Akiyuki Uzawa

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.

Different responses to interferon beta-1b treatment in patients with neuromyelitis optica and multiple sclerosis

Background:  Although the benefit of treatment for relapsing–remitting multiple sclerosis (MS) is firmly established, whether interferon beta‐1b (IFNB‐1b) therapy is efficacious for neuromyelitis optica (NMO) has been debated.

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.

“Bright spotty lesions” on spinal magnetic resonance imaging differentiate neuromyelitis optica from multiple sclerosis

Background: Spinal magnetic resonance imaging (MRI) finding of longitudinally extensive spinal cord lesions (LESCL) extending over three vertebral segments and involvements of spinal central gray matter have been reported in patients with neuromyelitis optica (NMO). Objectives: We aimed to review spinal MRI findings in NMO and multiple sclerosis (MS), and to determine whether the “bright spotty lesions” (BSLs) are a discriminative finding of NMO. Methods: For this study, 24 consecutive patients with NMO and 34 patients with MS were enrolled. BSLs were defined as very hyperintense spotty lesions on axial T2WI. We also studied the length, distribution, signal homogeneity, size, and presence of contrast-enhanced lesions. Results: BSLs were more frequently found in patients with NMO (54%) than in those with MS (3%; p < 0.01). LESCL were found in 67% of the NMO patients. BSLs were seen in 63% of the patients without LESCL. BSLs or LESCL were found in 88% of the NMO patients. Inhomogeneous lesions, transversally extensive lesions, and central lesions were more frequently seen in NMO than in MS. Conclusions: BSLs are a newly defined spinal MRI finding specifically seen in NMO. In combination with LESCL, BSLs can help differentiate patients with NMO from those with MS with higher sensitivity than LESCL alone.

Association of anti-aquaporin-4 antibody-positive neuromyelitis optica with myasthenia gravis.

We describe 2 patients who developed anti-aquaporin-4 antibody-positive neuromyelitis optica (NMO) following the development of anti-acetylcholine receptor antibody-positive myasthenia gravis (MG). A literature review of 13 similar cases in addition to the present 2 cases of NMO with MG showed predominance among Asian women and frequent development of NMO following thymectomy for MG. Moreover, in one of our patients, serial assays of anti-aquaporin-4 antibody and anti-acetylcholine receptor antibody were performed. Accumulating evidence for the coexistence of NMO and MG suggests that a common immunopathogenesis of NMO and MG may exist, and the association of NMO with MG may be more frequent than hitherto believed.

Meningitis-retention syndrome : An unrecognized clinical condition

AbstractBackgroundA combination of acute urinary retention and aseptic meningitis has not been well known. This combination can be referred to as meningitis–retention syndrome (MRS), when accompanied by no other abnormalities.ObjectiveTo describe the results of a uro–neurological assessment in our patients with MRS.MethodsIn three patients (two men, one woman; age, 34–68 years), we performed urodynamic studies and relevant imaging and neurophysiological tests, in addition to cerebrospinal fluid (CSF) examination.ResultsAll three patients developed acute urinary retention along with headache, fever and stiff neck.None had obvious neurological abnormalities, other than a slightly brisk reflex in the lower extremities. One had previously experienced generalized erythematous eruptions, but none had pain, hypalgesia or skin eruptions in the sacral dermatomes suggestive of Elsberg syndrome (infectious sacral polyradiculitis; mostly genital herpes). Brain/spinal/lumbar plexus MRI scans and nerve conduction studies were normal. CSF examination showed mild mononuclear pleocytosis, increased protein content, and normal to mildly decreased glucose content in all patients; increased myelin basic protein suggestive of central nervous system demyelination in one; and increased viral titers in none.Urodynamic study revealed, during the voiding phase, an underactive detrusor in all patients and an unrelaxing sphincter in one. These clinical manifestations were ameliorated within 3 weeks.ConclusionsWe reported three cases of MRS, a peculiar syndrome that could be regarded as a mild variant of acute disseminated encephalomyelitis (ADEM). Urinary retention might reflect acute shock phase of this disorder. Although MRS has a benign and selfremitting course, management of the acute urinary retention is necessary.

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.

Serum cytokine and chemokine profiles in patients with myasthenia gravis

Myasthenia gravis (MG) is an autoimmune‐mediated inflammatory disease of the neuromuscular junction. Previous studies of animal MG models have suggested important roles of cytokines in MG pathogenesis, but adequate studies on cytokines in human MG are lacking. Using a multiplex suspension array system, we measured the serum levels of 27 cytokines/chemokines in 47 anti‐acetylcholine receptor antibody‐positive patients with MG and 20 normal controls (NC) to investigate the contribution of cytokines/chemokines toward MG pathogenesis. Correlations between clinical parameters and cytokine/chemokine levels in patients with MG were also examined. The serum levels of interleukin (IL)‐15 (mean ± standard deviation: 6·85 ± 6·97 pg/ml) and vascular endothelial growth factor (VEGF) (96·21 ± 71·60 pg/ml) significantly increased, whereas IL‐4 levels (3·57 ± 0·86 pg/ml) decreased in patients with MG compared with NC (IL‐15: 4·42 ± 1·55 pg/ml; VEGF: 63·51 ± 32·95 pg/ml; IL‐4: 4·15 ± 0·81 pg/ml, P < 0·05). In addition, eight cytokines (IL‐4, IL‐8, IL‐15, eotaxin, macrophage inflammatory protein‐1α, macrophage inflammatory protein‐1β, VEGF and IL‐1b) were significantly changed among MG patients with thymoma, MG patients without thymoma and NC (P < 0·05). Some cytokines, such as IL‐4, IL‐15, and VEGF, may play roles in the pathogenesis of MG.

Cytokines and chemokines in neuromyelitis optica: pathogenetic and therapeutic implications.

Neuromyelitis optica (NMO) is characterized by severe optic neuritis and longitudinally extensive transverse myelitis. The discovery of an NMO‐specific autoantibody to the aquaporin‐4 (AQP4) water channel has improved knowledge of NMO pathogenesis. Many studies have focused on inflammatory and pathological biomarkers of NMO, including cytokines and chemokines. Increased concentrations of T helper (Th)17‐ and Th2‐related cytokines and chemokines may be essential factors for developing NMO inflammatory lesions. For example, interleukin‐6 could play important roles in NMO pathogenesis, as it is involved in the survival of plasmablasts that produce anti‐AQP4 antibody in peripheral circulation and in the enhancement of inflammation in the central nervous system. Therefore, assessment of these useful biomarkers may become a supportive criterion for diagnosing NMO. Significant advances in the understanding of NMO pathogenesis will lead to the development of novel treatment strategies. This review focuses on the current advances in NMO immunological research, particularly that of cytokines and chemokines.

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.