Epstein-Barr virus persistence and reactivation in neuromyelitis optica.

OBJECTIVE: Epstein-Barr virus (EBV) infection has been thought to be a key environmental factor in the development of multiple sclerosis (MS). The aim of this study is to investigate the association of EBV infection with neuromyelitis optica (NMO). METHODS: We measured levels of serum antibodies against EBV antigens, including anti-viral capsid antigen (VCA) IgM, anti-VCA IgG, anti-early antigen (EA) IgM, anti-EA IgG and anti-EBV nuclear antigen-1 IgG, in 50 patients with NMO (including 12 partial form with antiaquaporin 4 antibodies), 51 patients with MS, and 52 healthy controls, and cerebrospinal fluid (CSF) antibodies in 37 patients with NMO and 33 patients with MS with ELISA. RESULT: Compared with patients with MS and normal participants, patients with NMO more frequently had serum anti-EA IgG antibodies (52%), indicating more active viral replication than patients with MS (26%) and controls (25%). The antibody titres were significantly higher in the NMO group than in the MS (p=0.005) and control (p=0.005) groups. The CSF antibody titres were also higher in patients with NMO than in those with MS (p=0.03). CONCLUSIONS: Our results raise the hypothesis that persistent, active EBV replication is present in NMO, and may contribute to the immunological alterations that play a pathogenetic role in the disorder.

Benign neuromyelitis optica is rare in Japanese patients.

Good-outcome neuromyelitis optica (NMO) is defined as an Expanded Disability Status Scale (EDSS) score of ≤3.0 at 10 years after onset. The clinical courses of 80 consecutive patients with NMO were analyzed to identify the frequency and features of Japanese patients with good-outcome NMO. Of the 80 patients, 37 had a disease duration of >10 years; of these, eight (21.6%) presented a good outcome. These cases presented lower EDSS scores during the early phase of disease compared with those with conventional NMO. However, half of these patients developed severe disabilities later on, indicating that truly benign NMO is rare.

Cerebrospinal fluid interleukin-6 and glial fibrillary acidic protein levels are increased during initial neuromyelitis optica attacks.

BACKGROUND: The current 2006 neuromyelitis optica (NMO) criteria is useful for diagnosing NMO, however this criteria seemed to be insufficient at early stage of NMO. Hence, the development of diagnostic marker besides anti-aquaporin 4 antibody at early stage of NMO may be required. Our main aim of this study is to test the usefulness of measuring cerebrospinal fluid (CSF) interleukin (IL)-6 and glial fibrillary acidic protein (GFAP) concentrations as early diagnostic markers during initial NMO attacks. METHODS: We investigated CSF IL-6 and GFAP concentrations in 13 NMO spectrum disorder (NMOSD) patients at initial attacks, 24 idiopathic central nervous system inflammatory disease patients (9 optic neuritis, 9 myelitis and 6 encephalitis) and 20 other non-inflammatory neurological disorders (ONNDs) patients, retrospectively. RESULTS: The mean CSF IL-6 and GFAP concentrations during the initial NMOSD attack were 91.4 pg/ml and 369.3 ng/ml, respectively, and were significantly higher than in ONNDs, idiopathic optic neuritis and myelitis patients (P<0.01). The sensitivity of high CSF IL-6 during initial NMO attack was 76.9% and that of high CSF GFAP was 84.6%, respectively. CONCLUSION: Our data suggests that CSF IL-6 and GFAP may be useful early diagnostic markers of NMOSD.

CSF high-mobility group box 1 is associated with intrathecal inflammation and astrocytic damage in neuromyelitis optica.

OBJECTIVE: High-mobility group box 1 (HMGB1) acts as a proinflammatory mediator when released by cells. Recent studies implicate extracellular HMGB1 in the pathogenesis of various autoimmune diseases. Our main aim of this study is to determine whether HMGB1 is involved in the neuromyelitis optica (NMO) inflammatory process. METHODS: Cerebrospinal fluid (CSF) and serum HMGB1 levels in 42 NMO patients were compared with those in 30 multiple sclerosis (MS) patients, and 30 patients with other noninflammatory neurological disorders (ONNDs). We also tested the possible correlation between CSF HMGB1 levels and the clinical and laboratory variables in NMO patients. RESULTS: CSF HMGB1 levels in NMO patients were higher than those in MS and ONNDs patients (p<0.001), and these levels in MS patients were higher than those in ONNDs patients (p<0.001). After treatment, the CSF HMGB1 levels in NMO patients decreased to normal. In addition, CSF HMGB1 levels correlated with CSF cell counts, CSF protein levels, CSF interleukin-6 levels, CSF glial fibrillary acidic protein levels, and CSF/serum albumin ratio (p≤0.001). Serum HMGB1 levels in MS patients were significantly higher than those in ONNDs patients (p=0.002). CONCLUSIONS: HMGB1 could play a key role in central nervous system inflammation in NMO patients.

A case of adult-onset alexander disease featuring severe atrophy of the medulla oblongata and upper cervical cord on magnetic resonance imaging.

Adult-onset Alexander disease (AOAD) has been increasingly recognized since the identification of the glial fibrillary acidic protein gene mutation in 2001. We report on a 56-year-old man who was genetically confirmed as AOAD with the glial fibrillary acidic protein mutation of p.M74T. He developed spastic tetraparesis, sensory disturbances in four limbs, and mild cognitive impairment without apparent dysarthria and dysphagia. The case was characterized by severe atrophy of the medulla oblongata and upper cervical cord with intramedullary signal intensity changes on magnetic resonance imaging. While AOAD is diverse in clinical presentation, the peculiar magnetic resonance imaging findings of marked atrophy of the medulla oblongata and cervical cord are thought to be highly suggestive of the diagnosis of AOAD.

When is neuromyelitis optica diagnosed after disease onset?

To diagnose neuromyelitis optica (NMO), the 2006 NMO diagnostic criteria is commonly used. However, adequate studies about the time course of NMO according to the criteria have been lacking. The aim of the study was to identify the interval between disease onset and diagnosis of NMO, as well as the clinical characteristics and time course, according to the 2006 NMO diagnostic criteria in Japanese patients with NMO. Clinical progression and time course of 43 Japanese patients with NMO who fulfilled the 2006 NMO diagnostic criteria with mean disease duration of 14.2 years were investigated retrospectively. The initial inflammatory event was myelitis in 44.2% (long extensive transverse myelitis [LETM] in 14.3%), optic neuritis in 41.9%, and concurrent myelitis and optic neuritis in 9.3% of the patients. The presence of LETM and anti-aquaporin-4 antibody seropositivity by the end of the observation period was found in 85.7 and 93.0% of the patients, respectively. Among the patients whose medical information were sufficiently available, the median intervals between NMO onset and the time until development of both optic neuritis and myelitis, LETM, or fulfillment of the 2006 NMO criteria were 16.5, 35.1, and 27.8 months, respectively. The development of diagnostic method at an early stage of NMO may be needed in order to initiate early treatment.

Markedly elevated soluble intercellular adhesion molecule 1, soluble vascular cell adhesion molecule 1 levels, and blood-brain barrier breakdown in neuromyelitis optica.

OBJECTIVE: To evaluate the degree of blood-brain barrier disruption in patients with neuromyelitis optica (NMO) and to clarify whether the levels of soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vascular cell adhesion molecule 1 (sVCAM-1) in patients with NMO can be useful biomarkers for blood-brain barrier breakdown. DESIGN: Descriptive historical cohort. SETTING: Department of Neurology, Graduate School of Medicine, Chiba University. PATIENTS: The levels of sICAM-1 and sVCAM-1 in 25 patients with NMO, 21 patients with multiple sclerosis, and 20 patients with other noninflammatory neurologic disorders in the serum and cerebrospinal fluid (CSF) were measured using a multiplexed fluorescent magnetic bead-based immunoassay. MAIN OUTCOME MEASURES: Levels of the soluble adhesion molecules in serum and CSF and their associations with blood-brain barrier disruption. RESULTS: The CSF levels of sICAM-1 and sVCAM-1 increased in patients with NMO compared with patients with multiple sclerosis and other noninflammatory neurologic disorders (P < .001), and serum levels of sICAM-1 increased in patients with NMO compared with healthy control individuals (P = .003). The CSF sICAM-1 levels from patients with NMO were correlated with the albumin quotient (P = .02) and the presence of lesions detected via gadolinium-enhanced magnetic resonance imaging. CONCLUSIONS: Severe blood-brain barrier breakdown occurs in patients with NMO. Measuring adhesion molecules is useful to evaluate this barrier disruption.

Relapse of neuromyelitis optica spectrum disorder associated with intravenous lidocaine.

Lidocaine unmasks silent symptoms and eases neuropathic pain in multiple sclerosis patients; however, the effects of lidocaine in neuromyelitis optica have never been reported. We describe the case of a 59-year-old Japanese woman with neuromyelitis optica spectrum disorder who developed optic neuritis 1 day after intravenous lidocaine injection for treating allodynia. Her symptom seemed to result from a relapse of neuromyelitis optica induced by lidocaine administration, and not because of the transient effects of intravenous lidocaine administration. The possibility that lidocaine administration results in relapse of neuromyelitis optica due to its immunomodulating effects cannot be ruled out.

Expression of chemokine receptors on peripheral blood lymphocytes in multiple sclerosis and neuromyelitis optica.

BACKGROUND: The role of different chemokine receptors in the pathogenesis of multiple sclerosis (MS) has been extensively investigated; however, little is known about the difference in the role of chemokine receptors between the pathogenesis of neuromyelitis optica (NMO) and MS. Therefore, we examined the expression of chemokine receptors on peripheral blood lymphocytes (PBL) in MS and NMO. METHODS: We used flow cytometry to analyse lymphocyte subsets in 12 patients with relapsing NMO, 24 with relapsing-remitting MS during relapse, 3 with NMO and 5 with MS during remission. RESULTS: Compared with healthy controls (HC), the percentage of lymphocytes in white blood cells was significantly lower in NMO and MS patients. The percentage of T cells expressing CD4+CD25+ and CD4+CD45RO+ was higher, while that of CD4+CC chemokine receptor (CCR)3+ (T helper 2, Th2) was significantly lower in MS patients than in HC. The ratios of CD4+CXC chemokine receptors (CXCR)3+/CD4+CCR3+ (Th1/Th2) and CD8+CXCR3+/CD8+CCR4+ (T cytotoxic 1, Tc1/Tc2) were higher in MS patients than in HC. The percentage of CD8+CXCR3+ T cell (Tc1) and CD4+CXCR3+ T cell (Th1) decreased significantly during remission in MS patients (P <0.05). No significant differences were identified in the expression of the chemokine receptors on PBL in NMO patients compared with MS patients and HC. CONCLUSIONS: Th1 dominance of chemokine receptors on blood T cells and the correlation between CXCR3+ T cell (Th1 and Tc1) and disease activity in MS patients were confirmed by analysing chemokines receptors on PBL. In contrast, deviation in the Th1/Th2 balance was not observed in NMO patients.

Cytokine and chemokine profiles in neuromyelitis optica: significance of interleukin-6.

BACKGROUND: Neuromyelitis optica (NMO) is assumed to be immunologically distinct from multiple sclerosis (MS). Adequate studies about cytokines and chemokines in NMO have been lacking. OBJECTIVE: To investigate the contribution of cytokines/chemokines in the pathogenesis of NMO. METHODS: We measured 27 cytokines/chemokines and Th17 cell-associated cytokines in the cerebrospinal fluid (CSF) of 31 NMO, 29 MS and 18 other non-inflammatory neurological disorders patients. The serum levels of some cytokines/ chemokines were also measured. The correlations between clinical characteristics/laboratory findings and levels of cytokines/chemokines in NMO were examined. RESULTS: The CSF levels of interleukin (IL)-1 receptor antagonist, IL-6, IL-8, IL-13 and granulocyte colony-stimulating factor were significantly increased in NMO, while IL-9, fibroblast growth factor-basic, granulocyte macrophage colony-stimulating factor, macrophage inflammatory protein-1-beta and tumor necrosis factor-alpha were increased in MS. IL-10 and interferon-gamma-inducible protein-10 were elevated in NMO and MS. In serum analyses, only the IL-6 level showed significant elevation in NMO. The CSF IL-6 level had a significant correlation with the CSF glial fibrillary acidic protein level and CSF cells, and a weak correlation with anti-aquaporin-4 antibody titers. CONCLUSIONS: Different immunological status and pathophysiologies exist between NMO and MS, and IL-6 may play important roles in the pathogenesis of NMO.

Markedly increased CSF interleukin-6 levels in neuromyelitis optica, but not in multiple sclerosis.

To investigate differences in helper T cell immune responses in cerebrospinal fluid (CSF) between neuromyelitis optica (NMO) and multiple sclerosis (MS), we measured CSF levels of interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor-a and interferon-c at the time of relapse in 17 NMO patients and 21 MS patients using fluorescence-activated cell sorting. CSF IL-6 levels were significantly higher in NMO patients than in patients with MS (P = 0.001) and other neurological diseases (P = 0.001). The other cytokines tested were undetectable. Elevated CSF levels of IL-6 in only NMO supports the view of different pathophysiologies of NMO and MS. CSF IL-6 levels may be useful in the differential diagnosis of the two disorders.