Association of serum Gasdermin D with anti-N-methyl-D-aspartate receptor encephalitis.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disease of the central nervous system. Gasdermin D (GSDMD) is associated with autoimmune disorders and neuroinflammatory disorders, but its role in anti-NMDAR encephalitis is unclear. In this study, we measured serum levels of GSDMD in 42 patients with anti-NMDAR encephalitis and 25 healthy controls. Of the 42 patients, 17 had follow-up evaluation of GSDMD levels and modified Rankin scale (mRS) scores at 3 months. Association of GSDMD with anti-NMDAR encephalitis and its clinical parameters were evaluated. Serum GSDMD levels were significantly higher in patients with anti-NMDAR encephalitis than in healthy controls (p = 0.002, padjusted  = 0.009), especially in males (p = 0.001, padjusted  = 0.022). This was also evident in patients with severe impairment (mRS >3 vs mRS ≤3; p < 0.001). Serum GSDMD was associated with mRS before and after adjustment for age and gender (r = 0.440 and 0.430, p = 0.004 and 0.006, respectively) as well as serum CH50 (r = -0.419 and -0.426, p = 0.011 and 0.012, respectively). Furthermore, 3-month follow-up evaluation revealed that after treatment, anti-NMDAR encephalitis patients had significantly decreased serum GSDMD levels (p = 0.007) and significantly decreased mRS scores (p = 0.002) compared with before treatment. Furthermore, the changes in mRS scores were negatively associated with changes in GSDMD levels, although the associations were not significant (r = -0.222, p = 0.393). Our findings show that serum GSDMD levels are elevated in anti-NMDAR encephalitis and are associated with disease prognosis.

Myelin oligodendrocyte glycoprotein-associated disorders are associated with HLA subtypes in a Chinese paediatric-onset cohort.

OBJECTIVE: Myelin oligodendrocyte glycoprotein-associated disorders (MOGADs) are a rare new neurological autoimmune disease with unclear pathogenesis. Since a linkage of the disease to the human leucocyte antigen (HLA) has not been shown, we here investigated whether MOGAD is associated with the HLA locus. METHODS: HLA genotypes of 95 patients with MOGADs, assessed between 2016 and 2018 from three academic centres, were compared with 481 healthy Chinese Han individuals. Patients with MOGADs included 51 paediatric-onset and 44 adult-onset cases. All patients were seropositive for IgG targeting the myelin oligodendrocyte glycoprotein (MOG). RESULTS: Paediatric-onset MOGAD was associated with the DQB1*05:02-DRB1*16:02 alleles (OR=2.43; OR=3.28) or haplotype (OR=2.84) of HLA class II genes. The prevalence of these genotypes in patients with paediatric-onset MOGAD was significantly higher than healthy controls (padj=0.0154; padj=0.0221; padj=0.0331). By contrast, adult-onset MOGAD was not associated with any HLA genotype. Clinically, patients with the DQB1*05:02-DRB1*16:02 haplotype exhibited significantly higher expanded disability status scale scores at onset (p=0.004) and were more likely to undergo a disease relapse (p=0.030). HLA-peptide binding prediction algorithms and computational docking analysis provided supporting evidence for the close relationship between the MOG peptide subunit and DQB1*05:02 allele. In vitro results indicated that site-specific mutations of the predicted target sequence reduced the antigen-antibody binding, especially in the paediatric-onset group with DQB1*05:02 allele. CONCLUSIONS: This study demonstrates a possible association between specific HLA class II alleles and paediatric-onset MOGAD, providing evidence for the conjecture that different aetiology and pathogenesis likely underlie paediatric-onset and adult-onset cases of MOGAD.

Neutralization of interleukin-9 ameliorates experimental stroke by repairing the blood-brain barrier via down-regulation of astrocyte-derived vascular endothelial growth factor-A.

Astrocytes mediate the destruction of the blood-brain barrier (BBB) during ischemic stroke (IS). IL-9 is a pleiotropic cytokine that we previously found to be highly expressed in peripheral blood mononuclear cells from patients with IS, and the presence of IL-9 receptors on astrocytes has been reported in the literature. Here, we detected the effect of IL-9 on astrocytes using an anti-IL-9-neutralizing antibody to treat rats with experimental stroke. Supernatants from astrocytes treated with or without oxygen-glucose deprivation and/or IL-9 were incubated with bEnd.3 cell monolayers after blocking the IL-9 receptor on the endothelium. Immunofluorescence staining and Western blot analyses were conducted to observe the change in tight junction proteins (TJPs) in bEnd.3 cells as well as the level of VEGF-A and possible signal pathways in astrocytes. We also applied middle cerebral artery occlusion (MCAO) models to determine the effect of anti-IL-9-neutralizing antibodies on IS. As a result, astrocyte-conditioned medium treated with IL-9 aggravated the disruption of the BBB accomplished by the degradation of TJPs in endothelial cells. In addition, IL-9 increased the level of VEGF-A in astrocytes, and blocking the effect of VEGF-A reversed the breakdown of the BBB. In the MCAO model, anti-IL-9-neutralizing antibody reduced the infarct volume and BBB destruction. Mechanistically, the anti-IL-9-neutralizing antibody repaired the damaged TJPs (zonula occludens 1, occludin, and claudin-5) and induced a decrease in VEGF-A expression in ischemic lateral brain tissue. In contrast, a local injection of recombinant murine IL-9 to the brain resulted in a marked up-regulation of VEGF-A in the striatum. In conclusion, anti-IL-9-neutralizing antibody can reduce the severity of IS partially by alleviating the destruction of the BBB via down-regulation of astrocyte-derived VEGF-A. This finding suggests that targeting IL-9 or VEGF-A could provide a new direction for the treatment of IS.-Tan, S., Shan, Y., Lin, Y., Liao, S., Zhang, B., Zeng, Q., Wang, Y., Deng, Z., Chen, C., Hu, X., Peng, L., Qiu, W., Lu, Z. Neutralization of IL-9 ameliorates experimental stroke by repairing the blood-brain barrier via down-regulation of astrocyte-derived vascular endothelial growth factor-A.

The Effects of Carbenoxolone against Experimental Autoimmune Encephalomyelitis in a Mouse Model.

INTRODUCTION: Multiple sclerosis (MS) is a complex demyelinating disease involving central nervous system (CNS). It is still a challenge to secure an effective therapeutic strategy against this disease. Carbenoxolone (CBX) is a derivative of glycyrrhetinic acid, which is widely used in brain research for its gap-junction inhibition effects. Many researchers have observed CBX-mediated suppression of CNS inflammation in their studies. OBJECTIVE: We want to further examine its anti-inflammation effects in CNS demyelinating disease like MS. METHODS: Thus, our study applied an experimental autoimmune encephalomyelitis (EAE) mouse model and examined the effects of CBX on it. RESULTS AND CONCLUSIONS: We found that CBX significantly reversed the EAE severity and pathology in EAE. IL-17-secreting and IFN-γ-secreting CD4+ T lymphocytes were remarkably lower in the spleen of CBX-treated mice. Production of IL-23 and IL-17 from cortex in EAE animals was markedly reduced by CBX. Furthermore, CBX treatment increased the expression of brain-derived neurotrophic factor. This study provides evidence for the protective role of CBX against EAE.

The glucagon-like peptide-1 receptor agonist reduces inflammation and blood-brain barrier breakdown in an astrocyte-dependent manner in experimental stroke.

BACKGROUND: Preserving the integrity of the blood-brain barrier (BBB) is beneficial to avoid further brain damage after acute ischemic stroke (AIS). Astrocytes, an important component of the BBB, promote BBB breakdown in subjects with AIS by secreting inflammatory factors. The glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 (Ex-4) protects the BBB and reduces brain inflammation from cerebral ischemia, and GLP-1R is expressed on astrocytes. However, the effect of Ex-4 on astrocytes in subjects with AIS remains unclear. METHODS: In the present study, we investigated the effect of Ex-4 on astrocytes cultured under oxygen-glucose deprivation (OGD) plus reoxygenation conditions and determined whether the effect influences bEnd.3 cells. We used various methods, including permeability assays, western blotting, immunofluorescence staining, and gelatin zymography, in vitro and in vivo. RESULTS: Ex-4 reduced OGD-induced astrocyte-derived vascular endothelial growth factor (VEGF-A), matrix metalloproteinase-9 (MMP-9), chemokine monocyte chemoattractant protein-1 (MCP-1), and chemokine C-X-C motif ligand 1 (CXCL-1). The reduction in astrocyte-derived VEGF-A and MMP-9 was related to the increased expression of tight junction proteins (TJPs) in bEnd.3 cells. Ex-4 improved neurologic deficit scores, reduced the infarct area, and ameliorated BBB breakdown as well as decreased astrocyte-derived VEGF-A, MMP-9, CXCL-1, and MCP-1 levels in ischemic brain tissues from rats subjected to middle cerebral artery occlusion. Ex-4 reduced the activation of the JAK2/STAT3 signaling pathway in astrocytes following OGD. CONCLUSION: Based on these findings, ischemia-induced inflammation and BBB breakdown can be improved by Ex-4 through an astrocyte-dependent manner.

HLA class II allele DRB1*16:02 is associated with anti-NMDAR encephalitis.

BACKGROUND AND OBJECTIVE: Aetiology and pathogenesis of anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, the most common autoimmune encephalitis, is largely unknown. Since an association of the disease with the human leucocyte antigen (HLA) has not been shown so far, we here investigated whether anti-NMDAR encephalitis is associated with the HLA locus. METHODS: HLA loci of 61 patients with anti-NMDAR encephalitis and 571 healthy controls from the Chinese Han population were genotyped and analysed for this study. RESULTS: Our results show that the DRB1*16:02 allele is associated with anti-NMDAR encephalitis (OR 3.416, 95% CI 1.817 to 6.174, p=8.9×10-5, padj=0.021), with a higher allele frequency in patients (14.75%) than in controls (4.82%). This association was found to be independent of tumour formation. Besides disease susceptibility, DRB1*16:02 is also related to the clinical outcome of patients during treatment, where patients with DRB1*16:02 showed a lower therapeutic response to the treatment than patients with other HLA alleles (p=0.033). Bioinformatic analysis using HLA peptide-binding prediction algorithms and computational docking suggested a close relationship between the NR1 subunit of NMDAR and the DRB1*16:02. CONCLUSIONS: This study for the first time demonstrates an association between specific HLA class II alleles and anti-NMDAR encephalitis, providing novel insights into the pathomechanism of the disease.

Lack of short-chain fatty acids and overgrowth of opportunistic pathogens define dysbiosis of neuromyelitis optica spectrum disorders: A Chinese pilot study.

BACKGROUND: Intestinal microbiota is an important environmental factor in the initiation and progression of autoimmune diseases. However, investigations on the gut microbiome in neuromyelitis optica spectrum disorders (NMOSD) are relatively insufficient, especially for that of the Asia population. OBJECTIVES: To evaluate whether or not the intestinal microbiota of NMOSD patients had specific microbial signatures. METHODS: Next-generation sequencing and gas chromatography were employed to compare the fecal microbial composition and short-chain fatty acids (SCFAs) spectrum between patients with NMOSD (n = 84) and healthy controls (n = 54). RESULTS: The gut microbial composition of NMOSD distinguished from healthy individuals. Streptococcus, significantly increased in NMOSD, is positively correlated with disease severities (p < 0.05). The use of immunosuppressants results in a decrease of Streptococcus, suggesting that Streptococcus might play a significant role in the pathogenesis of NMOSD. A striking depletion of fecal SCFAs was observed in NMOSD patients (p < 0.0001), with acetate and butyrate showing significantly negative correlation with disease severities (p < 0.05). CONCLUSION: The fecal organismal structures and SCFAs level of patients with NMOSD were distinctive from healthy individuals. These findings not only could be critical events driving the aberrant immune response responsible for the pathogenesis of these disorders but could also provide suggestions for disease therapy.

Elevated soluble syndecan-1 levels in neuromyelitis optica are associated with disease severity.

Syndecan-1 (SDC-1) is a transmembrane member that has a profound influence on the resolution of inflammation. Soluble syndecan-1 (sSDC-1) levels have been shown to increase in many inflammatory diseases. However, it remains unknown whether sSDC-1 concentration is elevated in neuromyelitis optica (NMO) and multiple sclerosis (MS) patients. The aims of this pilot study were to investigate the relationship between sSDC-1 and disease severity in NMO and MS and whether sSDC-1 has potential as an effective marker for disease severity. We measured sSDC-1 concentrations by using an enzyme-linked immunosorbent assay (ELISA). NMO patients had significantly higher CSF sSDC-1 levels than MS patients or controls. We also found a positive correlation between the increased CSF sSDC-1 levels and increased severity in NMO disease, but not in MS. In NMO, CSF sSDC-1 concentrations were positively correlated with CSF interleukin (IL)-6, IL-8 and IL-17. Overall, we showed levels of CSF sSDC-1 were higher in NMO patients and had a positive relationship with disease severity of NMO but not with MS. CSF sSDC-1 may be an effective marker of NMO disease severity.

Cerebrospinal Fluid Level of Soluble CD27 Is Associated with Disease Severity in Neuromyelitis Optica Spectrum Disorder.

OBJECT: CD27 belongs to the tumor necrosis factor receptor family and is constitutively expressed on T cells. The concentration of cerebrospinal fluid (CSF) soluble (s)CD27 is elevated in patients with multiple sclerosis (MS). However, whether the level of CSF sCD27 is elevated in neuromyelitis optica spectrum disorder (NMOSD) remains unknown. The aim of this study was to measure the CSF concentration of sCD27 and to determine its relationship with NMOSD disease activity. METHODS: CSF CXCL13 was measured by ELISA in neuromyelitis optica (NMO) (n = 31) and MS (n = 23) patients and in controls (CTLs) (n = 22). RESULTS: The concentration of sCD27 was higher in the NMO group than in the MS (p = 0.082) and CTL (p = 0.002) groups, and there was a positive correlation with CSF IL-6 (p = 0.000) and a negative correlation with IL-10 (p = 0.073). In the NMO group, patients with higher sCD27 concentrations exhibited worse disease disability in their CSF (p = 0.006). Moreover, the sCD27 concentrations had a significantly positive correlation with the level of CSF total protein (p = 0.030). Furthermore, the patients positive for AQP4-IgG (n = 26) seemed to have higher levels of sCD27 in their CSF (p = 0.069) than those negative for AQP4-IgG (n = 5). CONCLUSIONS: We revealed that the level of CSF sCD27 was elevated in NMOSD and correlated with NMOSD disease activity.

Serum Bilirubin and Albumin in Anti-N-Methyl-D-Aspartate Receptor Encephalitis.

BACKGROUND AND OBJECTIVE: Low serum levels of bilirubin and albumin are associated with multiple autoimmune diseases, but their role in anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is unknown. METHODS: Serum bilirubin and albumin levels were evaluated in 60 patients with anti-NMDAR encephalitis, 50 cryptococcal encephalitis, and 145 healthy controls (CTLs). Of the 60 anti-NMDAR encephalitis patients, 30 had a follow-up evaluation at 3 months after admission. RESULTS: Serum bilirubin and albumin levels were both significantly lower in anti-NMDAR encephalitis than in CTLs, and serum bilirubin levels were significantly lower in anti-NMDAR encephalitis than in cryptococcal encephalitis. Serum bilirubin levels were significantly lower in patients with psychiatric symptoms, with severe impairment, and with limited responses to treatment than those without psychiatric symptoms, with mild impairment, and with favorable responses to treatment, respectively. A follow-up evaluation of 30 patients revealed that the modified Rankin Scale scores were significantly decreased after treatment. Serum bilirubin significantly associated with serum albumin, and plasma hemoglobin. CONCLUSIONS: Our results revealed for the first time an association between the serum levels of bilirubin in the anti-NMDAR encephalitis. Further studies investigating the role of bilirubin and albumin in anti-NMDAR encephalitis are required.

Brain Immunohistopathology in a Patient with Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy.

BACKGROUND: Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a novel meningoencephalomyelitis. However, the pathogenesis of this disease is unclear. We therefore examined a brain biopsy from a patient with autoimmune GFAP astrocytopathy by immunohistopathology. METHODS: We examined brain biopsy sections from a patient with autoimmune GFAP astrocytopathy using hematoxylin and eosin (HE) and Luxol fast blue (LFB) staining, and immunostaining with antibodies for CD4, CD8, CD3, CD20, CD68, CD138, Neu-N, GFAP, myelin oligodendrocyte glycoprotein (MOG), and aquaporin-4 (AQP4). RESULTS: HE staining revealed extensive inflammatory cells (marked lymphocytes) around brain vessels, and LFB showed no signs of demyelination or axon loss. Immunohistochemical analysis showed CD3+ and CD4+ T cells cuffing around brain vessels, accompanied by CD8+ T cells, CD20+ B cells, and CD138+ plasma cells, while some macrophages (CD68+) were scattered throughout the brain parenchyma. There was no loss of AQP4 or MOG expression in this patient, while GFAP was abundantly expressed. CONCLUSIONS: These findings suggest that inflammatory cells, including T cells, B cells, plasma cells, and macrophages, are involved in autoimmune GFAP astrocytopathy. Demyelination and astrocyte loss may not necessarily occur in this disease.

Exacerbation of oxygen-glucose deprivation-induced blood-brain barrier disruption: potential pathogenic role of interleukin-9 in ischemic stroke.

Interleukin (IL)-9 exerts a variety of functions in autoimmune diseases. However, its role in ischemic brain injury remains unknown. The present study explored the biological effects of IL-9 in ischemic stroke (IS). We recruited 42 patients newly diagnosed with IS and 22 age- and sex-matched healthy controls. The expression levels of IL-9 and percentages of IL-9-producing T cells, including CD3+CD4+IL-9+ and CD3+CD8+IL-9+ cells, were determined in peripheral blood mononuclear cells (PBMCs) obtained from patients and control individuals. We also investigated the effects of IL-9 on the blood-brain barrier (BBB) following oxygen-glucose deprivation (OGD) and the potential downstream signaling pathways. We found that patients with IS had higher IL-9 expression levels and increased percentages of IL-9-producing T cells in their PBMCs. The percentages of CD3+CD4+IL-9+ and CD3+CD8+IL-9+ T cells were positively correlated with the severity of illness. In in vitro experiments using bEnd.3 cells, exogenously administered IL-9 exacerbated the loss of tight junction proteins (TJPs) in cells subjected to OGD plus reoxygenation (RO). This effect was mediated via activation of IL-9 receptors, which increased the level of endothelial nitric oxide synthase (eNOS), as well as through up-regulated phosphorylation of signal transducer and activator of transcription 1 and 3 and down-regulated phosphorylated protein kinase B/phosphorylated phosphatidylinositol 3-kinase signaling. These results indicate that IL-9 has a destructive effect on the BBB following OGD, at least in part by inducing eNOS production, and raise the possibility of targetting IL-9 for therapeutic intervention in IS.

Risk factors, topographic patterns and mechanism analysis of intracranial atherosclerotic stenosis ischemic stroke.

BACKGROUND: The association between topographic patterns, risk factors and stroke mechanisms of ICAS in first-ever stroke remains unknown. METHODS: A large sample sized retrospective study was performed on first-ever ICAS ischemic stroke using DWI and MRA. RESULTS: Hypertension (60.92%), cigarette smoking (26.82%), MCA (76.65%) and multiple vessels (65.37%) stenosis, were the major factors favoring different mechanisms. Subcortical lesions were the most occurring topographic patterns (41.4%). The common mechanism was LBO (66.3%). Statistical analysis showed a significant relationship between lesion patterns and mechanisms (r = 0.384, P = 0.001). Single mechanism had the higher apoB/apoAI ratio (P = 0.005) and levels of plasma apoB (P = 0.007) compared with multiple mechanisms. The anterior circulation stroke were more multiple mechanisms as compared to the posterior circulation stroke (P = 0.001). LBO was more prevalent in posterior circulation stroke than in anterior circulation stroke (P = 0.001). CONCLUSIONS: The topographic patterns of ischemic lesions is helpful in early identification of different mechanisms of ICAS. Monitoring apoB and apoB/apoA1 may help to predict the mechanism of stroke with ICAS. The prevalence of mechanisms differ between anterior and posterior circulation stroke with ICAS.

Cytokine and Chemokine Profiles in Patients with Neuromyelitis Optica Spectrum Disorder.

OBJECTIVE: To screen cytokines and chemokines and determine their dynamic changes in the serum and cerebrospinal fluid (CSF) of patients with neuromyelitis optica spectrum disorder (NMOSD). METHODS: Eight NMOSD with seropositive aquaporin-4 antibody (AQP4-IgG) were enrolled, as well as 8 matched patients with multiple sclerosis (MS) and 8 with noninflammatory neurological diseases, who were included as controls. In total, 102 cytokines and 34 chemokines were detected in the CSF and serum of NMOSD patients and controls. RESULTS: CSF interleukin (IL)-17A levels were significantly higher in NMOSD patients in the relapsing phase (27.15 ± 11.33) than in those in the remitting phase (10.04 ± 3.11, p = 0.0017), and patients with MS (14.72 ± 3.20, p = 0.0283) and other controls (10.39 ± 11.38, p = 0.0021). CSF IL-6 levels were higher in the NMOSD patients in the relapsing phase (12.23 ± 3.47) than in those in the remitting phase (5.87 ± 2.78, p = 0.0001), and MS patients (7.38 ± 2.35, p = 0.0033) and other controls (7.50 ± 0.37, p = 0.0043). CSF CCL19 levels were also significantly higher in NMOSD patients in the relapsing phase (35.87 ± 27.07) than in those in the remitting phase (10.71 ± 3.62, p = 0.0215). Serum IL-19 levels were lower in NMOSD patients in the relapsing phase (6.23 ± 1.95) than in those in the remitting phase (10.72 ± 4.46, p = 0.0092). Further, there was a positive, significant correlation between serum IL-9 concentration and the Expanded Disability Status Scale score in the NMOSD patients in the relapsing phase (p = 0.04). CONCLUSION: In addition to IL-6 and IL-17A, IL-16 and CCL19 act as proinflammatory cytokines/chemokines, while IL-19 plays a protective role in NMOSD pathogenesis.

The role of anti-aquaporin 4 antibody in the conversion of acute brainstem syndrome to neuromyelitis optica.

BACKGROUND: Acute brainstem syndrome (ABS) may herald multiple sclerosis (MS), neuromyelitis optica (NMO), or occur as an isolated syndrome. The aquaporin 4 (AQP4)-specific serum autoantibody, NMO-IgG, is a biomarker for NMO. However, the role of anti-AQP4 antibody in the conversion of ABS to NMO is unclear. METHODS: Thirty-one patients with first-event ABS were divided into two groups according to the presence of anti-AQP4 antibodies, their clinical features and outcomes were retrospectively analyzed. RESULTS: Fourteen of 31 patients (45.16 %) were seropositive for NMO-IgG. The 71.43 % of anti-AQP4 (+) ABS patients converted to NMO, while only 11.76 % of anti-AQP4 (-) ABS patients progressed to NMO. Anti-AQP4 (+) ABS patients demonstrated a higher IgG index (0.68 ± 0.43 vs 0.42 ± 0.13, p < 0.01) and Kurtzke Expanded Disability Status Scale (4.64 ± 0.93 vs 2.56 ± 0.81, p < 0.01) than anti-AQP4 (-) ABS patients. Area postrema clinical brainstem symptoms occurred more frequently in anti-AQP4 (+) ABS patients than those in anti-AQP4 (-) ABS patients (71.43 % vs 17.65 %, p = 0.004). In examination of magnetic resonance imaging (MRI), the 78.57 % of anti-AQP4 (+) ABS patients had medulla-predominant involvements in the sagittal view and dorsal-predominant involvements in the axial view. CONCLUSIONS: ABS represents an inaugural or limited form of NMO in a high proportion of anti-AQP4 (+) patients.

Involvement of the optic nerve in mutated CSF1R-induced hereditary diffuse leukoencephalopathy with axonal spheroids.

BACKGROUND: Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal dominant disorder characterized by cerebral white matter degeneration and caused by mutations in the colony-stimulating factor 1 receptor (CSF1R) gene. Involvement of the optic nerves in hereditary diffuse leukoencephalopathy is rare. CASE PRESENTATION: We report the case of a 30-year-old Chinese woman with HDLS, who carried a heterozygous c.2345 G > A (p.782Arg > His) mutation in exon 18 of CSF1R. She developed a gradual decline in motor ability, as well as cognitive and visual function, over the course of 4 months. Brain T2 fluid-attenuated inversion recovery-weighted magnetic resonance imaging revealed high signal lesions in the bilateral frontoparietal and periventricular deep white matter. Optical coherence tomography showed that the right peripapillary retinal nerve fiber layer was atrophic in the temporal quadrant while the left peripapillary retinal nerve fiber layer was thin in the temporal superior quadrant. CONCLUSIONS: A diagnosis of HDLS should be considered in patients with white matter lesions and optic nerves injury upon magnetic resonance imaging that mimics progressive multiple sclerosis.

Comparison of the Chinese ischemic stroke subclassification and Trial of Org 10172 in acute stroke treatment systems in minor stroke.

BACKGROUND: The underlying causes of minor stroke are difficult to assess. Here, we evaluate the reliability of the Chinese Ischemic Stroke Subclassification (CISS) system in patients with minor stroke, and compare it to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) system. METHODS: A total of 320 patients with minor stroke were retrospectively registered and categorized into different subgroups of the CISS and TOAST by two neurologists. Inter- and intra-rater agreement with the two systems were assessed with kappa statistics. RESULTS: The percentage of undetermined etiology (UE) cases in the CISS system was 77.3 % less than that in the TOAST system, which was statistically significant (P < 0.001). The percentage of large artery atherosclerosis (LAA) in the CISS system was 79.7 % more than that in the TOAST system, which was also statistically significant (P < 0.001). The kappa values for inter-examiner agreement were 0.898 (P = 0.031) and 0.732 (P = 0.022) for the CISS and TOAST systems, respectively. The intra-observer reliability indexes were moderate (0.569 for neurologist A, and 0.487 for neurologist B). CONCLUSIONS: The CISS and TOAST systems are both reliable in classifying patients with minor stroke. CISS classified more patients into known etiologic categories without sacrificing reliability.

Intractable pruritus in neuromyelitis optica.

Neuromyelitis optica (NMO) is an immune-mediated disease of the central nervous system. Pruritus in patients with NMO has rarely been reported. We aimed to explore the characteristics and underlying mechanisms of pruritus in NMO patients. We reviewed the case records of 64 NMO patients who visited the Department of Neurology at the Third Hospital of Sun Yat-sen University between 2009 and 2015. Of the 64 aquaporin-4 antibody-positive NMO patients, 18 had pruritus. Spinal magnetic resonance imaging (MRI) showed lesions in all of these patients. A total of 13 patients presented with brain lesions, and four had lesions in the periaqueductal gray matter on cerebral MRI. However, the anatomical distribution of pruritus did not always correspond to the dermatomal distributions of the involved spinal cord segments. Pruritus was completely or partially relieved after treatment. Pruritus is not a rare occurrence and may be a characteristic feature of NMO.

Late-onset neuromyelitis optica spectrum disorder in AQP4-seropositivepatients in a Chinese population.

BACKGROUND: Increasing rates of AQP4-seropositive neuromyelitis optica spectrum disorder (NMOSD) have been reported in late-onset patients (LONMOSD). However, the full range of clinical differences between early-onset and late-onset variants remain unclear. We describe the clinical features and outcomes of AQP4-seropositive LONMOSD patients in a Chinese population. METHODS: This was a retrospective analysis of medical records in a cohort study of AQP4-seropositive NMOSD patients with early-onset (≤49 years) and late-onset (≥50 years) variants between January 2006 and February 2014. Demographic, clinical, neuroimaging and cerebrospinal fluid (CSF) findings and prognosis data were analyzed. RESULTS: We identified thirty AQP4-seropositive LONMOSD patients (86.7 % women). The median age at onset was 57.5 years (range 50-70). There were similar onset frequencies between optic neuritis (ON) and longitudinally extensive transverse myelitis (LETM). Longer interval between (first) ON and LETM (median 13 vs. 4 months; p < 0.05), time from first symptoms to diagnosis of NMO (median 17 vs. 7 months, p < 0.05), higher comorbidities (66.7 vs. 26.7 %; p < 0.05), and more hypertension (26.7 vs.3.3 %; p < 0.05) were prevalent. NMO-like lesions were less common (10.7 vs. 41.6 %; p < 0.05), while the rate of non-specific lesions tended to be higher (53.6 vs. 29 %; p = 0.067). These patients displayed more severe Expanded Disability Status Scale (EDSS) in nadir (median 6.75vs.5; p < 0.05). Attacks often resulted in EDSS 4 within a short period (median 8 vs. 13.5 months; p < 0.05). At last follow-up, the EDSS score was more severe in these patients (median 5.25 vs. 4; p < 0.05). No significant predictors were identified. CONCLUSIONS: This study provides an overview of the clinical and paraclinical features of AQP4-seropositive LONMOSD patients in China and demonstrates a number of distinct disease characteristics in early vs. late onset. Older patients are more susceptible to disability in short course. However, these patients do not always display NMO-like lesions in the brain. Initial LETM may not necessarily be predominant as the initial symptom, contrary to previous reports. The higher comorbidities may warrant a modified approach of treatment.

[Correlation of AQP4 gene polymorphism with NMO clinical phenotypes and its underlying mechanism].

OBJECTIVE: To explore the correlation between aquaporin-4 (AQP4) gene single nucleotide polymorphism (SNP) and clinical phenotypes of neuromyelitis optica (NMO) and its underlying mechanism. METHODS: Eight SNPs in AQP4 gene regulatory region were selected and genotyped for 208 anti-AQP4 autoantibodies (NMO-IgG) seropositive cases during January 2010 to January 2014 and 204 healthy subjects. Then the correlation was further analysed between genotypes and NMO phenotypes. And the effect of microRNA (miRNA) on the expression of AQP4 gene was examined by dual-luciferase reporter technique. RESULTS: The A/T genotype of rs1058424 (50.61% vs 70.45%, OR = 0.430, 95% CI 0.210-0.880) and C/T (50.00% vs 68.18%, OR = 0.467, 95%CI 0.231-0.994) genotype of rs3763043 in 3'-UTR were correlated with longitudinal extensive transverse myelitis; the A/T genotype of rs1058424 (46.72% vs 66.28%, OR = 0.525, 95% CI 0.276-0.999) and A/C genotype of rs335929 (45.08% vs 58.14%, OR = 0.527, 95% CI 0.281-0.987) in 3'-UTR as well as C/T genotype of rs151244 (50.82% vs 69.77%, OR = 0.450, 95% CI 0.230-0.881) in promoter 0 region were correlated with optic neuritis. The polymorphism of rs6508459 in 3'-UTR and rs3763040 in intron region were correlated with concurrent systemic autoimmune diseases (P = 0.012 and 0.023 respectively).miRNA 323-3p could regulate AQP4 gene expression.However, variation in SNP rs1058424 failed to affect this regulation. CONCLUSION: SNP in 3'-UTR of AQP4 gene may be associated with NMO phenotypes.miRNA 323-3p may participate in the pathogenesis of NMO by binding to certain SNP sites in 3'-UTR of AQP4 gene and regulating its expression.