Distinct virtual histology of grey matter atrophy in four neuroinflammatory diseases.

Gray matter (GM) atrophies were observed in multiple sclerosis, neuromyelitis optica spectrum disorders (both anti-aquaporin-4 antibody-positive [AQP4+], and -negative [AQP4-] subtypes NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Revealing the pathogenesis of brain atrophy in these disorders would help their differential diagnosis and guide therapeutic strategies. To determine the neurobiological underpinnings of GM atrophies in multiple sclerosis, AQP4+ NMOSD, AQP4- NMOSD, and MOGAD, we conducted a virtual histology analysis that links T1-weighted image derived GM atrophy and gene expression using a multicenter cohort of 324 patients with multiple sclerosis, 197 patients with AQP4+ NMOSD, 75 patients with AQP4- NMOSD, 47 patients with MOGAD, and 2,169 healthy controls (HCs). First, interregional GM atrophy profiles across the cortical and subcortical regions were determined by Cohen's d between patients with multiple sclerosis, AQP4+ NMOSD, AQP4- NMOSD, MOGAD and HCs. Then, the GM atrophy profiles were spatially correlated with the gene expressions extracted from the Allen Human Brain Atlas, respectively. Finally, we explored the virtual histology of clinical feature relevant GM atrophy by subgroup analysis that stratified by physical disability, disease duration, number of relapses, lesion burden, and cognitive function. Multiple sclerosis showed severe widespread GM atrophy pattern, mainly involving subcortical nuclei and brainstem. AQP4+ NMOSD showed obvious widespread GM atrophy pattern, predominately located in occipital cortex as well as cerebellum. AQP4- NMOSD showed mild widespread GM atrophy pattern, mainly located in frontal and parietal cortices. MOGAD showed GM atrophy mainly involving the frontal and temporal cortices. High expression of genes specific to microglia, astrocytes, oligodendrocytes, and endothelial cells in multiple sclerosis, S1 pyramidal cells in AQP4+ NMOSD, as well as S1 and CA1 pyramidal cells in MOGAD had spatial correlations with GM atrophy profiles were observed, while no atrophy profile related gene expression was found in AQP4- NMOSD. Virtual histology of clinical feature relevant GM atrophy mainly pointed to the shared neuronal and endothelial cells among the four neuroinflammatory diseases. The unique underlying virtual histology patterns were microglia, astrocytes, and oligodendrocytes for multiple sclerosis; astrocytes for AQP4+ NMOSD; and oligodendrocytes for MOGAD. Neuronal and endothelial cells were shared potential targets across these neuroinflammatory diseases. These findings might help their differential diagnosis and optimal therapeutic strategies.

Relapsing meningitis and limbic encephalitis in anti-AQP4-Ab-associated neuromyelitis optica spectrum disorder.

OBJECTIVES: neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease mainly affecting optic nerves and the spinal cord. Due to the potentially irreversible tissue damage, prevention of relapses is of utmost importance. METHODS: We describe the atypical clinical course and pathology results of a patient with anti-aquaporin-4 antibody (anti-AQP4-Ab)-associated NMOSD who developed aseptic meningitis followed by limbic-encephalitis-like presentation with extensive brain lesions upon treatment with rituximab and tocilizumab. RESULTS: The patient developed subacute cognitive decline with magnetic resonance imaging (MRI) evidence of extensive brain white matter lesions. In the hypothesis of an opportunistic brain infection, she underwent brain biopsy of the temporal pole. Pathology results revealed typical NMOSD findings with complement activation, supporting the hypothesis of an atypical presentation of anti-AQP-Ab-associated NMOSD. Accordingly, treatment with the complement-targeting drug eculizumab was started, leading to a dramatic clinical and MRI improvement. DISCUSSION: aseptic meningitis and limbic encephalitis could represent a rare phenotype of anti-AQP4-Ab-associated NMOSD.

Epilepsia Partialis Continua as a manifestation of aquaporin-4 autoimmunity.

A 52-year-old man experienced two seizures in January and June 2021. In October, the neurological examination did not reveal sensory/motor deficits. Brain magnetic resonance imaging (MRI) showed hyperintense lesions with contrast enhancement (CE) involving white matter bilaterally, brainstem, and cerebellum. Spine MRI showed hyperintense C2-C3 and C4-C6 lesions with CE. Anti-aquaporin-4 (AQP4) antibodies were detected, confirming the diagnosis of neuromyelitis optica spectrum disorder (NMOSD). The patient experienced a status epilepticus compatible with Epilepsia Partialis Continua treated with antiseizure medications. He was also treated with methylprednisolone, plasma exchange, and rituximab. Status epilepticus can be a rare manifestation of NMOSD, heightening the broad spectrum of AQP4 autoimmunity.

Prevalence of neuromyelitis optica spectrum disorder in the United States.

BACKGROUND: Neuromyelitis optic spectrum disorder (NMOSD) is a rare demyelinating, autoimmune disease and the burden in United States is not well characterized. OBJECTIVE: The objective of this study was to determine the 2022 US prevalence of NMOSD. METHODS: We constructed a cross-sectional study using aggregated electronic health record data for 25.7 million patients who had a 2022 clinical encounter. The data originated from the TriNetX US Collaborative Network of 55 healthcare organizations that span all 50 states. NMOSD prevalence was determined by querying for age-interval, sex, and race combinations, with direct standardization to the 2022 US Census data. RESULTS: There were 1772 NMOSD patients among 25,743,039 patients for a prevalence of 6.88/100,000. Prevalence was the highest in Blacks (12.99/100,000) who represented 27.7% of NMOSD patients, then Asians (9.41/100,000and Whites (5.58/100,000). Among females, the prevalence of NMOSD was 9.48/100,000, and Black and Asian females had a 2.65- and 1.94-times higher prevalence than White females. In males, the prevalence of NMOSD was 3.52/100,000 and it did not differ by race. We observed a 3/5:1 female-to-male ratio in NMOSD. The age- and sex-adjusted 2022 estimate of persons with NMOSD in the United States was 15,413 females and 6233 males. CONCLUSION: We estimate that there were near 22,000 Americans living with NMOSD in 2022.

Co-occurrence of glial fibrillary acidic protein astrocytopathy in a patient with Leber's hereditary optic neuropathy due to DNAJC30 mutations.

Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease characterized by visual loss, and rarely associated with extraocular manifestations including multiple sclerosis-like lesions. The association of LHON and neuromyelitis optica spectrum disorders has rarely been reported. Here is reported a case of glial fibrillary acidic protein astrocytopathy presenting with area postrema syndrome in a patient with previously diagnosed recessive LHON due to mutations in the nuclear gene DNAJC30. This case emphasizes the necessity of extensive investigations for other treatable conditions in patients with LHON and otherwise unexplained extraocular involvement and the possibility that also visual symptoms can respond to immune therapy.

Perspectives on Neuromyelitis Optica Spectrum Disorders, the Narrative Medicine contribution to care.

BACKGROUND: This research aimed to investigate the experience of Neuromyelitis Optica Spectrum Disorders (NMOSD) by integrating the perspectives of patients, caregivers and clinicians through narrative-based medicine to provide new insights to improve care relationships. METHODS: The research was conducted in the second half of 2022 and involved six Italian centres treating NMOSD and targeted adult patients, their caregivers and healthcare providers to collect the three points of view of living with or caring for this rare disease, still difficult to treat despite the pharmacological options. Narratives followed a structured outline according to the time: yesterday-today-tomorrow, to capture all disease phases. RESULTS: Twenty-five patients diagnosed with NMOSD, ten caregivers and 13 healthcare providers participated in the research. Patients reported symptoms limiting their daily activities and strongly impacting their social dimension. We noticed improvements across disease duration, whilst the persistence of limitations was recurrent in patients with longer diagnoses. Caregivers' narratives mainly share experiences of their daily life changes, the burden of the caregiving role and the solutions identified, if any. Healthcare providers defined their role as a guide. CONCLUSION: Limitations in activities are prominent in the lives of people with NMOSD, along with fatigue. Family members are the weakest link in the chain and need information and support. Healthcare professionals are attentive to the helping dimension.

Combined platelet-to-lymphocyte ratio and blood-brain barrier biomarkers as indicators of disability in acute neuromyelitis optica spectrum disorder.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a complex neuroinflammatory disease characterized by severe disability. In this study, we investigated the relationship between cerebrospinal fluid (CSF)/serum albumin quotient (Qalb) and platelet to lymphocyte ratio (PLR) in assessing disease severity. METHOD: A retrospective analysis of 72 NMOSD patients and 72 healthy controls was conducted, and patients were divided into two groups based on their Expanded Disability Status Scale (EDSS) scores. RESULTS: NMOSD patients had significantly higher levels of serum PLR, neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and C-reactive protein (CRP) compared to healthy controls (all P<0.01). Patients in the EDSS≥4 group exhibited significantly elevated levels of Qalb, QIgG, QIgA, QIgM, and PLR (P=0.000, P<0.0001, P=0.0019, P=0.0001, respectively). Spearman's correlation test revealed significant positive associations between Qalb, QIgG, QIgA, QIgM, PLR, and EDSS score. Specifically, Qalb (r=0.571; P<0.001), QIgG (r=0.551; P<0.001), QIgA (r=0.519; P<0.001), and QIgM (r=0.541; P<0.001) demonstrated significant positive correlations with EDSS score, while PLR exhibited a moderate positive correlation (r=0.545; P<0.001) with EDSS score and a mild positive association (r=0.387; P<0.001) with Qalb. The increase of Qalb was positively correlated with the increased EDSS score (r=0.528, P=0.001), as well as the increase of QIgG (r=0.509, P=0.001), and the increase of QIgA (r=0.4989, P=0.03). ROC analysis indicated that Qalb, QIgG, QIgA, QIgM, and PLR levels could effectively serve as indicators of NMOSD severity (all P<0.0001). Multivariate analysis confirmed the independent significance of Qalb and PLR in assessing disease severity (P=0.000). CONCLUSION: These findings provide valuable insights into the risk and pathogenesis of NMOSD and highlight the potential of Qalb and PLR as independent markers for disease severity assessment in NMOSD patients.

Clinical and demographic characteristics of patients with NMOSD: a longitudinal retrospective analysis of a Slovak cohort of 63 patients.

BACKGROUND: Neuromyelitis optica spectrum disorders (NMOSD) are autoantibody-mediated inflammatory diseases of the central nervous system predominantly targeting optic nerves and the spinal cord. Two distinct phenotypes are recognized based on the presence of serum aquaporin-4 (AQP4-IgG) antibodies. However, contrasting clinical course patterns have been identified between AQP4-IgG-positive and AQP4-IgG-negative patients. AIMS: This study aimed to present demographic and clinical characteristics of patients with NMOSD in Slovakia and to evaluate the significance of differences between AQP4-IgG-seropositive and AQP4-IgG-seronegative patients. METHODS: We performed a longitudinal multi-centric retrospective study and analysed the clinical and demographic characteristics of a cohort of 63 Slovak NMOSD patients. RESULTS: Eighty-six percent of patients were women, and ninety-four patients were Caucasian. The median age at diagnosis was 37 years. The most frequent initial manifestations were optic neuritis (47.6% of patients) and transverse myelitis (39.7% of patients). The median EDSS score deteriorated from the initial 3.0 to 4.0 at the last follow-up. Sixty-eight percent of patients were AQP4-IgG positive; 10% of patients were MOG-IgG positive; 27% of patients had no NMOSD-specific antibodies detected. There was a higher prevalence of autoimmune thyroiditis among AQP4-IgG-positive patients (25.6%) compared to AQP4-IgG-negative patients (0%) (p = 0.01). CONCLUSION: This study provides a detailed overview of the clinical and demographic characteristics of NMOSD based on a retrospective analysis of a Slovak cohort of 63 NMOSD patients and extends information provided by similar recently published studies. The most important finding is that there is a high prevalence of autoimmune thyroiditis among AQP4-IgG-negative patients (25%).

Neuromyelitis optica associated with the use of Atezolizumab in a patient with advanced lung adenocarcinoma.

Immune checkpoint inhibitors (ICIs) are a pharmacological group increasingly used in Oncology and Hematology. These treatments can lead to autoimmune complications, with neurological conditions, especially central nervous system (CNS) involvement, being rare. We describe a case of seropositive neuromyelitis optica in a patient with locally advanced lung adenocarcinoma treated with Atezolizumab.

Neuromyelitis Optica Spectrum Disorder in Latin America: State-of-the-Art and Current Challenges.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease of the central nervous system characterized by severe attacks of optic neuritis, myelitis, and/or area postrema. Advances in understanding the pathophysiology of NMOSD have led to improved diagnostic and therapeutic approaches. There has been a notable increase in research efforts worldwide, including in Latin America (LATAM). In recent years, LATAM has witnessed a surge in research on NMOSD, resulting in a growing body of evidence on various aspects such as epidemiology, clinical manifestations, paraclinical features (including AQP4-IgG [Aquaporin-4-immunoglobulin G] and imaging), acute and long-term treatment strategies, as well as accessibility to diagnostic tests. This narrative review aims to present the most relevant findings from different NMOSD cohorts in LATAM, providing a comprehensive overview of the current understanding of the disease in the region, while considering its unique characteristics and challenges. LATAM-focused evidence is crucial for adding valuable information to the international dataset and is therefore summarized in this review.

Clinical applications of deep learning in neuroinflammatory diseases: A scoping review.

BACKGROUND: Deep learning (DL) is an artificial intelligence technology that has aroused much excitement for predictive medicine due to its ability to process raw data modalities such as images, text, and time series of signals. OBJECTIVES: Here, we intend to give the clinical reader elements to understand this technology, taking neuroinflammatory diseases as an illustrative use case of clinical translation efforts. We reviewed the scope of this rapidly evolving field to get quantitative insights about which clinical applications concentrate the efforts and which data modalities are most commonly used. METHODS: We queried the PubMed database for articles reporting DL algorithms for clinical applications in neuroinflammatory diseases and the radiology.healthairegister.com website for commercial algorithms. RESULTS: The review included 148 articles published between 2018 and 2024 and five commercial algorithms. The clinical applications could be grouped as computer-aided diagnosis, individual prognosis, functional assessment, the segmentation of radiological structures, and the optimization of data acquisition. Our review highlighted important discrepancies in efforts. The segmentation of radiological structures and computer-aided diagnosis currently concentrate most efforts with an overrepresentation of imaging. Various model architectures have addressed different applications, relatively low volume of data, and diverse data modalities. We report the high-level technical characteristics of the algorithms and synthesize narratively the clinical applications. Predictive performances and some common a priori on this topic are finally discussed. CONCLUSION: The currently reported efforts position DL as an information processing technology, enhancing existing modalities of paraclinical investigations and bringing perspectives to make innovative ones actionable for healthcare.

Decreased kynurenine in cerebrospinal fluid and potential role in neuromyelitis optica spectrum disorder.

Tryptophan (Trp) metabolism has been implicated in neuroinflammatory and neurodegenerative disorders, but its relationship with neuromyelitis optica spectrum disorder (NMOSD) is unclear. In this pilot study, cerebrospinal fluid (CSF) was prospectively collected from 26 NMOSD patients in relapse and 16 controls with noninflammatory diseases and 6 neurometabolites in the tryptophan metabolic pathway, including 5-hydroxytryptamine (5-HT), kynurenine (KYN), melatonin (MLT), 5-hydroxyindoleacetic acid (5HIAA), 3-hydroxy-o-aminobenzoic acid (3-HAA), and kynurenic acid (KYA), were measured by ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The association of Trp metabolites with NMOSD and its clinical parameters was evaluated. The role of KYN, which is a Trp metabolite involved in the binding of NMOSD-IgG antibody to aquaporin 4 (AQP4), was also evaluated in vitro. CSF KYN was significantly decreased in patients with relapsing NMOSD compared to controls, and CSF KYN was associated with CSF white blood cells in NMOSD. In vitro experiments showed that NMOSD-IgG specifically recognized KYN, which reversed the NMOSD-IgG-induced downregulation of AQP4 expression. Our results show that abnormal Trp metabolism occurs in NMOSD and that KYN might be a potential target for the treatment of AQP4-IgG-positive NMOSD patients.

NMOSD IgG Impact Retinal Cells in Murine Retinal Explants.

Neuromyelitis optica spectrum disorders (NMOSD) are chronic inflammatory diseases of the central nervous system, characterized by autoantibodies against aquaporin-4. The symptoms primarily involve severe optic neuritis and longitudinally extensive transverse myelitis. Although the disease progression is typically relapse-dependent, recent studies revealed retinal neuroaxonal degeneration unrelated to relapse activity, potentially due to anti-aquaporin-4-positive antibodies interacting with retinal glial cells such as Müller cells. In this exploratory study, we analysed the response of mouse retinal explants to NMOSD immunoglobulins (IgG). Mouse retinal explants were treated with purified IgG from patient or control sera for one and three days. We characterized tissue response patterns through morphological changes, chemokine secretion, and complement expression. Mouse retinal explants exhibited a basic proinflammatory response ex vivo, modified by IgG addition. NMOSD IgG, unlike control IgG, increased gliosis and decreased chemokine release (CCL2, CCL3, CCL4, and CXCL-10). Complement component expression by retinal cells remained unaltered by either IgG fraction. We conclude that human NMOSD IgG can possibly bind in the mouse retina, altering the local cellular environment. This intraretinal stress may contribute to retinal degeneration independent of relapse activity in NMOSD, suggesting a primary retinopathy.

Severe febrile neutropenia associated with satralizumab in an Argentinian neuromyelitis optica spectrum disorder patient.

BACKGROUND: Recently, satralizumab (interleukin-6 receptor blocker) was approved for seropositive neuromyelitis optica spectrum disorder (NMOSD) patients. In SAkuraSky trial, mild neutropenia was reported in 15% of patients under satralizumab. Most neutropenias were transient; grade 3-4 was not related to serious infections. So far, no severe neutropenia (<100 cell/mm3) has been reported worldwide. METHODS: We present an aquaporin-4-antibody-positive NMOSD patient who developed severe febrile neutropenia 2 weeks after adding satralizumab to her azathioprine treatment. CONCLUSION: Analytic control for satralizumab is recommended at 4 weeks. However, we recommend this control at week 2, in order to closely monitor neutrophil count and prevent further complications.

Frequency of NMOSD misdiagnosis in a cohort from Latin America: Impact and evaluation of different contributors.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) misdiagnosis (i.e. the incorrect diagnosis of patients who truly have NMOSD) remains an issue in clinical practice. We determined the frequency and factors associated with NMOSD misdiagnosis in patients evaluated in a cohort from Latin America. METHODS: We retrospectively reviewed the medical records of patients with NMOSD, according to the 2015 diagnostic criteria, from referral clinics in six Latin American countries (Argentina, Chile, Paraguay, Colombia, Ecuador, and Venezuela). Diagnoses prior to NMOSD and ultimate diagnoses, demographic, clinical and paraclinical data, and treatment schemes were evaluated. RESULTS: A total of 469 patients presented with an established diagnosis of NMOSD (73.2% seropositive) and after evaluation, we determined that 56 (12%) patients had been initially misdiagnosed with a disease other than NMOSD. The most frequent alternative diagnoses were multiple sclerosis (MS; 66.1%), clinically isolated syndrome (17.9%), and cerebrovascular disease (3.6%). NMOSD misdiagnosis was determined by MS/NMOSD specialists in 33.9% of cases. An atypical MS syndrome was found in 86% of misdiagnosed patients, 50% had NMOSD red flags in brain and/or spinal magnetic resonance imaging (MRI), and 71.5% were prescribed disease-modifying drugs. CONCLUSIONS: NMOSD misdiagnosis is relatively frequent in Latin America (12%). Misapplication and misinterpretation of clinical and neuroradiological findings are relevant factors associated with misdiagnosis.

A national case-control study investigating demographic and environmental factors associated with NMOSD.

BACKGROUND: Risk factors for aquaporin-4 (AQP4+) antibody neuromyelitis optica spectrum disorder (NMOSD) are not well-established. OBJECTIVE: To investigate demographic and environmental factors associated with NMOSD using a validated questionnaire and case-control design. METHODS: We enrolled patients with AQP4 + NMOSD through six Canadian Multiple Sclerosis Clinics. Participants completed the validated Environmental Risk Factors in Multiple Sclerosis Study (EnvIMS) questionnaire. Their responses were compared to those of 956 unaffected controls from the Canadian arm of EnvIMS. We calculated odds ratios (ORs) for the association between each variable and NMOSD using logistic regression and Firth's procedure for rare events. RESULTS: In 122 participants (87.7% female) with NMOSD, odds of NMOSD in East Asian and Black participants were ⩾8 times that observed in White participants. Birthplace outside Canada was associated with an increased risk of NMOSD (OR = 5.5, 95% confidence interval (CI) = 3.6-8.3) as were concomitant autoimmune diseases (OR = 2.7, 95% CI = 1.4-5.0). No association was observed with reproductive history or age at menarche. CONCLUSION: In this case-control study, risk of NMOSD in East Asian and Black versus White individuals was greater than that observed in many previous studies. Despite the preponderance of affected women, we did not observe any association with hormonal factors such as reproductive history or age at menarche.

Characteristics of multiple sclerosis and demyelinating disease in an Asian American population.

BACKGROUND: Race and ancestry influence the course of multiple sclerosis (MS). OBJECTIVES: Explore clinical characteristics of MS and neuromyelitis optica spectrum disorder (NMOSD) in Asian American patients. METHODS: Chart review was performed for 282 adults with demyelinating disease who self-identified as Asian at a single North American MS center. Demographics and clinical characteristics were compared to non-Asian MS patients and by region of Asian ancestry. RESULTS: Region of ancestry was known for 181 patients. Most (94.7%) preferred English, but fewer East Asian patients did (80%, p = 0.0001). South Asian patients had higher neighborhood household income (p = 0.002). Diagnoses included MS (76.2%) and NMOSD (13.8%). More patients with NMOSD than MS were East and Southeast Asian (p = 0.004). For MS patients, optic nerve and spinal cord involvement were similar across regions of ancestry. Asian MS patients were younger at symptom onset and diagnosis than non-Asian MS patients. MS Severity Scale scores were similar to non-Asian MS patients but worse among Southeast Asians (p = 0.006). CONCLUSIONS: MS severity was similar between Asian American patients and non-Asian patients. Region of ancestry was associated with differences in sociodemographics and MS severity. Further research is needed to uncover genetic, socioeconomic, or environmental factors causing these differences.

The effect of smoking on MRI lesion resolution in NMOSD-AQP4 and MOGAD.

BACKGROUND: The effect of smoking on the resolution of magnetic resonance imaging (MRI) lesions in patients with neuromyelitis optica spectrum disorders with aquaporin-4 positive antibody (NMOSD-AQP4) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) has not been studied before. OBJECTIVE: We aimed to determine the effect of smoking on lesion resolution in MRI and assess its correlation with clinical recovery after a relapse. METHODS: We conducted a cohort study including NMOSD-AQP4 and MOGAD patients with acute and follow-up MRI scans. We collected demographic, clinical, imaging and smoking data. Logistic regression models were fitted to predict the effect of smoking on lesion resolution and to assess whether clinical recovery was associated with MRI lesion resolution. RESULTS: A total of 105 patients were included (57 with NMOSD-AQP4 and 48 with MOGAD). Current and past smoking was associated with a higher risk of persistent lesions in NMOSD-AQP4 and MOGAD (risk ratio (RR) = 3.4, 95% confidence interval (CI) = 2.5-4.7, p < 0.001). Additionally, the presence of lesion resolution was associated with better clinical recovery (RR = 1.9, 95% CI = 1.7-2.2, p < 0.001). CONCLUSION: Smoking is associated with worse MRI lesion resolution in patients with NMOSD-AQP4 and MOGAD, and lesion resolution correlates with clinical recovery. Our findings suggest a detrimental effect of smoking in inflammatory central nervous system (CNS) diseases.

Different clinical phenotypes of AQP4-IgG positive NMOSD in two first degree relatives.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) are autoimmune inflammatory disorders of the CNS in which patients have severe relapses of optic neuritis and myelitis. Aquaporin-4 antibody (AQP4-IgG) positive NMOSD has not been reported in members of the same family in Sub Saharan Africa. We report the uncommon scenario in which both a Ugandan HIV positive woman and her HIV negative daughter were diagnosed with AQP4-IgG positive NMOSD. We discuss pathogenic mechanisms that may underlie familial presentation of AQP4-IgG positive NMOSD. CASE PRESENTATION: Case 1, a 54-year-old female teacher with a 20-year history of HIV infection and virally suppressed on Tenofovir, Lamivudine and Dolutegravir HAART regimen, presented with 8 months of progressive quadriparesis and urinary incontinence with a T6 sensory level. She had gadolinium enhancing longitudinally extensive transverse myelitis on MRI and was AQP4-IgG positive on serum studies. She received IV Methylprednisone 1 g daily for 3 days as a pulse and was continued on tapering doses of oral Prednisone with maintenance doses of Azathioprine. She showed slow improvements in limb motor function. Her daughter, case 2, is a 35-year-old HIV negative nutritionist, independently ambulant, with no known comorbidities or precedent autoimmune disease. She presented 1 year before her mother's AQP4-IgG positive NMOSD diagnosis with 7 months history of bilateral visual loss of rapid onset, with gadolinium-enhancing optic nerves on Brain and orbit MRI, in keeping with bilateral optic neuritis. She was AQP4-IgG positive on serum studies. She stabilized on tapered doses of oral Prednisone and continues daily oral Azathioprine with moderate improvement in her vision and no further relapses as yet. CONCLUSIONS: We add to existing literature and hypothesize that NMOSD appears to show a complex genetic background. To our knowledge, this is the first report in Sub-Saharan Africa, of familial AQP4-IgG positive NMOSD presenting with clinical heterogeneity between first degree relatives. A better understanding of the pathogenic mechanisms involved, including genome wide studies for particular risk loci for familial NMOSD, will be pivotal for future preventative and therapeutic strategies.

A Clinical Approach to Existing and Emerging Therapeutics in Neuromyelitis Optica Spectrum Disorder.

PURPOSE OF REVIEW: Neuromyelitis optica spectrum disorder (NMOSD) is a rare but highly disabling disease of the central nervous system. Unlike multiple sclerosis, disability in NMOSD occurs secondary to relapses that, not uncommonly, lead to blindness, paralysis, and death. Recently, newer, targeted immunotherapies have been trialed and are now in the treatment arsenal. We have endeavoured to evaluate the current state of NMOSD therapeutics. RECENT FINDINGS: This review provides a pragmatic evaluation of recent clinical trials and post-marketing data for rituximab, inebilizumab, satralizumab, eculizumab, and ravalizumab, contrasted to older agents. We also review contemporary issues such as treatment in the context of SARS-CoV2 infection and pregnancy. There has been a dramatic shift in NMOSD morbidity and mortality with earlier and improved disease recognition, diagnostic accuracy, and the advent of more effective, targeted therapies. Choosing a maintenance therapy remains nuanced depending on patient factors and accessibility. With over 100 putative agents in trials, disease-free survival is now a realistic goal for NMOSD patients.