High-risk Neuromyelitis Optica Research Articles

Clinical Significance of AQP4 Antibody Detection in Chinese Patients with Neuromyelitis Optica (NMO) and High-Risk NMO: A Meta-Analysis

Clinical Significance of AQP4 Antibody Detection in Chinese Patients with Neuromyelitis Optica (NMO) and High-Risk NMO: A Meta-Analysis

Prolonged and Devastating Clinical Course in Atypical Neuromyelitis Optica

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease affecting the optic nerve and the spinal cord. Antibodies (Ab) to Aquaporin-4 (AQP-4) and sometimes to myelin oligodendrocyte glycoprotein (MOG) are characteristic serological findings. We present the case of a 9-year-old boy with seronegative atypical NMO showing recurrent episodes of isolated longitudinal extensive transverse myelitis (LETM). He presented in December 2010 with paresis of his left leg following flu vaccination. LETM with areas of beginning necrosis was diagnosed. Blood-brain barrier disruption, oligoclonal band and highly elevated interleukin 6 were found in cerebrospinal fluid. Clinically, the entire spinal cord was affected with tetraparesis and inverted breathing. He was treated with steroids, plasmapheresis, cyclophosphamide (CPM), and immunoglobulins. Paraplegia starting from Th9 and a neurogenic bladder disorder persisted. AQP4- and MOG-Ab were repeatedly tested negative. There was no evidence of optic neuritis during the follow-up period. In July 2013, he experienced a first relapse with weakness of the upper extremities following oral herpes infection. CSF, blood, and magnetic resonance images showed identical findings to the first episode. After steroids, plasmapheresis and CPM he showed no clinical improvement and lost his hand function. After 27 days, application of CPM again following oral herpes infection he experienced a second relapse with tetraparesis, sensibility loss starting at Th2, dry mouth, and neck pain. Lumbar puncture was no longer possible. He showed no improvement to steroids and plasmapheresis, but the inflammation progressed to the midbrain. Finally, respiratory failure, seizures, and cardiac arrest September 2013. In conclusion, we suspect NMO-spectrum disorder (high-risk NMO), possibly triggered by infection or vaccination without NMO- and MOG-Ab nor optic nerve involvement. The clinical picture is characterized by a polyphasic course with late relapses and poor prognosis. Our case demonstrates an unusual clinical course of LETM and should open discussion about the variable clinical picture of NMO in childhood.

Antibodies target microvessels in neuromyelitis optica and multiple sclerosis patients

Objective: This study investigated the presence of serum antibodies targeting microvessels in Chinese patients with multiple sclerosis (MS) and neuromyelitis optica (NMO).Methods: Serum samples were collected from 50 patients with NMO, 10 with longitudinally extensive transverse myelitis (LETM), 4 with recurrent optic neuritis, 42 with MS and 27 controls. Serum antibodies binding to microvessels were measured by indirect immunofluorescence (IIF) assay of tissue sections from the brain, stomach and pancreas, and human umbilical vein endothelial cells (HUVEC). Aquaporin-4 (AQP4) antibodies were detected using a cell-based assay.Results: Indirect immunofluorescence assay of tissue sections from 42 samples (30·4%, 42/138) were positive for microvessel antibodies, where microvessel antibody positivity was 38% (19/50) in patients with NMO, 57·1% (8/14) in high-risk NMO (hrNMO), 26·2% (11/42) in MS, and 14·8% (4/27) in controls. Based on HUVEC analysis, 14 patients with NMO (28%, 14/50), 5 with hrNMO (35·7%, 5/14), 15 with MS (35·7%, 15/42), and 5 controls (18·5%, 5/27) had (AECA). Sixteen patients (32%, 16/50) with NMO, four with hrNMO (28·6%, 4/14), two with MS (4·8%, 2/42), and 0% of controls were positive for antinuclear antibodies (ANA). In MS patients, seropositive AECA MS patients had higher numbers of relapse events and increased spinal lesions than seronegative MS patients (P < 0·05).Conclusions: Serum microvessel antibodies were present in patients with NMO and MS and the role of microvessel antibodies in diseases may be heterogeneous. This study suggests that AECA may have some significance in MS patients.

Helicobacter pylori Infection in Neuromyelitis Optica and Multiple Sclerosis

Objective: To determine the Helicobacter pylori infection status in patients with multiple sclerosis (MS) and neuromyelitis optica (NMO) spectrum. Methods:H. pylori infection was certified by indirect immunofluorescence assay. Aquaporin-4 (AQP4) antibody was detected by cell-based assay. H. pylori seroprevalence was measured in 118 patients with NMO (n = 52), high-risk NMO (hrNMO, longitudinally extensive transverse myelitis, n = 17 and recurrent optic neuritis, n = 7), MS (n = 42) and healthy controls (n = 27). Logistic regression analysis was used to determine associations between H. pylori infection and NMO and MS. Results:H. pylori antibodies were present in 119 serum samples (82.1%, 119/145), with antibody positivity in 90.4% (47/52) of the patients with NMO, 95.8% (23/24) of the patients with hrNMO, 73.8% (31/42) of the patients with MS and 59.3% (16/27) of the controls. NMO spectrum patients had greater positivity for H. pylori than MS patients (p < 0.05) and controls (p < 0.05). The frequency of H. pylori seropositivity did not significantly differ between MS patients and controls (p = 0.726). H. pylori seropositivity was significantly higher in AQP4 antibody-positive patients (54/58, 93.1%; p = 0.038) than in AQP4 antibody-negative patients (48/60, 80%). Logistic regression analysis showed that H. pylori seropositivity was significantly associated with hrNMO [odds ratio (OR) = 9.311, p = 0.005] or hrNMO + NMO (OR = 6.350, p = 0.028). Conclusion:H. pylori infection was present in most Chinese patients with NMO and hrNMO, and may be a risk factor for the NMO spectrum.

Persisting myelin oligodendrocyte glycoprotein antibodies in aquaporin-4 antibody negative pediatric neuromyelitis optica

Background: Recently we showed that antibodies to myelin oligodendrocyte glycoprotein (MOG) can be found in aquaporin-4 (AQP4)-immunoglobulin (IgG) seronegative pediatric and adult patients with definite and high-risk neuromyelitis optica (NMO). Objective: The purpose of this study was to describe the clinical characteristics and temporal dynamics of MOG-IgG in AQP4-IgG seronegative pediatric patients presenting with definite NMO. Methods: Children with definite NMO who were referred for further testing of serum antibodies for AQP4 and MOG with a cell-based assay were included in this study. Clinical disease course, cerebrospinal fluid and magnetic resonance imaging (MRI) studies of these patients were reviewed. Results: Between 2008 and 2012 eight children who fulfilled the diagnostic criteria of definite NMO were recruited. Two children with definite NMO tested positive for AQP4-IgG but were negative for MOG-IgG antibodies. Three children had an absence of AQP4-IgG and MOG-IgG antibodies. Three children with definite NMO had high titers of serum MOG-IgG antibodies (≥1: 160), but no AQP4-directed humoral immune response. Longitudinal analysis of serum samples of the latter three children showed persisting high MOG-IgG titers over time. Conclusion: Pediatric patients presenting with clinical symptoms and MRI findings highly suggestive of NMO but with high and persisting MOG-IgG antibody titers are most likely to represent a distinct subgroup of acute demyelinating diseases with important clinical and therapeutic implications.

The role of aquaporin-4 antibodies in Chinese patients with neuromyelitis optica

We determined the presence of aquaporin-4 (AQP4) antibodies by indirect immunofluorescence in human AQP4-transfected cells, and evaluated the diagnostic and prognostic relevance of AQP4 antibodies in 210 Chinese patients with neuromyelitis optica (NMO), high-risk NMO (HR-NMO), classic multiple sclerosis (MS), and other neurologic diseases. Patients were enrolled from The General Hospital of the Chinese People’s Liberation Army and followed-up for a median of 2years. The patients with HR-NMO had optico-spinal MS (OSMS; n=3), longitudinally extensive transverse myelitis (TM) (n=35), recurrent optic neuritis (ON) (n=2), ON with Sjögren’s syndrome (n=1) and TM positive for Sjögren-A(SSA) antibody (n=1). The sensitivity and specificity of AQP4 antibodies in NMO were 70.9% and 91%, respectively. The median AQP4 antibody titer was significantly higher in patients with NMO (1:320) than in those with HR-NMO (1:100) and MS (1:50). Relapse of ON or TM was more likely in patients with AQP4 seropositive, than AQP4 seronegative, HR-NMO. Among AQP4 seropositive patients, 66.7% (36/55) had severe ON, 75.9% (41/55) had TM, and 55.6% (30/55) had spinal cord lesions longer than three segments, and there were relapses in eight of 55 patients with ON (14.8%) and 19 of 55 patients with TM (35.2%) during the 2-year follow-up. In conclusion, our study reveals that AQP4 antibody is a sensitive and specific biomarker for discrimination of NMO, classic MS, and other neurological diseases, and is particularly useful for the diagnosis of HR-NMO. AQP4 antibody-positive patients showed higher frequencies of relapse of ON or TM compared with AQP4 antibody-negative patients.

Clinical Usefulness of Cell-based Indirect Immunofluorescence Assay for the Detection of Aquaporin-4 Antibodies in Neuromyelitis Optica Spectrum Disorder

BackgroundThe presence of antibodies to aquaporin-4 (AQP4) has been identified as a key characteristic of neuromyelitis optica spectrum disorder (NMOSD), an autoimmune inflammatory demyelinating central nervous system (CNS) disorder. We evaluated the performance of a cell-based indirect immunofluorescence assay (CIIFA) for detecting AQP4 antibodies using antigen prepared with a recombinant AQP4 peptide transfection technique and assessed the usefulness of CIIFA for diagnosis of NMOSD in routine clinical practice.MethodsForty-six serum samples from 36 patients as a comparison set and another 101 patients enrolled consecutively from a neurology clinic were included. CIIFA and fluorescence immunoprecipitation assays (FIPA) were performed. CIIFA was performed at 2 different institutions for comparison purposes.ResultsCIIFA and FIPA sensitivity in the comparison set was 86% and 79% in neuromyelitis optica (NMO) patients and 55% and 36% in high-risk NMO patients, respectively. The semiquantitative titer measured by CIIFA correlated well with the arbitrary unit (fluorescence units [FU]) derived from FIPA (r=0.66). Titers measured by CIIFA and FIPA were elevated in NMO patients compared to high-risk NMO patients (1:240 vs. 1:180 and 8,390 vs. 4,059 FU, respectively). The frequency of AQP4 antibody detection by CIIFA in 101 consecutively enrolled patients was 100% in NMO and 23% in high-risk NMO patients, while only 4.6% in control patients, including those with multiple sclerosis.ConclusionsDetection of AQP4 antibodies by CIIFA provides sensitive and highly specific diagnostic information for NMO and high-risk NMO patients, which can be used to differentiate these conditions from other demyelinating CNS diseases.

Complement activating antibodies to myelin oligodendrocyte glycoprotein in neuromyelitis optica and related disorders

BackgroundSerum autoantibodies against the water channel aquaporin-4 (AQP4) are important diagnostic biomarkers and pathogenic factors for neuromyelitis optica (NMO). However, AQP4-IgG are absent in 5-40% of all NMO patients and the target of the autoimmune response in these patients is unknown. Since recent studies indicate that autoimmune responses to myelin oligodendrocyte glycoprotein (MOG) can induce an NMO-like disease in experimental animal models, we speculate that MOG might be an autoantigen in AQP4-IgG seronegative NMO. Although high-titer autoantibodies to human native MOG were mainly detected in a subgroup of pediatric acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS) patients, their role in NMO and High-risk NMO (HR-NMO; recurrent optic neuritis-rON or longitudinally extensive transverse myelitis-LETM) remains unresolved.ResultsWe analyzed patients with definite NMO (n = 45), HR-NMO (n = 53), ADEM (n = 33), clinically isolated syndromes presenting with myelitis or optic neuritis (CIS, n = 32), MS (n = 71) and controls (n = 101; 24 other neurological diseases-OND, 27 systemic lupus erythematosus-SLE and 50 healthy subjects) for serum IgG to MOG and AQP4. Furthermore, we investigated whether these antibodies can mediate complement dependent cytotoxicity (CDC). AQP4-IgG was found in patients with NMO (n = 43, 96%), HR-NMO (n = 32, 60%) and in one CIS patient (3%), but was absent in ADEM, MS and controls. High-titer MOG-IgG was found in patients with ADEM (n = 14, 42%), NMO (n = 3, 7%), HR-NMO (n = 7, 13%, 5 rON and 2 LETM), CIS (n = 2, 6%), MS (n = 2, 3%) and controls (n = 3, 3%, two SLE and one OND). Two of the three MOG-IgG positive NMO patients and all seven MOG-IgG positive HR-NMO patients were negative for AQP4-IgG. Thus, MOG-IgG were found in both AQP4-IgG seronegative NMO patients and seven of 21 (33%) AQP4-IgG negative HR-NMO patients. Antibodies to MOG and AQP4 were predominantly of the IgG1 subtype, and were able to mediate CDC at high-titer levels.ConclusionsWe could show for the first time that a subset of AQP4-IgG seronegative patients with NMO and HR-NMO exhibit a MOG-IgG mediated immune response, whereas MOG is not a target antigen in cases with an AQP4-directed humoral immune response.

Quantitative measurement of anti-aquaporin-4 antibodies by enzyme-linked immunosorbent assay using purified recombinant human aquaporin-4

Background: Antibodies to aquaporin-4 (AQP4-Ab), known as NMO-IgG, are a sensitive and specific marker for neuromyelitis optica (NMO). Methods: To develop an enzyme-linked immunosorbent assay (ELISA) for AQP4-Ab, we expressed M23 isoform of human AQP4 in a baculovirus system, and used it as an antigen. We measured AQP4-Ab in the sera of 300 individuals: 64 with definite NMO, 31 with high-risk NMO, 105 with multiple sclerosis (MS), 57 with other neurological diseases (ONDs), and 43 healthy controls. We also performed longitudinal measurements of AQP4–Ab in 787 samples collected from 51 patients with definite or high-risk NMO. Results: AQP4-Abs were positive in 72% with definite NMO, 55% with high-risk NMO, and 4% with MS, but none of the OND patients and the healthy individuals. The longitudinal measurement showed AQP4-Ab levels correlating with disease activity. Out of 38 initially seropositive patients, 21 became seronegative under effective immunosuppressive therapy. During most relapses, the serum AQP4-Ab levels were either high or rising compared with the previous value, although rising AQP4-Ab levels did not always lead to acute exacerbation. Two of the 13 initially seronegative patients converted to seropositive following acute exacerbations. Conclusions: We established an AQP4-Ab ELISA, which could be a potential monitoring tool of disease activity.

Patterns of Antibody Binding to Aquaporin-4 Isoforms in Neuromyelitis Optica

BackgroundNeuromyelitis optica (NMO), a severe demyelinating disease, represents itself with optic neuritis and longitudinally extensive transverse myelitis. Serum NMO-IgG autoantibodies (Abs), a specific finding in NMO patients, target the water channel protein aquaporin-4 (AQP4), which is expressed as a long (M-1) or a short (M-23) isoform.Methodology/Principal FindingsThe aim of this study was to analyze serum samples from patients with NMO and controls for the presence and epitope specificity of IgG and IgM anti-AQP4 Abs using an immunofluorescence assay with HEK293 cells expressing M-1 or M-23 human AQP4. We included 56 patients with definite NMO (n = 30) and high risk NMO (n = 26), 101 patients with multiple sclerosis, 27 patients with clinically isolated syndromes (CIS), 30 patients with systemic lupus erythematosus (SLE) or Sjögren's syndrome, 29 patients with other neurological diseases and 47 healthy controls. Serum anti-AQP4 M-23 IgG Abs were specifically detected in 29 NMO patients, 17 patients with high risk NMO and two patients with myelitis due to demyelination (CIS) and SLE. In contrast, IgM anti-AQP4 Abs were not only found in some NMO and high risk patients, but also in controls. The sensitivity of the M-23 AQP4 IgG assay was 97% for NMO and 65% for high risk NMO, with a specificity of 100% compared to the controls. Sensitivity with M-1 AQP4 transfected cells was lower for NMO (70%) and high risk NMO (39%). The conformational epitopes of M-23 AQP4 are the primary targets of NMO-IgG Abs, whereas M-1 AQP4 Abs are developed with increasing disease duration and number of relapses.ConclusionsOur results confirm M-23 AQP4-IgG Abs as reliable biomarkers in patients with NMO and high risk syndromes. M-1 and M-23 AQP4-IgG Abs are significantly associated with a higher number of relapses and longer disease duration.

Evaluation of diagnostic value for NMO-IgG in patients with neuromyelitis optica

To investigate the value of NMO-IgG in the diagnosis of neuromyelitis optica (NMO). A total of 80 patients with NMO, high-risk NMO (HR-NMO), multiple sclerosis (MS), clinical isolated syndrome (CIS) and other neurological diseases (subacute combined degeneration, cerebral infarction, intracranial hemorrhage and neurofibroma) were included in to the study. The titers of all patients' serum NMO-IgG were detected by indirect immunofluorence. There were significant differences in NMO, HR-NMO MS, and CIS between patients with severe optical neuritis, transverse myelitis, normal brain MRI scan, spinal-cord lesion > 3 segments and serum NMO-IgG positive (P < 0.05). The level of serum NMO-IgG of NMO, HR-NMO was higher than that of MS, while the level of serum NMO-IgG of MS was slightly higher than that of CIS and other diseases. The sensitivity and specificity of NMO-IgG were 82.6% versus 96.2% in the diagnosis of NMO. NMO-IgG is valuable for diagnosing NMO and differentiating it from MS.