Neuromyelitis optica spectrum disorders (NMOSD) include a rare group of autoimmune conditions that primarily affect the central nervous system. They are characterized by inflammation and damage to the optic nerves, brain and spinal cord, leading to severe vision impairment, locomotor disability and sphynteric disturbances. In the majority of cases, NMOSD arises due to specific serum immunoglobulin G (IgG) autoantibodies targeting aquaporin 4 (AQP4-IgG), which is the most prevalent water-channel protein of the central nervous system. Early diagnosis and treatment are crucial to manage symptoms and prevent long-term disability in NMOSD patients. NMOSD were previously associated with a poor prognosis. However, recently, a number of randomized controlled trials have demonstrated that biological therapies acting on key elements of NMOSD pathogenesis, such as B cells, interleukin-6 (IL-6) pathway, and complement, have impressive efficacy in preventing the occurrence of clinical relapses. The approval of the initial drugs marks a revolutionary advancement in the treatment of NMOSD patients, significantly transforming therapeutic options and positively impacting their prognosis. In this review, we will provide an updated overview of the key immunopathological, clinical, laboratory, and neuroimaging aspects of NMOSD. Additionally, we will critically examine the latest advancements in NMOSD treatment approaches. Lastly, we will discuss key aspects regarding optimization of treatment strategies and their monitoring.

UNASSIGNED: Neuromyelitis optica spectrum disorder (NMOSD) is a central nervous system demyelinating disease. Current therapy methods, however, have limited effect on acute attacks except for intravenous methylprednisolone (IVMP). Efgartigimod is a first-in-class novel human immunoglobulin G1 (IgG1) Fc fragment approved for the treatment of generalized myasthenia gravis. Its capacity to rapidly decrease serum IgG levels, including pathogenic autoantibodies, positions it as a potentially effective option for managing the acute phase of NMOSD.
UNASSIGNED: We report the case of a 59-year-old female patient with acute NMOSD, presenting with vision loss and numbness in all four limbs. Despite an initial inadequate response to intravenous methylprednisolone (IVMP), the addition of Efgartigimod to her treatment regimen led to rapid improvement, notably including a significant reduction in serum aquaporin-4 antibody titers, total IgG levels, and inflammation cytokine levels. Furthermore, no adverse events were reported during a four-month follow-up period.
UNASSIGNED: As an adjunct to glucocorticoid therapy, Efgartigimod has proven effective and safe for this patient. However, to ascertain its potential as a novel therapeutic option for acute NMOSD, larger-scale prospective clinical trials are required.

OBJECTIVE: The Italian Island of Sardinia (population, 1,578,146) is recognized for the high risk of multiple sclerosis (MS) but the epidemiological burden of other less common demyelinating diseases of the central nervous system (CNS), such as aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4-IgG+NMOSD), is unknown. In this study, we determined the incidence and prevalence of AQP4-IgG+NMOSD in Sardinia over a ten-year study period (2013-2022).
METHODS: Patients with a diagnosis of AQP4-IgG+NMOSD (per 2015 IPND diagnostic criteria) were retrospectively identified using two sources: (1) Archives of the reference and only laboratory for AQP4-IgG testing in Sardinia; and (2) medical records of the four MS units in the island. Incidence (January 2013-December 2022) and prevalence (December 31, 2022) were calculated.
RESULTS: A total of 45 cases were included: incident, 31; prevalent, 41. The median age (range) at disease presentation was 51 (6-78) years; female/male ratio was 9:1. The crude (95 % CI) incidence and prevalence were 1.9 (1.3-2.7) per million and 2.6 (1.9-3.5) per 100,000, respectively. Prevalence increased from 2013 (1.1 per 100,000) to 2022 (2.6 per 100,000); p = 0.002. After age-standardization to the world, incidence and prevalence (95 % CI) decreased to 1.3 (0.7-2) per million and 1.8 (1.3-2.3) per 100,000, respectively. Coexisting immune-mediated disorders, mostly autoimmune thyroiditis, were reported in 50 % of patients.
CONCLUSIONS: The epidemiology of AQP4-IgG+NMOSD in Sardinia is overall in line with other Caucasian populations. The high MS risk in the island seems disease-specific and not associated with an increased risk of other CNS demyelinating disorders, confirming different pathophysiology.

UNASSIGNED: Aquaporin-4-antibody-seropositive (AQP4-IgG+) Neuromyelitis Optica Spectrum Disorder (NMOSD) and Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disorder (MOGAD) are relapsing neuroinflammatory diseases, frequently leading to chronic pain. In both diseases, the spinal cord (SC) is often affected by myelitis attacks. We hypothesized that regional SC volumes differ between AQP4-IgG + NMOSD and MOGAD and that pain intensity is associated with lower SC volumes. To evaluate changes in the SC white matter (WM), gray matter (GM), and pain intensity in patients with recent relapses (myelitis or optic neuritis), we further profiled phenotypes in a case series with longitudinal imaging and clinical data.
UNASSIGNED: Cross-sectional data from 36 participants were analyzed in this retrospective study, including 20 AQP4-IgG + NMOSD and 16 MOGAD patients. Pain assessment was performed in all patients by the Brief Pain Inventory and painDETECT questionnaires. Segmentation of SC WM, GM, cervical cord volumes (combined volume of WM + GM) was performed at the C2/C3 cervical level. WM% and GM% were calculated using the cervical cord volume as a whole per patient. The presence of pain, pain severity, and clinical disability was evaluated and tested for associations with SC segmentations. Additionally, longitudinal data were deeply profiled in a case series of four patients with attacks between two MRI visits within one year.
UNASSIGNED: In AQP4-IgG + NMOSD, cervical cord volume was associated with mean pain severity within 24 h (β = -0.62, p = 0.009) and with daily life pain interference (β = -0.56, p = 0.010). Cross-sectional analysis showed no statistically significant SC volume differences between AQP4-IgG + NMOSD and MOGAD. However, in AQP4-IgG + NMOSD, SC WM% tended to be lower with increasing time from the last attack (β = -0.41, p = 0.096). This tendency was not observed in MOGAD. Our case series including two AQP4-IgG + NMOSD patients revealed SC GM% increased by roughly 2% with either a myelitis or optic neuritis attack between visits. Meanwhile, GM% decreased by 1-2% in two MOGAD patients with a myelitis attack between MRI visits.
UNASSIGNED: In AQP4-IgG + NMOSD, lower cervical cord volume was associated with increased pain. Furthermore, cord GM changes were detected between MRI visits in patients with disease-related attacks in both groups. Regional SC MRI measures are pertinent for monitoring disease-related cord pathology in AQP4-IgG + NMOSD and MOGAD.

Anti-aquaporin-4 autoantibodies (AQP4-IgG) are implicated in the pathogenesis of neuromyelitis optica spectrum disorders (NMOSD), and their removal from the blood circulation is considered to be an effective method for acute treatment. An ideal extracorporeal AQP4-IgG removal system should have high specificity, which means that it can selectively remove AQP4-IgG without affecting normal immunoglobulins. However, the conventional tryptophan immobilized column lacks sufficient specificity and cannot achieve this goal. In this study, we successfully prepared a fusion protein chimeric AQP4, which consists of the complete antigenic epitopes of human AQP4 and the constant region of scaffold protein DARPin. Chimeric AQP4 was expressed and purified from Escherichia coli, and then immobilized on agarose gel as a ligand for selective capture of AQP4-IgG immunosorbent. The prepared immunosorbent had a theoretical maximum adsorption capacity of 20.48 mg/g gel estimated by Langmuir isotherm. In vitro plasma perfusion tests demonstrated that the chimeric AQP4 coupled adsorbent had remarkable adsorption performance, and could eliminate more than 85 % of AQP4-IgG under the gel-to-plasma ratio of 1:50. Moreover, it exhibited high specificity because other human plasma proteins were not adsorbed in the dynamic adsorption experiment. These results suggest that the chimeric AQP4 coupled immunosorbent can provide a new approach for specific immunoadsorption (IA) treatment of NMOSD.

Aquaporin-4-IgG positive neuromyelitis optica spectrum disorder (AQP4+NMOSD) and myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are antibody-associated diseases targeting astrocytes and oligodendrocytes, respectively. Their recognition as distinct entities has led to each having its own diagnostic criteria that require a combination of clinical, serologic, and MRI features. The therapeutic approach to acute attacks in AQP4+NMOSD and MOGAD is similar. There is now class 1 evidence to support attack-prevention medications for AQP4+NMOSD. MOGAD lacks proven treatments although clinical trials are now underway. In this review, we will outline similarities and differences between AQP4+NMOSD and MOGAD in terms of diagnosis and treatment.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare relapsing neuroinflammatory autoimmune astrocytopathy, with a predilection for the optic nerves and spinal cord. Most cases are characterised by aquaporin-4-antibody positivity and have a relapsing disease course, which is associated with accrual of disability. Although the prognosis in NMOSD has improved markedly over the past few years owing to advances in diagnosis and therapeutics, it remains a severe disease. In this article, we review the evolution of our understanding of NMOSD, its pathogenesis, clinical features, disease course, treatment options and associated symptoms. We also address the gaps in knowledge and areas for future research focus.

BACKGROUND: Neuromyelitis Optica spectrum disorder (NMOSD) is an antibody-mediated autoimmune disease of the CNS, which especially affects the optic nerves and spinal cord. There is little known in Latin America (LATAM) about NMOSD, and few reports have been published in the literature so far. We aimed to describe an NMOSD study in a single center from Argentina.
METHODS: A retrospective cross sectional study was carried out in a single reference center in the city of Buenos Aires, Argentina. Data were collected from January 2000 through December 2021 using medical records from patients attending Ramos Mejia Hospital in Buenos Aires, Argentina. Here we describe the clinical, laboratory, MRI, disability course, and treatment of 92 NMOSD patients.
RESULTS: Mean age at the onset of symptoms was 31 years (range 2-68) with a female/male ratio of 4.8:1. 71.7 % had an early onset before the age of 50 years old, 8.7 % had a late onset of the disease and 19.6 % had an onset at pediatric age. The first symptom of NMOSD was optic neuritis in 47.8 % of the patients, followed by transverse myelitis, 33.7 % and area postrema syndrome, 5.4 %. 96.7 % of patients relapsed at least once during the follow-up period. The mean of the expanded disability status scale (EDSS) was 4.0 (range 2-8). 34,8 % had one or more associated autoimmune diseases. 78,6 % had a positive result for AQP4-IgG. The ratio of male to female was 1:8.4 vs.1:1.2 in the seropositive group vs. the seronegative. CSF results showed OCB type 2 in 6.3 %. The brain MRI did not show brain lesions in 71,7 % of the patients. 17 % presented spinal cord lesions with less than 3 vertebral segments. All patients received treatment with immunosuppressive drugs. Rituximab and azathioprine were the most used.
CONCLUSIONS: This is the largest hospital-based study in an Argentina cross-sectional study of patients with NMOSD. Recurrent disease, early age at onset, female prevalence in AQP4-IgG+ patients, and the difficulty to assess new treatments, are the highlight features in our study of patients. Further Argentinian and LATAM studies will provide more information.

Most patients with neuromyelitis optica spectrum disorders (NMOSD) test positive for aquaporin-4 antibody (AQP4-IgG) or myelin oligodendrocyte glycoprotein antibodies (MOG-IgG). Those who are negative are termed double-negative (DN) NMOSD and may constitute a diagnostic and therapeutic challenge. DN NMOSD is a syndrome rather than a single disease, ranging from a (postinfectious) monophasic illness to a more chronic syndrome that can be indistinguishable from AQP4-IgG+ NMOSD or develop into other mimics such as multiple sclerosis. Thus, underlying disease mechanisms are likely to be heterogeneous. This topical review aims to (1) reappraise antibody-negative NMOSD definition as it has changed over time with the development of the AQP4 and MOG-IgG assays; (2) outline clinical characteristics and the pathophysiological nature of this rare entity by contrasting its differences and similarities with antibody-positive NMOSD; (3) summarize laboratory characteristics and magnetic resonance imaging findings of DN NMOSD; and (4) discuss the current treatment for DN NMOSD.

Antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) or aquaporin 4 (AQP4-IgG) are associated with CNS inflammatory disorders. We directly compared MOG35-55-induced experimental autoimmune encephalomyelitis exacerbated by MOG- and AQP4-IgG (versus isotype IgG, Iso-IgG). Disease severity was highest after MOG-IgG application. MOG- and AQP4-IgG administration increased disease incidence compared to Iso-IgG. Inflammatory lesions appeared earlier and with distinct localizations after AQP4-IgG administration. AQP4 intensity was more reduced after AQP4- than MOG-IgG administration at acute disease phase. The described models are suitable for comparative analyses of pathological features associated with MOG- and AQP4-IgG and the investigation of therapeutic interventions.