Paraneoplastic Neuromyelitis Optica Spectrum Disorder Associated With Lung Adenocarcinoma: A Case Report

Neuromyelitis Optica spectrum disorder is an inflammatory demyelinating disease affecting the central nervous system (CNS), characterized by triad optic neuritis, transverse myelitis, and area postrema syndrome. Antibodies directed against aquaporin-4 (AQP-4), a water channel expressed on the astrocytic membrane, are supposed to play a pathogenic role and are detected in ~80% of cases. Clinical signs of Neuromyelitis Optica spectrum disorder (NMOSD) in elderly patients should arouse the suspicion of paraneoplastic etiology. In this article, we discussed a case of a 76-year-old woman with a 2-month history of confusion, dysarthria, and progressive bilateral leg weakness. A whole-body CT scan showed a neoformation of 5 cm in diameter in the median lobe infiltrating the mediastinal pleura. The tumor had already spread to both the upper and lower right lobes, parietal pleura, and multiple lymph nodes. Pleural cytology revealed adenocarcinoma cells. The brain MRI documented hyperintense alteration in fluid-attenuated inversion recovery (FLAIR) images, involving the anterior portion of the corpus callosum and the periependymal white matter surrounding the lateral ventricles, with mild contrast enhancement on the same areas and meningeal tissue. T2-weighted spinal cord MRI sequences showed extended signal hyperintensity from bulbo-cervical junction to D7 metamer, mainly interesting the central component and the gray matter. Cerebrospinal fluid analysis revealed no neoplastic cells. Serum AQP-4 immunoglobulin (IgG) antibodies were found. Meanwhile, the patient rapidly developed progressive paraparesis and decreased level of consciousness. High-dose intravenous methylprednisolone therapy was started but her conditions rapidly deteriorated. No other treatment was possible.

The frequencies of peripheral blood CD5+CD19+ B cells, CD3−CD16+CD56+ NK, and CD3+CD56+ NKT cells and serum interleukin-10 in patients with multiple sclerosis and neuromyelitis optica spectrum disorder

Background Multiple sclerosis (MS) and neuromyelitis optica syndrome disease (NMOSD) are inflammatory diseases of the central nervous system. The pathogenesis and treatments for these two conditions are very different. Natural killer (NK) and natural killer T (NKT) cells are immune cells with an important role in shaping the immune response. B cells are involved in antigen presentation as well as antibody and cytokine production. There is conflicting evidence of the roles of NK, NKT, and B cells in the two conditions. We aimed to compare the frequency of CD3−CD16+CD56+NK, CD3+ CD56+ NKT, and CD5+CD19+ B cells in the peripheral blood and serum Interleukin-10 (IL-10) in patients with MS and NMOSD. Methods CD19+CD5+ B, CD3− CD16+CD56+ NK, and CD3+CD56+ NKT cells were quantitated by flow cytometry in 15 individuals with Interferon-Beta (IFN-β) treated relapsing–remitting MS (RRMS), 15 untreated RRMS, and 15 NMOSD patients as well as 30 healthy controls (HC). Serum IL-10 was measured using an enzyme-linked immunosorbent assay (ELISA). Results The percentage of CD3−CD56+CD16+ NK cells in the peripheral blood of IFN-treated MS (1.81 ± 0.87) was significantly lower than for untreated RRMS (4.74 ± 1.80), NMOSD (4.64 ± 1.26) and HC (5.83 ± 2.19) (p < 0.0001). There were also differences for the percentage of CD3−CD16+ and CD3−CD56+ cells (p < 0.001 and p < 0.0007; respectively). IFN-treated RRMS (2.89 ± 1.51) had the lowest proportion of CD3+CD56+ among the study groups (p < 0.002). Untreated RRMS (5.56 ± 3.04) and NMOSD (5.47 ± 1.24) had higher levels of CD3+CD56+ than the HC (3.16 ± 1.98). The mean percentage of CD19+CD5+ B cells in the peripheral blood of untreated RRMS patients (1.32 ± 0.67) was higher compared to the patients with NMOSD (0.30 ± 0.20), HC (0.5 ± 0.22) and IFN-treated RRMS (0.81 ± 0.17) (p < 0.0001). Serum interleukin-10 was significantly higher in the IFN-treated RRMS (8.06 ± 5.39) and in HC (8.38 ± 2.84) compared to untreated RRMS (5.07 ± 1.44) and the patients with NMOSD (5.33 ± 2.56) (p < 0.003). Conclusions The lower proportion of CD3−CD56+ CD16+ NK and CD3+CD56+ cells in peripheral blood of IFN-treated RRMS compared to other groups suggests the importance of immunomodulation in patients with RRMS disorder. Based on the differences in CD19+CD5+ B cells and serum IL-10 between patients and HC, supplementary assessments could be of value in clarifying their roles in autoimmunity.

Comparative Study of Brain fMRI of Olfactory Stimulation in Neuromyelitis Optica Spectrum Disease and Multiple Sclerosis

Objective: To observe the characteristics of brain fMRI during olfactory stimulation in patients with neuromyelitis optica spectrum disease (NMOSD) and multiple sclerosis (MS), compare the differences of brain functional activation areas between patients with NMOSD and MS, and explore the characteristics of olfactory-related brain networks of NMOSD and MS.Methods: Nineteen patients with NMOSD and 16 patients with MS who met the diagnostic criteria were recruited, and 19 healthy controls matched by sex and age were recruited. The olfactory function of all participants was assessed using the visual analog scale (VAS). Olfactory stimulation was alternately performed using a volatile body (lavender and rose solution) and the difference in brain activation was evaluated by task-taste fMRI scanning simultaneously.Results: Activation intensity was weaker in the NMOSD group than in the healthy controls, including the left rectus, right superior temporal gyrus, and left cuneus. The activation intensity was stronger for the NMOSD than the controls in the left insula and left middle frontal gyrus (P &lt; 0.05). Activation intensity was weaker in the MS group than the healthy controls in the bilateral hippocampus, right parahippocampal gyrus, right insula, left rectus gyrus, and right precentral gyrus, and stronger in the left paracentral lobule among the MS than the controls (P &lt; 0.05). Compared with the MS group, activation intensity in the NMOSD group was weaker in the right superior temporal gyrus and left paracentral lobule, while it was stronger among the NMOSD group in the bilateral insula, bilateral hippocampus, bilateral parahippocampal gyrus, left inferior orbital gyrus, left superior temporal gyrus, left putamen, and left middle frontal gyrus (P &lt; 0.05).Conclusion: Olfactory-related brain networks are altered in both patients, and there are differences between their olfactory-related brain networks. It may provide a new reference index for the clinical differentiation and disease evaluation of NMOSD and MS. Moreover, further studies are needed.

High cell surface expression and peptide binding affinity of HLA-DQA1*05:03, a susceptible allele of neuromyelitis optica spectrum disorders (NMOSD)

Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing autoimmune disease characterized by the presence of pathogenic autoantibodies, anti-aquaporin 4 (AQP4) antibodies. Recently, HLA-DQA1*05:03 was shown to be significantly associated with NMOSD in a Japanese patient cohort. However, the specific mechanism by which HLA-DQA1*05:03 is associated with the development of NMOSD has yet to be elucidated. In the current study, we revealed that HLA-DQA1*05:03 exhibited significantly higher cell surface expression levels compared to other various DQA1 alleles, and that its expression strongly depended on the amino acid sequence of the α1 domain, with a preference for leucine at position 75. Moreover, in silico analysis indicated that the HLA-DQ encoded by HLA-DQA1*05:03 preferentially presents immunodominant AQP4 peptides, and that the peptide major histocompatibility complexes (pMHCs) are more energetically stable in the presence of HLA-DQA1*05:03 than other HLA-DQA1 alleles. In silico 3D structural models were also applied to investigate the validity of the energetic stability of pMHCs. Taken together, our findings indicate that HLA-DQA1*05:03 possesses a distinct property to play a pathogenic role in the development of NMOSD.

First Manifestation of AQP4-IgG-Positive Neuromyelitis Optica Spectrum Disorder Associated with the COVID-19 mRNA Vaccine BNT162b2

BNT162b2 is one of the effective COVID-19 vaccines. However, some researchers have also reported that the vaccines caused some neurological complications. Here, we present a case of a 52-year-old female who developed aquaporin (AQP) 4-IgG-positive neuromyelitis optica spectrum disorder (NMOSD) fourteen days after the first dose of BNT162b2. She experienced pain of the neck, weakness of the left arm and leg, numbness of the left hand, and impaired temperature sensation of the right leg. MRI showed T2WI hyperintense lesions in the area postrema and cervical spinal cord ranging from C1 to C6 level, and Gd-enhanced lesions from C3 to C5 level; especially left lateral column was predominantly enhanced. Cell-based assays showed anti-AQP4 antibody (AQP4Ab) was positive. We diagnosed AQP4-IgG-positive NMOSD. After high-dose glucocorticoid therapy, she is showing improved symptoms. The present case was characterized by the findings that a Gd-enhanced lesion in the cervical cord localized dominantly at the left lateral column, consistent with the side of the shoulder where the vaccine was injected. Many studies suggested that AQP4-IgG-positive NMOSD development has multistep mechanisms following the blood-brain barrier (BBB) breakdown. We suspected that BNT162b2-associated immune responses lead to BBB disruptions. Through the limitedly damaged BBB, the plasma cells producing AQP4Abs might be recruited to CNS, and AQP4Abs might bind to the cervical cord and the area postrema. A large population-based study revealed that BNT162b2-associated complications were less likely to be observed than COVID-19 infectious symptoms. However, considering the present case, neurologists need to observe the conditions following vaccination.

Use of B-Cell–Depleting Therapy in Women of Childbearing Potential With Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder

Purposeof Review: There is considerable heterogeneity in the use of B cell depletion in women of childbearing age, likely driven at least in part by the discrepancy between the product labels and what is known about the physiology of IgG1, including breastmilk and placental transfer.Recent Findings:We provide practical considerations on the use of this medication class in women of childbearing potential. We discuss pre-pregnancy planning including vaccinations, safety of B cell depletion during pregnancy as well as postpartum considerations including breastfeeding.Summary:B cell depleting monoclonal antibodies have shown to be effective for pre-pregnancy and postpartum prevention of inflammatory activity in multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). B cell depleting therapies are large IgG1 monoclonal antibodies which have minimal transfer across the placenta and into breastmilk. Consideration of risks and benefits of these therapies should be considered in counseling women planning pregnancy and postpartum.

Dysregulated B cell differentiation towards antibody-secreting cells in neuromyelitis optica spectrum disorder

Background Anti-aquaporin 4 (AQP4) antibody (AQP4-Ab) is involved in the pathogenesis of neuromyelitis optica spectrum disorder (NMOSD). However, the mechanism involved in AQP4-Ab production remains unclear. Methods We analyzed the immunophenotypes of patients with NMOSD and other neuroinflammatory diseases as well as healthy controls (HC) using flow cytometry. Transcriptome analysis of B cell subsets obtained from NMOSD patients and HCs was performed. The differentiation capacity of B cell subsets into antibody-secreting cells was analyzed. Results The frequencies of switched memory B (SMB) cells and plasmablasts were increased and that of naïve B cells was decreased in NMOSD patients compared with relapsing–remitting multiple sclerosis patients and HC. SMB cells from NMOSD patients had an enhanced potential to differentiate into antibody-secreting cells when cocultured with T peripheral helper cells. Transcriptome analysis revealed that the profiles of B cell lineage transcription factors in NMOSD were skewed towards antibody-secreting cells and that IL-2 signaling was upregulated, particularly in naïve B cells. Naïve B cells expressing CD25, a receptor of IL-2, were increased in NMOSD patients and had a higher potential to differentiate into antibody-secreting cells, suggesting CD25+ naïve B cells are committed to differentiate into antibody-secreting cells. Conclusions To the best of our knowledge, this is the first study to demonstrate that B cells in NMOSD patients are abnormally skewed towards antibody-secreting cells at the transcriptome level during the early differentiation phase, and that IL-2 might participate in this pathogenic process. Our study indicates that CD25+ naïve B cells are a novel candidate precursor of antibody-secreting cells in autoimmune diseases.

Pregnancy-Related Attack in Neuromyelitis Optica Spectrum Disorder With AQP4-IgG: A Single-Center Study and Meta-Analysis

ObjectiveThis study aimed to investigate the demographic characteristic of pregnancy-related attacks (PRAs) in neuromyelitis optica spectrum disorder (NMOSD). In addition, we investigated the predictors of PRAs as well as the effect of immunosuppressive (IS) therapy in patients with pregnancy-related NMOSD.MethodWe retrospectively analyzed data on clinical and diagnostic characteristics, therapeutic management, and pregnancy outcomes for PRAs in AQP4-IgG-positive NMOSD patients admitted to the Second Xiangya Hospital of Central South University. Moreover, we searched the literature (without any temporal restriction) to identify all such similar cohorts and performed a meta-analysis to evaluate the effectiveness and safety of IS therapy on NMOSD patients with PRAs.ResultWe collected clinical data on 117 women with AQP4 antibody-positive NMOSD; we ultimately included 33 patients (34 pregnancies). Ten patients were relapse-free during pregnancy, and 23 (69.7%) had PRA; attacks were most common during the first trimester of the postpartum period. Maintenance of IS treatment during pregnancy was found to greatly reduce PRAs in patients with NMOSD. PRAs were associated with a higher neutrophil-to-lymphocyte ratio (NLR) at relapse during pregnancy and shorter time interval between the last relapse and conception. The meta-analysis suggested that maintenance of IS treatment during pregnancy can significantly reduce the RR of NMOSD (95%CI=0.35-0.62; z=5.18, p&lt;0.0001) and had no adverse effect on the miscarriage rate. However, the unhealthy newborn occurrence among those receiving IS treatment was 3.73 times higher than that of those not receiving treatment during pregnancy (95%CI=1.40–9.91; z=2.64, p=0.008).ConclusionOur study results demonstrates that pregnancy can induce the onset or relapse of attacks in NMOSD patients. The increased NLR value and disease activity may be a predictor for PRAs in patients with NMOSD. Moreover, administration of IS treatment during pregnancy can reduce the relapse rate. However, the dosage of drugs and risks of adverse effects to the fetus need to be considered. Future prospective studies with larger sample sizes are needed to confirm and extend our findings.