Detection of mumps virus RNA in cerebrospinal fluid of patients with neuromyelitis optica.

Neuromyelitis optica (NMO) is an acute inflammatory disease that preferentially involves the optic nerves and spinal cord. Although many infectious agents, including mumps virus, are postulated to have a role in the pathogenesis of multiple sclerosis (MS), the relationship between NMO and infectious agents remains uncertain. To investigate the relationship between NMO and viruses that have special affinity for the central nervous system, we performed a nested polymerase chain reaction (PCR) to detect mumps virus or enterovirus RNA in cerebrospinal fluid samples from 13 patients with MS, 8 with NMO and 20 with other neurological diseases (ONDs). Nested PCR was positive for mumps virus in 2 (25%) of NMO patients, but in none of those with MS and ONDs. Moreover, nested PCR results became negative in the remission phase in the two PCR-positive NMO patients. Mumps virus may have some role in the pathogenesis of NMO.

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.

Serum levels of complement C4 fragments correlate with disease activity in multiple sclerosis: proteomic analysis.

To detect serum biomarkers associated with disease activity in relapsing-remitting multiple sclerosis (MS). We studied serum low-molecular peptide profiling of MS patients and normal controls comprehensively by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Serum level of 1741 Da peptide was increased at the time of clinical relapse in patients than in normal controls and returned toward normal during remission. Tandem mass spectrometry analysis revealed that the peptide was a fragment of complement C4 (NGFKSHALQLNNRQI). This fragment peptide could be a possible marker of disease activity. It may reflect complement activation in the pathogenesis of MS.

"Cloud-like enhancement" is a magnetic resonance imaging abnormality specific to neuromyelitis optica.

Neuromyelitis optica (NMO) is presumably mediated by an autoantibody against aquaporin-4 densely expressed at the blood-brain barrier. In 18 patients with NMO, brain magnetic resonance imaging (MRI) findings were systematically reviewed. Brain MRI abnormalities were found for 89% of the patients, and the most prominent feature was "cloud-like enhancement," multiple patchy enhancing lesions with blurred margin, found in 90% of the patients with positive contrast enhancement. In NMO, brain MRI abnormalities are frequent, and cloud-like enhancement appears to be an MRI finding specific to NMO, possibly caused by primary involvement of the blood-brain barrier by the autoantibodies.

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.

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.

Peripheral nerve demyelination in multiple sclerosis.

OBJECTIVE: To elucidate the frequency of peripheral nerve demyelination in multiple sclerosis (MS). There are a number of case reports describing MS patients associated with demyelinating neuropathy, but its frequency in a whole MS population is unknown. METHODS: Extensive nerve conduction studies were prospectively performed in 60 consecutive patients with relapsing-remitting MS. Multiple excitability measurements using threshold tracking were also performed in median motor axons and superficial radial sensory axons. RESULTS: Nerve conduction abnormalities suggestive of demyelination were found for 3 (5%) of the patients. Two of them developed clinically evident neuropathy, whereas the remaining one had only generalized areflexia in addition to MS symptoms/signs. In all the three, MS preceded demyelinating neuropathy by several years. Excitability testing showed that supernormality and threshold electrotonus at the tested sites (median motor axons at the wrist, and radial sensory axons at the mid-forearm) were similar in the normal and MS groups. CONCLUSIONS: MS patients do not generally have peripheral nerve demyelination, but approximately 5% of patients develop demyelinating neuropathy. The association could result from a common pathogenesis possibly due to epitope spreading during the long course of MS. SIGNIFICANCE: Association of chronic inflammatory demyelinating polyneuropathy with MS is not frequent, but needs to be recognized as a treatable condition.

Neuromyelitis optica and anti-aquaporin-4 antibodies measured by an enzyme-linked immunosorbent assay.

NMO-IgG, a disease-specific autoantibody for neuromyelitis optica, recognizes aquaporin-4 (AQP4) and has been examined by indirect immunofluorescence assay. We developed an enzyme-linked immunosorbent assay (ELISA) to detect anti-AQP4 antibodies by establishing methods for expression in a baculovirus system and purification of recombinant AQP4 as antigen. Elevated anti-AQP4 antibody titers in serum were found in 15 (71%) of 21 patients with neuromyelitis optica, 4.3% of 46 patients with multiple sclerosis, none of 51 normal controls, and 2.6% of 115 patients with other neurological diseases. The ELISA system can be substituted for the conventional NMO-IgG assay.

Moxibustion, an alternative therapy, ameliorated disturbed circadian rhythm of plasma arginine vasopressin and urine output in multiple system atrophy.

Previously no alternative therapy approach has been made to ameliorate disturbed circadian arginine vasopressin rhythm (C-AVP-R) in multiple system atrophy (MSA). A 65-year-old man with MSA showed loss of C-AVP-R and nocturnal polyuria. We performed moxibustion at specific acupuncture points on the bladder and inside the feet, once a day, 3 times a week, for 6 months. After the treatment, his C-AVP-R appeared to be normal, and the nocturnal urine output decreased to 75% (p<0.01). Together with the previous studies, it seems possible that somatic warm stimulation by moxibustion in specific points might have facilitated AVP secretion in this patient.