Association of serum gamma-glutamyltransferase and C-reactive proteins with neuromyelitis optica and multiple sclerosis.

BACKGROUND: Many studies have demonstrated that serum gamma glutamyltransferase (GGT) within normal range might be an early marker of oxidative stress. However the role of GGT in neuromyelitis optica (NMO) and multiple sclerosis (MS) is unknown. METHODS: We assessed the correlations among GGT and C-reactive protein (CRP) levels, as well as clinical characteristics of NMO and MS. Serum GGT and CRP levels were measured in 106 NMO patients, 87 MS patients, 79 patients with non-inflammatory neurological diseases (Parkinson disease) and 80 healthy controls (HC). Clinical parameters, blood-brain barrier (BBB) index and Delpech index of MS and NMO were also investigated. RESULTS: We found that NMO patients had higher serum GGT and CRP levels within their normal ranges compared to MS, PD, healthy controls. NMO patients exhibited significantly higher EDSS scores than MS patients. The BBB index in NMO patients was significantly higher than that in MS patients. Significant correlations existed between serum GGT and CRP levels and EDSS scores, BBB index in NMO and MS patients. CONCLUSION: Elevated GGT and CRP levels within their normal ranges in NMO and MS may be associated with inflammatory response, oxidative stress and BBB disturbance in the diseases. Further study into the underlying pathophysiology of this relationship is warranted.

Variants of CYP27B1 are associated with both multiple sclerosis and neuromyelitis optica patients in Han Chinese population.

Multiple sclerosis (MS) and neuromyelitis optica (NMO) are chronic demyelinating diseases of the central nervous system (CNS). Recently, variants of vitamin D metabolizing genes, including rs12368653, rs10876994, rs118204009 and rs703842 in CYP27B1, and rs2248359 in CYP24A1 have been identified to be associated with the pathogenicity of MS in Caucasian populations. However, these results have not been replicated in Han Chinese population. Here we investigated the association of these variants with MS and NMO susceptibility in 149 MS patients, 110 NMO patients and 294 healthy controls using MassARRAY system and Sanger sequencing. We found that the frequencies of the A allele of rs703842 were higher in MS patients than controls (p=0.032), and statistical differences were observed in the genotypes of both rs703842 (p=0.013) and rs10876994 (p=0.001) between NMO patients and controls. In addition, we found difference in the genotype of rs12368653 between MS patients and controls (p=0.008). However, no difference was found in rs2248359 among these three groups. The reported rare mutation p.R389H (rs118204009) was not found in our study. In conclusion, our study suggested that variants of CYP27B1 were associated with both MS and NMO patients in Han Chinese population.

Transient hyperckemia in the setting of neuromyelitis optica (NMO).

INTRODUCTION: Neuromyelitis optica (NMO) is characterized by inflammatory demyelinating lesions of the spinal cord and optic nerves from an autoimmune response against water channel aquaporin-4 (AQP4). We report 2 patients with transient hyperCKemia associated with NMO suggesting possible skeletal muscle damage. METHODS: Patient 1 was a 72-year-old man who presented with muscle soreness and elevated serum creatine kinase (CK) preceding an initial attack of NMO. Patient 2 was a 25-year-old woman with an established diagnosis of NMO who presented with diffuse myalgias, proximal upper extremity weakness, and hyperCKemia. Muscle biopsies were obtained for histopathologic evaluation, protein gel electrophoresis, immunofluorescence, and complement staining. RESULTS: In both patients the muscle showed only mild variation in fiber diameter. There were no inflammatory changes or muscle fiber necrosis, though there was reduced AQP4 expression and deposition of activated complement. CONCLUSIONS: Complement-mediated sarcolemmal injury may lead to hyperCKemia in NMO.

Transverse myelitis associated with an itchy rash and hyperckemia: neuromyelitis optica associated with dermatitis herpetiformis.

IMPORTANCE: Neuromyelitis optica is associated with severe neurodisability if not recognized and treated promptly. Several autoimmune disorders are associated with this condition and may vary in their presentation. It is essential that clinicians are aware of the uncommon presenting features of neuromyelitis optica and associated autoimmune conditions. OBSERVATIONS: A 53-year-old woman presented with nausea and vomiting and was noted to have an asymptomatic elevated creatinine kinase level, which improved with conservative management. She had a history of iron-deficiency anemia due to long-standing celiac disease that was managed with a gluten-free diet. She then presented with recurrent transverse myelitis and a vesicobullous rash over her arms and feet that was pruritic and excoriating. Skin biopsy results confirmed a clinical diagnosis of dermatitis herpetiformis and antibody test findings against aquaporin-4 were positive, leading to a diagnosis of neuromyelitis optica spectrum disorder. She was treated with methylprednisolone sodium succinate, plasma exchange, and azathioprine and has remained in remission. CONCLUSIONS AND RELEVANCE: This report highlights the association of neuromyelitis optica with dermatitis herpetiformis, which can present even without clinical features of celiac disease. Nausea, vomiting, and asymptomatic hyperCKemia should be recognized as rare presenting features of neuromyelitis optica.

Neuromyelitis optica preceded by hyperCKemia and a possible association with coxsackie virus group A10 infection.

We report the case of a 48-year-old woman presenting with an elevated serum creatine kinase level (hyperCKemia) associated with an initial attack of neuromyelitis optica (NMO). The patient initially showed general fatigue with fever. Laboratory findings showed hyperCKemia and subsequently she developed a slight weakness of both lower limbs and reduced vision. Autoantibodies against aquaporin 4 were found in her serum, and a retrospective examination of viral titers indicated a possible coxsackie virus group A10 infection. The present case suggests that hyperCKemia-mediated disease onset is involved in some patients with NMO, and furthermore, it may be related to muscular destruction associated with viral infection.

HyperCKemia related to the initial and recurrent attacks of neuromyelitis optica.

We herein report the case of a 60-year-old man showing overexpression of creatine kinase (hyperCKemia) related to initial and recurrent attacks of neuromyelitis optica (NMO). He showed reduced vision, ataxia and dysesthesia, but no symptoms originating in the muscles. Magnetic resonance imaging (MRI) revealed lesions in the optic nerve, medulla oblongata, and spinal cord similar to typical NMO patients. However, femoral MRI and whole positron emission tomography (PET) demonstrated no abnormal findings during an episode of hyperCKemia. This case suggests that hyperCKemia is partly involved in the pathogenesis of NMO in both the central nervous system and myofiber surface, which is usually difficult to detect by clinical imaging modalities alone.

Neutrophil protease inhibition reduces neuromyelitis optica-immunoglobulin G-induced damage in mouse brain.

OBJECTIVE: Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system associated with pathogenic autoantibodies against the astrocyte water channel protein aquaporin-4 (AQP4). The presence of neutrophils is a characteristic feature in NMO lesions in humans. Neutrophils are not generally found in multiple sclerosis lesions. We evaluated the role of neutrophils in a mouse NMO model. METHODS: NMO lesions were produced in mice by intracerebral injection of immunoglobulin G (IgG) isolated from NMO patient serum and human complement. We previously reported that this mouse model produces the characteristic histological features of NMO, including perivascular complement activation, inflammatory cell infiltration, and loss of myelin, AQP4, and glial fibrillary acidic protein. Lesions are absent when AQP4 null mice are used or when IgG from non-NMO patients is injected. RESULTS: We found remarkably reduced neuroinflammation, myelin loss, and AQP4 loss in brains of neutropenic mice at 24 hours and 7 days, and increased severity of NMO lesions in mice made neutrophilic by granulocyte colony stimulating factor. NMO lesions were greatly reduced by intracerebral administration of the neutrophil protease inhibitors Sivelestat and cathepsin G inhibitor I or by intraperitoneal injection of Sivelestat alone. Immunostaining of human NMO lesions for neutrophil elastase revealed many degranulating perivascular neutrophils, with no equivalent perivascular neutrophils in human multiple sclerosis lesions. INTERPRETATION: Our data implicate a central role of neutrophils in the pathogenesis of early NMO lesions and suggest the potential utility of neutrophil protease inhibitors such as Sivelestat in NMO therapy.

Increased serum matrix metalloproteinase-9 in neuromyelitis optica: implication of disruption of blood-brain barrier.

Matrix metalloproteinase-9 (MMP-9) plays an important role in some neuroinflammatory diseases through the blood-brain barrier (BBB) disruption. To investigate the pathogenicity of MMP-9 in neuromyelitis optica (NMO), serum and CSF MMP-9 concentrations were measured in 13 NMO and 15 multiple sclerosis (MS) patients and 14 healthy controls, and correlated with clinical and laboratorial parameters. Serum MMP-9 concentrations were significantly higher in NMO than MS and controls, and correlated with EDSS score, CSF/serum albumin ratio, and CSF IL-8 concentrations. Our results indicate that MMP-9, promoted by elevated IL-8 activation, plays a crucial role in the pathogenesis of NMO through the BBB disruption.

Chitinase effects on immune cell response in neuromyelitis optica and multiple sclerosis.

BACKGROUND: Recent studies conducted in arthritis, asthma, and inflammatory bowel disease suggest that chitinases are important in inflammatory processes and tissue remodeling. OBJECTIVE: To investigate the role of chitinases in multiple sclerosis (MS) and neuromyelitis optica (NMO). METHODS: Levels of chitotriosidase, acid mammalian chitinase (AMCase), and chitinase 3-like-1 (CHI3L1) were measured using ELISA, in cerebrospinal fluid (CSF) and in serum from 24 patients with relapsing remitting (RR) MS, 24 patients with secondary progressive (SP) MS, 12 patients with NMO, 24 patients with other inflammatory neurological diseases (OIND), and 24 healthy controls (HCs). The number of anti-MOG cytokine-secreting cells was studied using ELISPOT. Eotaxins, MCP-1, RANTES, and IL-8 were assessed using ELISA. Cell transmigration was determined using an in vitro blood-brain barrier (BBB) model, in the presence and absence of chitinases. RESULTS: CSF chitinase levels were significantly increased in patients with RRMS and NMO compared with HCs and patients with SPMS and OIND. In contrast, no significant differences were detected in serum chitinase levels between groups. Chitinase CSF levels showed correlation with anti-MOG IL-13-producing cells, and eotaxin levels. In vitro experiments showed macrophage chitinase secretion was significantly increased by IL-13, but not by IL-5, IL-6, IL-12, or IFN-γ. Moreover, chitinases enhanced IL-8, RANTES, MCP-1, and eotaxin production, increasing migratory capacity in eosinophils, T cells, and macrophages across an in vitro BBB model. CONCLUSIONS: Chitinases increased in the CSF from patients with NMO in response to IL-13. These enhanced levels could contribute to central nervous system inflammation by increasing immune cell migration across the BBB.

Platelet-activating factor acetylhydrolase gene polymorphism and its activity in Japanese patients with multiple sclerosis.

We evaluated the association of the plasma platelet-activating factor acetylhydrolase (PAF-AH) gene polymorphism (G(994)-->T) and PAF-AH activity with susceptibility and severity of multiple sclerosis (MS) in Japanese. DNA was collected from 216 patients with clinically definite MS (65 opticospinal MS (OS-MS) and 151 conventional MS (C-MS)) and from 213 healthy controls. The missense mutation G(994)-->T that disrupts the PAF-AH activity was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). No statistically significant difference in the frequency of genotypes and alleles of the plasma PAF-AH polymorphism was observed among OS-MS patients, C-MS patients and healthy controls. However, the missense mutation tended to be associated with the severity of OS-MS, especially in females (GT/TT genotypes; 51.7% in female rapidly progressive OS-MS vs. 26.6% in female controls, p=0.0870). Moreover, PAF-AH activities were significantly lower in MS than in controls, irrespective of clinical subtypes, among those carrying the identical polymorphism in terms of nucleotide position 994 of the PAF-AH gene. These findings suggest that the PAF-AH gene missense mutation has no relation to either susceptibility or severity of C-MS, yet its activity is down-regulated, and that the mutation has no relation with susceptibility of OS-MS, yet it may confer the severity of female OS-MS.