Polyautoimmunity and multiple autoimmune syndrome in patients with neuromyelitis optica spectrum disorder.

BACKGROUND: The coexistence of neuromyelitis optica spectrum disorders (NMOSD) with other autoimmune diseases (AID) has been increasingly reported. The prevalence and significance of this association are not fully understood. OBJECTIVES: This study aimed to compare the clinical and laboratory characteristics in NMOSD patients with and without AID. METHODS: Retrospective cross-sectional observational study was conducted involving adults meeting NMOSD criteria followed in a neuroimmunology clinic at a tertiary center. Descriptive analysis of clinical/paraclinical/treatment/outcome data collected from the medical records was compared between NMOSD patients with AID (polyautoimmunity) and those without AID. RESULTS: From a cohort of 46 NMOSD patients, 16 (34.8 %) patients, mostly women around 40 years of age, presented with polyautoimmunity: 10 anti-AQP4 positive, 4 anti-MOG positive, and 2 seronegative. Five different organ -specific AID, and six systemic AID were identified in the polyautoimmunity patients group, in addition to 6 cases of multiple autoimmune syndrome. The AID manifestation preceded NMOSD in 10 (62.5 %) patients, with a median interval of 7 years. The NMOSD with polyautoimmunity and NMOSD without AID groups had similar initial clinical manifestations with optic neuritis and/or myelitis being most frequent. Inflammatory CSF, namely elevated proteins, was more common in the polyautoimmunity group (13.0 % in NMOSD vs. 31.3 % in NMOSD+AID, p = 0.003). After a 10±6 years follow-up period, more patients with polyautoimmunity had a relapsing disease (75.0 % in NMOSD vs. 46.7 % in NMOSD+AID, p = 0.012) but no difference in the functional outcome evaluated by the EDSS score was identified. CONCLUSIONS: Polyautoimmunity was common in AQP4 positive NMOSD patients leading to a significantly higher risk of disease recorrence. The presence of polyautoimmunity and multiple autoimmune syndrome in NMOSD patients suggests the existence of common susceptibility factors or pathophysiological mechanisms, emphasizing the importance of a multidisciplinary approach to those patients.

Pediatric inflammatory leukoencephalopathies.

Acquired demyelinating syndromes (ADS) represent acute neurologic illnesses characterized by deficits persisting for at least 24hours and involving the optic nerve, brain, or spinal cord, associated with regional areas of increased signal on T2-weighted images. In children, ADS may occur as a monophasic illness or as a relapsing condition, such as multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). Almost all young people with MS have a relapsing-remitting course with clinical relapses. Important strides have been made in delineating MS from other ADS subtypes. Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and aquaporin 4-antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) were once considered variants of MS; however, studies in the last decade have established that these are in fact distinct entities. Although there are clinical phenotypic overlaps between MOGAD, AQP4-NMOSD, and MS, cumulative biologic, clinical, and pathologic evidence allows discrimination between these conditions. There has been a rapid increase in the number of available disease-modifying therapies for MS and novel treatment strategies are starting to appear for both MOGAD and AQP4-NMOSD. Importantly, there are a number of both inflammatory and noninflammatory mimics of ADS in children with implications of management for these patients in terms of treatment.

NMOSD and MOGAD: an evolving disease spectrum.

Neuromyelitis optica (NMO) spectrum disorder (NMOSD) is a relapsing inflammatory disease of the CNS, characterized by the presence of serum aquaporin 4 (AQP4) autoantibodies (AQP4-IgGs) and core clinical manifestations such as optic neuritis, myelitis, and brain or brainstem syndromes. Some people exhibit clinical characteristics of NMOSD but test negative for AQP4-IgG, and a subset of these individuals are now recognized to have serum autoantibodies against myelin oligodendrocyte glycoprotein (MOG) - a condition termed MOG antibody-associated disease (MOGAD). Therefore, the concept of NMOSD is changing, with a disease spectrum emerging that includes AQP4-IgG-seropositive NMOSD, MOGAD and double-seronegative NMOSD. MOGAD shares features with NMOSD, including optic neuritis and myelitis, but has distinct pathophysiology, clinical profiles, neuroimaging findings (including acute disseminated encephalomyelitis and/or cortical encephalitis) and biomarkers. AQP4-IgG-seronegative NMOSD seems to be a heterogeneous condition and requires further study. MOGAD can manifest as either a monophasic or a relapsing disease, whereas NMOSD is usually relapsing. This Review summarizes the history and current concepts of NMOSD and MOGAD, comparing epidemiology, clinical features, neuroimaging, pathology and immunology. In addition, we discuss new monoclonal antibody therapies for AQP4-IgG-seropositive NMOSD that target complement, B cells or IL-6 receptors, which might be applied to MOGAD in the near future.

Autoimmune astrocytopathy double negative for AQP4-IgG and GFAP-IgG: Retrospective research of clinical practice, biomarkers, and pathology.

OBJECTIVE: The objective of this study is to investigate the presence of astrocyte antibodies in patients, excluding aquaporin-4 or glial fibrillary acidic protein (GFAP) antibodies, while evaluating associated biomarkers and pathologies. METHODS: Patient serum and cerebrospinal fluid (CSF) were tested for antibodies using tissue- and cell-based assays. Neurofilament light chain (NFL) and GFAP in the CSF were detected using single-molecule array (SIMOA). RESULTS: 116 patients accepted SIMOA. Fifteen functional neurological disorders patients without antibodies were designated as controls. Thirty-five patients were positive for astrocyte antibodies (Anti-GFAP: 7; Anti-AQP4: 7; unknown antibodies: 21, designed as the double-negative group, DNAP). The most frequent phenotype of DNAP was encephalitis (42.9%), followed by myelitis (23.8%), movement disorders (19.0%), and amyotrophic lateral sclerosis-like (ALS-like) disease (14.2%). The levels of CSF GFAP and NFL in DNAP were higher than in the control (GFAP: 1967.29 [776.60-13214.47] vs 475.38 [16.80-943.60] pg/mL, p < 0.001; NFL: 549.11 [162.08-2462.61] vs 214.18 [81.60-349.60] pg/mL, p = 0.002). GFAP levels decreased in DNAP (n = 5) after immunotherapy (2446.75 [1583.45-6277.33] vs 1380.46 [272.16-2005.80] pg/mL, p = 0.043), while there was no difference in NFL levels (2273.78 [162.08-2462.61] vs 890.42 [645.06-3168.06] pg/mL, p = 0.893). Two brain biopsy patterns were observed: one exhibited prominent tissue proliferation and hypertrophic astrocytes, with local loss of astrocytes, while the other showed severe astrocyte depletion with loss of neurofilaments around the vessels. Eighteen patients received immunotherapy, and improved except one with ALS-like symptoms. We identified anti-vimentin in this patient. DISCUSSION: There are unidentified astrocyte antibodies. The manifestations of double-negativity are heterogeneous; nevertheless, the pathology and biomarkers remain consistent with astrocytopathy. Immunotherapy is effective.

Investigation of health care use and a possible prodrome before the first attack in NMOSD and MOGAD.

BACKGROUND: Prodromal phases are well recognized in many inflammatory and neurodegenerative diseases, including multiple sclerosis. We evaluated the possibility of a prodrome in aquaporin-4 antibody positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD) using health administrative data. METHODS: We investigated individuals with AQP4 + NMOSD and MOGAD, confirmed by medical chart review, in Ontario, Canada. Each NMOSD and MOGAD participant was matched 1:5 to general population controls by sex, birth year, immigrant status, and region. Total outpatient visits and hospitalizations were compared in the 5 years preceding the incident attack in multivariable negative binomial models. RESULTS: We identified 96 people with AQP4 + NMOSD, matched to 479 controls, and 61 people with MOGAD, matched to 303 controls. In the 5 years preceding the incident attack, health care use was elevated for outpatient visits and hospitalizations for the NMOSD cohort (adjusted rate ratio (aRR): 1.47; 95% confidence interval (CI): 1.25-1.73; aRR: 1.67; 95% CI: 1.19-2.36, respectively) but not for MOGAD. Rate ratios steadily increased in NMOSD for outpatient visits in the 2 years preceding the incident attack. CONCLUSION: Our findings support a prodromal phase preceding clinical onset of AQP4 + NMOSD. Earlier recognition and management of NMOSD patients may be possible.

[Mistakes in the diagnosis of neuromyelitis optic spectrum diseases lead to wrong therapy and deterioration of patients' condition]. / Oshibki v diagnostike zabolevanii spektra optikoneiromielita privodyat k nepravil'noi terapii i ukhudsheniyu sostoyaniya patsientov.

Neuromyelitis optic spectrum diseases (NMOSD) are a group of rare neuroimmunological diseases involving mainly the optic nerves and spinal cord, to a lesser extent the brain, and causing severe exacerbations that lead to persistent disability of patients. For many years, opticoneuromyelitis was considered a prognostically unfavorable variant of the course of multiple sclerosis (MS), however, in 2004, specific autoantibodies to aquaporin-4 were found in such patients, which made it possible to isolate NMOSD into a separate group of demyelinating diseases other than MS. Due to similar clinical signs and the predominantly remitting course of diseases, it is often difficult to make a correct diagnosis and, accordingly, prescribe effective therapy, which often leads to incorrectly selected therapy with incorrect diagnosis. In some cases, this leads to a worsening of the course of NMOSD. We present a case of late diagnosis of NMOSD that confirms the development of exacerbation in the patient 2 months after the first course of therapy with alemtuzumab prescribed as a highly effective therapy for highly active remitting MS. Timely diagnosis of NMOSD makes it possible to exclude such cases.

Update on aquaporin-4 antibody detection: the early diagnosis of neuromyelitis optica spectrum disorders.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune-mediated primary inflammatory myelinopathy of the central nervous system that primarily affects the optic nerve and spinal cord. The aquaporin 4 antibody (AQP4-Ab) is a specific autoantibody marker for NMOSD. Most patients with NMOSD are seropositive for AQP4-Ab, thus aiding physicians in identifying ways to treat NMOSD. AQP4-Ab has been tested in many clinical and laboratory studies, demonstrating effectiveness in diagnosing NMOSD. Recently, novel assays have been developed for the rapid and accurate detection of AQP4-Ab, providing further guidance for the diagnosis and treatment of NMOSD. This article summarizes the importance of rapid and accurate diagnosis for treating NMOSD based on a review of the latest relevant literature. We discussed current challenges and methods for improvement to offer new ideas for exploring rapid and accurate AQP4-Ab detection methods, aiming for early diagnosis of NMOSD.

Different Complement Activation Patterns Following C5 Cleavage in MOGAD and AQP4-IgG+NMOSD.

OBJECTIVES: In myelin oligodendrocyte glycoprotein IgG-associated disease (MOGAD) and aquaporin-4 IgG+ neuromyelitis optica spectrum disorder (AQP4+NMOSD), the autoantibodies are mainly composed of IgG1, and complement-dependent cytotoxicity is a primary pathomechanism in AQP4+NMOSD. We aimed to evaluate the CSF complement activation in MOGAD. METHODS: CSF-C3a, CSF-C4a, CSF-C5a, and CSF-C5b-9 levels during the acute phase before treatment in patients with MOGAD (n = 12), AQP4+NMOSD (n = 11), multiple sclerosis (MS) (n = 5), and noninflammatory neurologic disease (n = 2) were measured. RESULTS: CSF-C3a and CSF-C5a levels were significantly higher in MOGAD (mean ± SD, 5,629 ± 1,079 pg/mL and 2,930 ± 435.8 pg/mL) and AQP4+NMOSD (6,017 ± 3,937 pg/mL and 2,544 ± 1,231 pg/mL) than in MS (1,507 ± 1,286 pg/mL and 193.8 ± 0.53 pg/mL). CSF-C3a, CSF-C4a, and CSF-C5a did not differ between MOGAD and AQP4+NMOSD while CSF-C5b-9 (membrane attack complex, MAC) levels were significantly lower in MOGAD (17.4 ± 27.9 ng/mL) than in AQP4+NMOSD (62.5 ± 45.1 ng/mL, p = 0.0019). Patients with MOGAD with severer attacks (Expanded Disability Status Scale [EDSS] ≥ 3.5) had higher C5b-9 levels (34.0 ± 38.4 ng/m) than those with milder attacks (EDSS ≤3.0, 0.9 ± 0.7 ng/mL, p = 0.044). DISCUSSION: The complement pathway is activated in both MOGAD and AQP4+NMOSD, but MAC formation is lower in MOGAD, particularly in those with mild attacks, than in AQP4+NMOSD. These findings may have pathogenetic and therapeutic implications in MOGAD.

Indirect Immunofluorescence-Aided Detection of Antimyelin Oligodendrocyte Glycoprotein Antibodies in Neuromyelitis Optica Spectrum Disorder/Myelin Oligodendrocyte Glycoprotein-Associated Antibody Disorder: A Case Series Involving Five Patients.

Autoantibodies are the cause of the chronic inflammatory diseases known as neuromyelitis optica spectrum disorders (NMOSD). Serum antibodies (Abs) that specifically target the aquaporin-4 (AQP-4) water channel are the cause of recurrent episodes of optic neuritis, myelitis, and/or brain stem disorders. In contrast to AQP-4 Abs, myelin oligodendrocyte glycoprotein (MOG) Abs are detected in some patients exhibiting nonmotor cognitive impairment. These days, the term "MOG-encephalomyelitis" (MOG-EM) is frequently used to describe these clinical syndromes. The diagnosis of these cases involves the use of magnetic resonance imaging, optical coherence tomography, antibody detection, and additional laboratory testing. By detecting the patient's Abs in their serum or cerebrospinal fluid (CSF), indirect immunofluorescence (IIF) aids in the proper diagnosis. We highlight five NMOSD cases where serum anti-MOG antibody positivity was found using IIF, but CSF was not. In none of the cases, anti-AQP Abs were found. Effective patient management strategies include the treatment of acute attacks and long-term immunosuppressive drugs such as rituximab, azathioprine, and immunoglobulins. IIF is a quick and easy tool to detect anti-MOG Abs in patients with NMOSD/myelin oligodendrocyte glycoprotein antibody-associated disorder. CSF testing for MOG or AQP-4 Abs is not usually advised. It does not offer additional benefits to help with MOG-EM or NMOSD diagnosis.

RésuméLes autoanticorps sont à l'origine de maladies inflammatoires chroniques connues sous le nom de troubles du spectre de la neuromyélite optique (NMOSD). Sérum les anticorps (Abs) qui ciblent spécifiquement le canal hydrique de l'aquaporine-4 (AQP-4) sont à l'origine d'épisodes récurrents de névrite optique, de myélite, et/ou des troubles du tronc cérébral. Contrairement aux Abs AQP-4, les Abs glycoprotéines oligodendrocytes de myéline (MOG) sont détectés chez certains patients présentant déficience cognitive non motrice. De nos jours, le terme « MOG encéphalomyélite ¼ (MOG-EM) est fréquemment utilisé pour décrire ces troubles cliniques syndrome. Le diagnostic de ces cas fait appel à l'imagerie par résonance magnétique, à la tomographie par cohérence optique, à la détection d'anticorps, et des tests de laboratoire supplémentaires. En détectant les Abs du patient dans son sérum ou liquide céphalo-rachidien (LCR), immunofluorescence indirecte (IIF) aide au bon diagnostic. Nous mettons en évidence cinq cas de NMOSD où la positivité des anticorps anti-MOG sériques a été trouvée en utilisant l'IIF, mais le LCRn'était pas. Dans aucun des cas, des Ac anti-AQP n'ont été trouvés. Les stratégies efficaces de prise en charge des patients comprennent le traitement des crises aiguës et médicaments immunosuppresseurs à long terme tels que le rituximab, l'azathioprine et les immunoglobulines. IIF est un outil simple et rapide pour détecter les anti-MOG Abs chez les patients atteints d'un trouble associé aux anticorps anti-glycoprotéine oligodendrocytaire de NMOSD/myéline. Les tests CSF pour MOG ou AQP-4 Abs ne sont pas habituellement conseillé. Il n'offre pas d'avantages supplémentaires pour faciliter le diagnostic MOG-EM ou NMOSD.

NMOSD and MOGAD.

OBJECTIVE: This article reviews the clinical features, MRI characteristics, diagnosis, and treatment of aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). The main differences between these disorders and multiple sclerosis (MS), the most common demyelinating disease of the central nervous system (CNS), are also highlighted. LATEST DEVELOPMENTS: The past 20 years have seen important advances in understanding rare demyelinating CNS disorders associated with AQP4 IgG and myelin oligodendrocyte glycoprotein (MOG) IgG. The rapidly expanding repertoire of immunosuppressive agents approved for the treatment of AQP4-NMOSD and emerging as potentially beneficial in MOGAD mandates prompt recognition of these diseases. Most of the recent literature has focused on the identification of clinical and MRI features that help distinguish these diseases from each other and MS, simultaneously highlighting major diagnostic pitfalls that may lead to misdiagnosis. An awareness of the limitations of currently available assays for AQP4 IgG and MOG IgG detection is fundamental for identifying rare false antibody positivity and avoiding inappropriate treatments. For this purpose, diagnostic criteria have been created to help the clinician interpret antibody testing results and recognize the clinical and MRI phenotypes associated with AQP4-NMOSD and MOGAD. ESSENTIAL POINTS: An awareness of the specific clinical and MRI features associated with AQP4-NMOSD and MOGAD and the limitations of currently available antibody testing assays is crucial for a correct diagnosis and differentiation from MS. The growing availability of effective treatment options will lead to personalized therapies and improved outcomes.

Cortical plasticity in AQP4-positive NMOSD: a transcranial magnetic stimulation study.

Aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) is an autoimmune disease characterized by suboptimal recovery from attacks and long-term disability. Experimental data suggest that AQP4 antibodies can disrupt neuroplasticity, a fundamental driver of brain recovery. A well-established method to assess brain LTP is through intermittent theta-burst stimulation (iTBS). This study aimed to explore neuroplasticity in AQP4-NMOSD patients by examining long-term potentiation (LTP) through iTBS. We conducted a proof-of-principle study including 8 patients with AQP4-NMOSD, 8 patients with multiple sclerosis (MS), and 8 healthy controls (HC) in which iTBS was administered to induce LTP-like effects. iTBS-induced LTP exhibited significant differences among the 3 groups (p: 0.006). Notably, AQP4-NMOSD patients demonstrated impaired plasticity compared to both HC (p = 0.01) and pwMS (p = 0.02). This pilot study provides the first in vivo evidence supporting impaired neuroplasticity in AQP4-NMOSD patients. Impaired cortical plasticity may hinder recovery following attacks suggesting a need for targeted rehabilitation strategies.

[The diagnostic effectiveness of criteria for neuromyelitis optica spectrum disorders in the Russian clinical practice]. / Diagnosticheskaya effektivnost' kriteriev zabolevanii spektra optikoneiromielita v rossiiskoi klinicheskoi praktike.

OBJECTIVE: To compare the diagnostic criteria of 2006 (DC 2006) and 2015 (DC 2015) in the Russian population of patients with suspected neuromyelitis optica spectrum disorders (NMOSD), with the calculation of their sensitivity, specificity, accuracy and predictive value. MATERIAL AND METHODS: We reviewed medical records of suspected NMOSD patients who were therefore examined for the presence of serum autoantibodies targeting the aquaporin-4 water channel protein (AQP4-IgG) in 6 specialized Russian (Nizhny Novgorod and Moscow) medical centers. One hundred patients (78 female), aged 17 to 74 years (mean 38.1±13.3 years), were included. The follow-up period ranged from 4 to 108 months (mean 59.7±31.6 months). RESULTS: During the follow-up the diagnosis of NMOSD was confirmed in 32 people, and 68 patients had diagnoses different from NMOSD. At the disease onset, 68.8% of patients were seropositive for AQP4-IgG. The mean time for confirming NMOSD diagnosis was 15.2±14.2 months. At the disease onset, 36% of patients fulfilled the DC 2015, the diagnosis was subsequently confirmed in 77.8% out of them. 26% of the patients fulfilled the DC 2006, the diagnosis was subsequently confirmed in 84.6% out of them. The sensitivity of DC 2006/DC 2015 was 69%/88%, specificity 94%/88%, accuracy 86%/88%, negative predictive value 85%/94%, positive predictive value 86%/78%. CONCLUSION: The specificity, sensitivity and accuracy of modern diagnostic criteria for NMOSD In Russian patients is comparable to those obtained in foreign studies. DC 2015 helps to diagnose NMOSD earlier than DC 2006, but they have a lower specificity.

Hematopoietic stem cell transplantation for neuromyelitis optica spectrum disorder. Can immune tolerance be reestablished?

Neuromyelitis optica (NMO), which is also referred to as Devic's disease, was originally considered an aggressive subtype of multiple sclerosis (MS) presenting as optic neuritis and/or extensive transverse myelitis in which 50% of patients become blind or in a wheelchair within 5 years of onset. Subsequently, NMO was categorized as one of a spectrum of inflammatory and demyelinating autoimmune disorders that are distinct from multiple sclerosis and termed neuromyelitis optica spectrum disorder (NMOSD). NMOSD differs from multiple sclerosis by its clinical course, presentation, magnetic resonance imaging findings, clinical presentation, serum biomarker prognosis, and response to treatment. More recently, NMOSD has been subdivided according to auto-antibody status as aquaporin 4 (AQP4) seropositive NMO, myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), and seronegative NMOSD. The only treatment to date that has resulted in treatment-free remissions, now lasting for more than 5-10 years with posttreatment disappearance of anti-AQP4 antibodies, is hematopoietic stem cell transplantation (HSCT) using either an allogeneic (matched sibling or unrelated) donor with a reduced toxicity conditioning regimen or an autologous stem cell source using a nonmyeloablative conditioning regimen of plasmapheresis (PLEX), cyclophosphamide (Cytoxan®), rabbit antithymocyte (ATG), and rituximab (Rituxan®). Post-HSCT long-term resolution of disease activity and disappearance of AQP4 antibodies is consistent with HSCT-induced immune tolerance.

Prognostic factors associated with disability in a cohort of neuromyelitis optica spectrum disorder and MOG-associated disease from a nationwide Portuguese registry.

INTRODUCTION: Neuromyelitis optica spectrum disorders (NMOSD) and MOG-associated disease (MOGAD) are an increasingly recognized group of demyelinating disorders of the central nervous system. Previous studies suggest that prognosis is predicted by older age at onset, number of relapses, the severity of the first attack and autoantibody status. OBJECTIVE: To study prognostic factors associated with disability progression and additional relapses in the 3-year follow-up of a national NMOSD/MOGAD cohort. RESULTS: Out of 180 of the initial Portuguese cohort, data on 82 patients was available at the end of the follow-up period (2019-2022). Two patients died. Twenty (24.4%) patients had one or more attack in this period (25 attacks in total), mostly transverse myelitis (TM) (56.0%) or optic neuritis (32.0%). MOGAD was significantly associated with a monophasic disease course (p = 0.03), with milder attacks (p = 0.01), while AQP4 + NMOSD was associated with relapses (p = 0.03). The most common treatment modalities were azathioprine (38.8%) and rituximab (18.8%). AQP4 + NMOSD more frequently required chronic immunosuppressive treatment, particularly rituximab (p = 0.01). Eighteen (22.5%) had an EDSS ≥6 at the end of the follow-up. AQP4 + NMOSD (p < 0.01) and the occurrence of transverse myelitis (TM) during disease (p = 0.04) correlated with an EDSS≥6 at the end of the follow-up period. MOGAD was significantly associated with an EDSS<6 (p < 0.01), and MOG+ cases that reached an EDSS>6 were significantly older (64.0 ± 2.8 versus 31.0 ± 17.1, p = 0.017). A bivariate logistic regression model including the serostatus and TM attacks during disease history successfully predicted 72.2% of patients that progressed to an EDSS≥6. CONCLUSION: This study highlights that myelitis predict increased disability (EDSS≥6) in NMOSD/MOGAG and AQP4 positivity is associated with increased disability.

The levels of circulating cytokines and risk of neuromyelitis optica spectrum disorder: a Mendelian randomization study.

Background: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory autoimmune disease affecting the central nervous system (CNS). NMOSD pathogenesis involves systemic inflammation. However, a causal relationship between circulating cytokine levels and NMOSD remains unclear. Methods: Mendelian randomization (MR) approaches were used to investigate the potential association between genetically determined circulating 19 inflammatory cytokines and 12 chemokines levels and the risk of developing NMOSD. Results: After Bonferroni correction, the risk of aquaporin 4-antibody (AQP4-ab)-positive NMOSD was suggested to be causally associated with the circulating levels of three cytokines, including interleukin (IL)-4 [odds ratio (OR): 11.01, 95% confidence interval (CI): 1.16-104.56, P = 0.037], IL-24 (OR: 161.37; 95% CI: 2.46-10569.21, P = 0.017), and C-C motif chemokine 19 (CCL19) (OR: 6.87, 95% CI: 1.78-26.93, P = 0.006). Conclusion: These findings suggest that a genetic predisposition to higher levels of IL-4, IL-24, and CCL19 may exert a causal effect on the risk of AQP4-ab-positive NMOSD. Further studies are warranted to clarify how these cytokines affect the development of AQP4-ab-positive NMOSD.

Pearls & Oy-sters: Optic Neuritis as First Demyelinating Event During Pregnancy in 2 Young Hispanic Women: MS vs MOGAD.

Optic neuritis (ON) can present as the first demyelinating attack in both multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), which may require different treatment depending on the final diagnosis. We present 2 young Hispanic women who presented with ON during pregnancy, one of whom was diagnosed with MS and the other with MOGAD. We describe key clinical features to help differentiate between MS and MOGAD including ON features, brain and spinal MRI, CSF profiles, and serum MOG and aquaporin-4 (AQP-4) antibodies, which all can help guide clinicians to an ultimate diagnosis. Pregnancy is usually considered an immunotolerant state because complex immunologic shifts arising to support tolerance of the developing fetus seem to decrease the risk of relapses. However, relapses may still occur during pregnancy, and relapse rates increase immediately postpartum. Our cases raise the possibility that young Hispanic patients may face increased risk of demyelinating disease activity even during the relatively immunotolerant state of pregnancy. A high index of suspicion for demyelinating disease should be maintained to accelerate diagnosis and prevent disability.

The relationship between neuromyelitis optica spectrum disorder and autoimmune diseases.

Objective: There have been reports of neuromyelitis optica spectrum disorder (NMOSD) coexisting with connective tissue disorders. The objective of this study was to describe the characteristics of NMOSD coexisting with autoimmune diseases (AID). Methods: This retrospective study evaluated NMOSD patients with and without AID. The enrolled patients had at least one attack, with duration of more than 1 year. Data on the demographics, clinical features, and laboratory findings were assessed. The Poisson model was used to investigate the risk factors associated with the annualized relapse rate (ARR), whereas the Cox model was used to evaluate the risk factors for the first relapse. Results: A total of 180 patients (154 women and 26 men) with NMOSD were identified: 45 had AID and 135 did not. Female patients had a higher prevalence of concomitant AID (p = 0.006) and a greater relapse rate within the first year. There were no statistically significant differences in the characteristics of patients. Kaplan-Meier analysis revealed that NMOSD patients with seropositive aquaporin 4 antibodies (AQP4-Ab; log-rank: p = 0.044), had a shorter time to relapse. Patients seropositive for AQP4-Ab (HR = 2.402, 95%CI = 1.092-5.283, p = 0.029) had a higher risk of suffering a first relapse, according to the Cox model. Patients with and without AID showed a similar declining tendency in terms of change in ARR throughout the first 5 years of the disease. The ARR was greater in the first year [incidence rate ratio (IRR) = 1.534, 95%CI = 1.111-2.118] and the first 2 years (IRR = 1.474, 95%CI = 1.056-2.058) in patients with coexisting AID diagnosis prior to the NMOSD onset. Conclusions: Patients with NMOSD with coexisting AID had similar characteristics when compared with those without AID. NMOSD patients with AID diagnosed before onset had a higher risk of relapse in the early stage of the disease.

Paraneoplastic neuromyelitis optica spectrum disorder associated with ovarian dysgerminoma: a case report and literature review.

Neuromyelitis optica spectrum disorder (NMOSD) is a clinical syndrome characterized by attacks of acute optic neuritis and transverse myelitis. We report a case with paraneoplastic NMOSD that improved after immunosuppressive therapy, surgical resection, and chemotherapy. A 48-year-old woman initially presented with gradual binocular visual loss over the course of one week. The patient was evaluated using magnetic resonance imaging (MRI), computed tomography (CT), visual evoked potential (VEP), pathological biopsy, immunohistochemistry, and autoimmune antibody testing. The brain MRI findings were normal. The VEP revealed prolonged P100 latencies in the right eye and an absence of significant waves in the left eye. Positive serum AQP4-IgG antibodies were found. The patient was diagnosed as NMOSD. Then the patient responded well to treatment with methylprednisolone. An ovarian tumor was found in the patient using abdominal MRI and CT. The tumor was surgically resected, and a pathological biopsy revealed that it was ovarian dysgerminoma. The patient received four rounds of chemotherapy after surgery. One month after the final chemotherapy treatment, a positron emission tomography (PET) scan revealed no tumor. The vision of the patient gradually recovered and serum AQP4 was negative. Furthermore, we summarized the characteristics of patients diagnosed with paraneoplastic NMOSD associated with ovarian neoplasms in previous studies. This is a characteristic case of overlapping NMOSD and ovarian dysgerminoma, demonstrating the importance of tumor therapy in cases of paraneoplastic NMOSD.

Protein-A immunoadsorption combined with immunosuppressive treatment in refractory primary Sjögren's syndrome coexisting with NMOSD: a case report and literature review.

The treatment of primary Sjögren's syndrome (pSS) coexisting with neuromyelitis optica spectrum disorder (NMOSD) using protein-A immunoadsorption combined with immunosuppressive therapy has rarely been reported. Herein, we present the case of a 35-year-old female diagnosed with pSS concomitant with NMOSD (pSS-NMOSD) who demonstrated a positive response to protein-A immunoadsorption after failing to respond to therapy comprising high-dose intravenous methylprednisolone (IVMP) and intravenous immunoglobulin (IVIG). Within one week of receiving three sessions of immunoadsorption combined with immunosuppressive treatment, the patient's clinical symptoms (blurred vision, paraparesis, and dysfunctional proprioception) significantly improved. Additionally, a rapid decrease in the circulating levels of Aquaporin-4 immunoglobulin G antibodies (AQP4-IgG), immunoglobulin (Ig) A, IgG, IgM, erythrocyte sedimentation rate (ESR), and rheumatoid factor (RF) were observed. Magnetic resonance imaging (MRI) further revealed a significant reduction in the lesions associated with longitudinal extensive transverse myelitis. During the follow-up period, prednisolone was gradually tapered to a maintenance dose of 5-10 mg/day, whereas mycophenolate mofetil (MMF) was maintained at 1.0-1.5 g/day. The patient's condition has remained stable for four years, with no signs of recurrence or progression observed on imaging examination. Therefore, this case suggests that protein A immunoadsorption may represent a potentially effective therapeutic option for patients with pSS-NMOSD who are refractory to conventional treatments.

Cancer-associated neuromyelitis optica spectrum disorder: a case report with literature review.

Neuromyelitis optica spectrum disorders (NMOSD) is one of autoimmune inflammatory diseases and is characterized by area postrema syndrome, brainstem syndrome, optic neuritis, and/or myelitis. Typical myelitis is longitudinally extended transverse myelitis (LETM) which extends over three vertebral bodies. Several previous case reports have suggested association between cancer and NMOSD. A 50-year-old woman had breast cancer and underwent mastectomy and, 10 months later, she had developed acutely progressive dysbasia. Spine MRI showed LETM in 13 vertebrae length and blood test revealed positive anti-aquaporin 4 (anti-AQP4) antibody based on enzyme-linked immunosorbent assay with index of over 40. She was treated by intravenous methylprednisolone, plasma exchange, and intravenous immunoglobulin, followed by oral prednisolone. The condition had mostly recovered after the treatment. A small population of NMOSD has the aspect of paraneoplastic neurological syndrome. The age of onset in patients with cancer-associated NMOSD tends to be higher than that in individuals with NMOSD due to any causes of NMOSD.