica spectrum disorders.

BACKGROUND: Some patients with neuromyelitis optica spectrum disorders (NMOSD) present with spinal cord lesions extending fewer than three vertebral segments (short transverse myelitis, STM), hindering an early diagnosis. OBJECTIVE: We investigated the frequency and imaging characteristics of STM lesions in patients presenting with myelitis as an initial manifestation of NMOSD. METHODS: Patients seen at three referral hospitals in Korea between June 2005 and March 2015 who met the following inclusion criteria were recruited for review: seropositivity for aquaporin-4 antibody, initial presentation with myelitis and spinal cord magnetic resonance imaging (MRI) performed within 1 month of initial myelitis onset. RESULTS: Of the 76 enrolled patients, 65 (85.5%) collectively had 69 longitudinally extensive transverse myelitis lesions, while the remaining 11 (14.5%) had a total of 15 STM lesions. Of the 15 STM lesions, 5 spanned 2.5 vertebral segments, 6 were continuous over two segments, 3 showed a length of 1.5 segments and 1 was confined to a single segment. On axial imaging, all of the STM lesions involved the central grey matter. CONCLUSION: These MRI findings suggested that STM does not preclude the possibility of an NMOSD diagnosis.

Comparative analysis of treatment outcomes in patients with neuromyelitis optica spectrum disorder using multifaceted endpoints.

BACKGROUND: There is still an unmet need for comparative analyses of available treatment options for neuromyelitis optica spectrum disorder (NMOSD). OBJECTIVE: We aimed to compare the efficacies of the immunosuppressants most commonly prescribed for patients with NMOSD using multifaceted endpoints. METHODS: We conducted a retrospective analysis of treatment outcomes in 138 NMOSD patients treated with azathioprine, mycophenolate mofetil (MMF), or rituximab. The primary outcome measures were the annualized relapse rate (ARR), annualized severe relapse rate, time to first relapse, and time to first severe relapse. RESULTS: A comparison of any relapse among the groups revealed that the azathioprine had a significantly higher risk of relapse relative to the rituximab (hazard ratio: 1.82; 95% CI: 1.1-3.1; p=0.03). A comparison of severe relapse among the groups revealed that the hazard ratios of severe relapse for the azathioprine and MMF relative to the rituximab were 11.66 (95% CI: 2.6-52.3; p=0.001) and 5.96 (95% CI: 1.0-35.1; p=0.048), respectively. The times to first relapse and first severe relapse were also significantly different among the treatment groups CONCLUSIONS: The present study showed that reductions in the risks of relapse and severe relapse differed among patients who were initially treated with azathioprine, MMF, and rituximab.

Comparison of myelin water fraction values in periventricular white matter lesions between multiple sclerosis and neuromyelitis optica spectrum disorder.

Multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) are inflammatory autoimmune diseases of the central nervous system. We hypothesized that the degree of demyelination within lesions in MS and NMOSD would differ as the pathophysiology of the two diseases do. We used myelin water imaging to compare the myelin water fraction (MWF) in 106 periventricular white matter (PVWM) lesions in 27 MS patients and 51 PVWM lesions in 20 NMOSD patients. The MWF was significantly reduced in the MS compared with the NMOSD lesions, suggesting that myelin loss was more severe in MS than in NMOSD.

Cognitive impairment differs between neuromyelitis optica spectrum disorder and multiple sclerosis.

OBJECTIVE: To compare the frequency and pattern of cognitive impairment (CI) between patients with neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS). METHODS: A total of 82 NMOSD patients, 58 MS patients, and 45 healthy controls (HCs) underwent a neuropsychological assessment. RESULTS: CI was observed in 29% of NMOSD and 50% of MS patients (p < 0.001); CI was considered present if a patient scored lower than the fifth percentile compared with HCs in at least three domains. A lower frequency of CI was consistently found when CI was indicated by at least two failed tests (p < 0.001). MS patients performed worse than did NMOSD patients on verbal learning and verbal and visual memory tests. Levels of education and depression and the interval from disease onset to treatment were associated with a negative influence on cognition in patients with NMOSD. CONCLUSION: CI in patients with NMOSD may be not as common as in patients with MS. MS patients exhibited severe impairment, particularly on learning and memory tests, compared with NMOSD patients. Differential prevalence and patterns of CI between NMOSD and MS patients suggest that the two diseases have different mechanisms of brain injury.

First-ever optic neuritis: distinguishing subsequent neuromyelitis optica from multiple sclerosis.

To identify factors distinguishing subsequent neuromyelitis optica (NMO) from multiple sclerosis (MS) after first-ever optic neuritis (ON), we compared ophthalmic findings and MRI features of 24 NMO and 55 MS patients who initially presented with ON. The female-to-male ratio was higher, and bilateral ON was more common in NMO patients than in MS patients (p = 0.044 and p = 0.020, respectively). The visual acuity (VA) score was higher in NMO patients (p = 0.034), and a greater proportion of NMO patients had a VA score ≥ 5 (p = 0.003). The frequency of patients without pattern-reversal and flash visual evoked potentials was higher in the NMO group (p = 0.015). Brain MRI abnormalities were more common in the MS group (p = 0.001). The optic chiasm was affected in 25 % of NMO patients and was unaffected in MS patients, although it did not reach statistical significance (p = 0.096). There were no differences with respect to the severity of swelling and enhancement of the optic nerve. In conclusion, severe optic nerve damage at the first ON attack was associated with subsequent development of NMO, whereas presence of brain MRI abnormalities was associated with developing MS.

The Suppression of Ubiquitin C-Terminal Hydrolase L1 Promotes the Transdifferentiation of Auditory Supporting Cells into Hair Cells by Regulating the mTOR Pathway.

In mammals, hearing loss is irreversible due to the lack of the regenerative capacity of the auditory epithelium. However, stem/progenitor cells in mammalian cochleae may be a therapeutic target for hearing regeneration. The ubiquitin proteasome system plays an important role in cochlear development and maintenance. In this study, we investigated the role of ubiquitin C-terminal hydrolase L1 (UCHL1) in the process of the transdifferentiation of auditory supporting cells (SCs) into hair cells (HCs). The expression of UCHL1 gradually decreased as HCs developed and was restricted to inner pillar cells and third-row Deiters' cells between P2 and P7, suggesting that UCHL1-expressing cells are similar to the cells with Lgr5-positive progenitors. UCHL1 expression was decreased even under conditions in which supernumerary HCs were generated with a γ-secretase inhibitor and Wnt agonist. Moreover, the inhibition of UCHL1 by LDN-57444 led to an increase in HC numbers. Mechanistically, LDN-57444 increased mTOR complex 1 activity and allowed SCs to transdifferentiate into HCs. The suppression of UCHL1 induces the transdifferentiation of auditory SCs and progenitors into HCs by regulating the mTOR pathway.

Heat Shock Factor 1 Prevents Age-Related Hearing Loss by Decreasing Endoplasmic Reticulum Stress.

Endoplasmic reticulum (ER) stress is a common stress factor during the aging process. Heat shock factor 1 (HSF1) plays a critical role in ER stress; however, its exact function in age-related hearing loss (ARHL) has not been fully elucidated. The purpose of the present study was to identify the role of HSF1 in ARHL. In this study, we demonstrated that the loss of inner and outer hair cells and their supporting cells was predominant in the high-frequency region (basal turn, 32 kHz) in ARHL cochleae. In the aging cochlea, levels of the ER stress marker proteins p-eIF2α and CHOP increased as HSF1 protein levels decreased. The levels of various heat shock proteins (HSPs) also decreased, including HSP70 and HSP40, which were markedly downregulated, and the expression levels of Bax and cleaved caspase-3 apoptosis-related proteins were increased. However, HSF1 overexpression showed significant hearing protection effects in the high-frequency region (basal turn, 32 kHz) by decreasing CHOP and cleaved caspase-3 and increasing the HSP40 and HSP70 proteins. These findings were confirmed by HSF1 functional studies using an auditory cell model. Therefore, we propose that HSF1 can function as a mediator to prevent ARHL by decreasing ER stress-dependent apoptosis in the aging cochlea.

Ischemia induces autophagy of endothelial cells and stimulates angiogenic effects in a hindlimb ischemia mouse model.

Although peripheral artery disease (PAD) is a major health problem, there have been limited advances in medical therapies. In PAD patients, angiogenesis is regarded as a promising therapeutic strategy to promote new arterial vessels and improve perfusion of ischemic tissue. Autophagy plays a critical role in catabolic processes for cell survival under normal and stressful conditions and plays fundamental biological roles in various cellular functions. In the present study, we showed that autophagy in endothelial cells is important for the repair and regeneration of damaged tissues. In a hindlimb ischemia mouse model, autophagy was stimulated in endothelial cells of the quadriceps muscle, and adjacent cells proliferated and regenerated. The autophagy pathway was induced under prolonged hypoxia in endothelial cells, and autophagy increased angiogenic activities. Moreover, conditioned media from endothelial cells blocked autophagy and inhibited the proliferation of muscle cells, suggesting that autophagic stimulation in endothelial cells affects the survival of adjacent cells, such as muscle. Collectively, hypoxia/ischemia-induced autophagy angiogenesis, and the damaged tissue surrounded by neo-vessels was regenerated in an ischemia model. Therefore, we strongly suggest that stimulation of autophagy in endothelial cells may be a potent therapeutic strategy in severe vascular diseases, including PAD.

Comparison of the Seroprevalence of Measles Antibodies among Healthcare Workers in Two Korean Hospitals in 2019.

We performed a point seroprevalence survey of measles among healthcare workers (HCWs) at two Korean teaching hospitals in 2019. A total of 2,830 HCWs underwent an antibody test. The overall seropositivity of measles was 93.1%. The seroprevalence of measles was lowest in HCWs aged 20 - 24 years (81.2%), followed by those aged 25 - 29 years (90.1%). The rates of anti-measles IgG positivity were significantly different between the two hospitals (97.0% vs. 89.4%, P <0.001). These results suggest that the seropositivity of measles in HCWs may differ depending on the hospital's vaccination policy.

Apoptotic activity of fatty acid derivatives may correlate with their inhibition of DNA replication.

The apoptogenic and DNA damaging effects of (E)-10-oxooctadec-8-enoic acid (S5C) and (E)-9-oxooctadec-10-enoic acid (S6C), two structurally related fatty acids isolated from Red Alga Gracilaria verrucosa, were compared and their apoptosis-inducing properties characterized against human lung carcinoma (A549) cells. Significantly, the two acids decreased the rates of proliferation and viability (IC50 of approximately 170 and approximately 140 microM) as well as evidence of the induction of apoptosis. Cell morphological changes observed under light microscopy confirmed apoptosis occurrence. The results from Annexin V/PI dual staining and the cell cycle arrest assay indicated that S5C and S6C induced an earlier apoptosis of A549 cells in a concentration-dependent manner. We found that they induced DNA damage and inhibited DNA replication followed by S-phase arrest. In addition, the very sensitive alkaline micro-gel electrophoresis technique (comet assay) was used to estimate the compound-induced DNA single- and double-strand breaks. These findings suggest that S5C and S6C induced A549 cell apoptosis and their effects are associated with DNA damage. Therefore, S5C and S6C have the potential to be developed into anticancer agents due to their relatively easy synthesis and structural manipulation.

Individualized metabolic profiling stratifies pancreatic and biliary tract cancer: a useful tool for innovative screening programs and predictive strategies in healthcare.

BACKGROUND: Pancreatic cancer (PC) and biliary tract cancer (BTC) are highly aggressive cancers, characterized by their rarity, difficulty in diagnosis, and overall poor prognosis. Diagnosis of PC and BTC is complex and is made using a combination of appropriate clinical suspicion, imaging and endoscopic techniques, and cytopathological examination. However, the late-stage detection and poor prognosis of this tumor have led to an urgent need for biomarkers for early and/or predictive diagnosis and improved personalized treatments. WORKING HYPOTHESIS: There are two hypotheses for focusing on low-mass metabolites in the blood. First, valuable information can be obtained from the masses and relative amounts of such metabolites, which present as low-mass ions (LMIs) in mass spectra. Second, metabolic profiling of individuals may provide important information regarding biological changes in disease states that is useful for the early diagnosis of PC and BTC. MATERIALS AND METHODS: To assess whether profiling metabolites in serum can serve as a non-invasive screening tool for PC and BTC, 320 serum samples were obtained from patients with PC (n = 51), BTC (n = 39), colorectal cancer (CRC) (n = 100), and ovarian cancer (OVC) (n = 30), and from healthy control subjects (control) (n = 100). We obtained information on the relative amounts of metabolites, as LMIs, via triple time-of-flight mass spectrometry. All data were analyzed according to the peak area ratios of discriminative LMIs. RESULTS AND CONCLUSIONS: The levels of the 14 discriminative LMIs were higher in the PC and BTC groups than in the control, CRC and OVC groups, but only two LMIs discriminated between PC and BTC: lysophosphatidylcholine (LysoPC) (16:0) and LysoPC(20:4). The levels of these two LysoPCs were also slightly lower in the PC/BTC/CRC/OVC groups compared with the control group. Taken together, the data showed that metabolic profiling can precisely denote the status of cancer, and, thus, could be useful for screening. This study not only details efficient methods to identify discriminative LMIs for cancer screening but also provides an example of metabolic profiling for distinguishing PC from BTC. Furthermore, the two metabolites [LysoPC(16:0), LysoPC(20:4)] shown to discriminate these diseases are potentially useful when combined with other, previously identified protein or metabolic biomarkers for predictive, preventive and personalized medical approach.

Metabolomic profiling of CSF in multiple sclerosis and neuromyelitis optica spectrum disorder by nuclear magnetic resonance.

Multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) are inflammatory diseases of the central nervous system. Although several studies have characterized the metabolome in the cerebrospinal fluid (CSF) from MS and NMOSD patients, comparative analyses between them and between the relapse and the remission of each disease have not been performed. Both univariate and multivariate analyses were used to compare 1H-NMR spectra of CSF from MS, NMOSD, and healthy controls (HCs). The statistical analysis showed alterations of eight metabolites that were dependent on the disease. Levels of 2-hydroxybutyrate, acetone, formate, and pyroglutamate were higher and levels of acetate and glucose were lower in both MS and NMOSD. Citrate was lower in MS patients, whereas lactate was higher in only NMOSD specifically. The shared feature of metabolic changes between MS and NMOSD may be related to altered energy metabolism and fatty acid biosynthesis in the brain. Another analysis to characterize relapse and remission status showed that isoleucine and valine were down-regulated in MS relapse compared to MS remission. The other metabolites identified in the disease comparison showed the same alterations regardless of disease activity. These findings would be helpful in understanding the biological background of these diseases, and distinguishing between MS and NMOSD, as well as determining the disease activity.

Severe Relapse After Cessation of Immunosuppressive Therapy in a Patient With Neuromyelitis Optica Spectrum Disorder.

INTRODUCTION: The optimal duration of immunosuppressive therapy (IT) for neuromyelitis optica spectrum disorder (NMOSD) has not been established. Here, we report a case of severe relapse after early cessation of IT. CASE REPORT: A 32-year-old woman presented with a 2-week history of intractable vomiting and hiccups followed by quadriplegia with respiratory insufficiency. Spinal cord MRI showed longitudinally extensive transverse myelitis (LETM) and aquaporin-4-immunoglobulin-G (AQP4-IgG) was positive. She was diagnosed with NMOSD and IT was initiated. She did not experience any clinical attacks during 42 months of IT and her AQP4-IgG status was negative. IT was discontinued on her own decision; 36 months later, the patient experienced a severe LETM relapse with paraplegia, and her AQP4-IgG status reverted to positive. CONCLUSION: This case suggests that clinicians should exercise caution before discontinuing effective IT in patients with NMOSD.

Successful treatment of Lambert-Eaton myasthenic syndrome in a small cell lung cancer patient using 3,4-diaminopyridine: A case report.

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder of the neuromuscular junction that is characterized by muscle weakness. LEMS is usually associated with cancer, most commonly small cell lung cancer (SCLC). The potassium-channel blocker 3,4-diaminopyridine (3,4-DAP), has been previously used for the symptomatic treatment of LEMS. 3,4-DAP increases the release of acetylcholine and prolongs the duration of nerve action potentials at the presynaptic membrane of the neuromuscular junction. The present study describes the case of a patient with LEMS and SCLC, for which the symptoms did not improve with anticancer therapy, but did so markedly following treatment with 3,4-DAP. The present study illustrates that 3,4-DAP is a useful treatment choice in patients with LEMS, particularly for patients who do not fully improve following anticancer therapy.

Leptomeningeal metastasis: Clinical experience of 519 cases.

BACKGROUND: Diagnosis of leptomeningeal metastasis (LM) has become increasingly common because of enhanced detection via routine use of magnetic resonance imaging (MRI) and longer survival of patients by better systemic control. We investigated clinical features and analyzed potential prognostic factors in a large cohort of patients with LM. METHODS: The clinical features of LM developing from systemic cancers were analyzed retrospectively in patients at the National Cancer Center during 2005-2014. RESULTS: A total of 519 patients were enrolled; 497 had solid, 19 had hematopoietic tumors and 3 had tumors of unknown etiology. Among the solid tumors, the most common primary tumor was lung cancer (334 patients), followed by breast cancer (96) and gastrointestinal cancer (39). Median age at onset was 56 years, and the median Karnofsky performance status (KPS) was 60. Thirty-five percent of patients were diagnosed by MRI alone, 22% by cerebrospinal fluid (CSF) cytology alone, and 42% by both. Treatment included chemotherapy alone in 45%, radiation therapy alone in 10%, and both in 17%; 28% received supportive care alone. Median overall survival was 3 months. KPS ≥70, CSF protein level ≤50 mg/dl at the diagnosis of LM, and active treatment were associated independently with longer overall survival. Upon subgroup analysis of lung cancer patients, non-small cell lung cancer was a favorable prognostic factor for overall survival. CONCLUSIONS: Despite improved diagnosis via MRI and vigorous therapy, most patients with LM had poor outcomes. However, patients with a high KPS or normal CSF protein levels had favorable prognoses upon active treatment.

Evaluation of the 2015 diagnostic criteria for neuromyelitis optica spectrum disorder.

OBJECTIVE: To evaluate the application of the 2015 International Panel for NMO Diagnosis (IPND) criteria to consecutive cases of neuromyelitis optica spectrum disorder (NMOSD) in a large cohort of individuals with CNS inflammatory diseases. METHODS: In total, 594 patients with CNS inflammatory diseases were included. Rigorous confirmation of the patients' aquaporin-4 immunoglobulin G antibodies (AQP4-IgG) status throughout the disease duration (mean 9.2 ± 5.7 years) using repeated assays, including ELISA and cell-based assay, was performed. RESULTS: A total of 252 patients fulfilled the IPND criteria (AQP4-IgG positive: 226 [90%], AQP4-IgG negative: 26 [10%]). Of these, 136 (54%) patients met the 2006 neuromyelitis optica criteria. When we assumed an unknown AQP4-IgG status in the confirmed NMOSD group with AQP4-IgG, 162 of 226 (72%) patients with AQP4-IgG were classified as having NMOSD by the IPND criteria. The majority of patients were diagnosed with NMOSD within 2 years of onset (73%) or after a second attack (72%). Acute myelitis (83%) and optic neuritis (65%) were the most common clinical features throughout the disease duration. Optic neuritis (42%) was the most common initial manifestation, followed by acute myelitis (38%) and area postrema syndrome (14%). CONCLUSIONS: The IPND criteria well-reflected the broader clinical spectrum of NMOSD and markedly improved the diagnostic yield compared to the previous criteria, even in patients with an unknown AQP4-IgG status.