Orhan Aktas

Chronic relapsing inflammatory optic neuropathy (CRION) is a steroid-dependent form of optic neuritis with incompletely understood pathophysiology. The identification of myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) in a substantial patient subset has challenged the diagnostic and therapeutic management. The aim of this study was to investigate clinical profiles and treatment outcomes of patients with CRION, comparing MOG-IgG-positive (MOG+) and seronegative (MOG-) subgroups. Patients from 6 European tertiary centers fulfilling diagnostic criteria for CRION were included. All underwent cell-based autoantibody testing. Clinical outcomes (visual acuity and annualized relapse rate), laboratory and imaging findings (MRI, OCT), and treatment responses were retrospectively analyzed. Sixty patients were included (median age 33 years; 70% female); 27 (45%) were MOG+. MOG+ CRION was associated with later onset, higher annualized relapse rate (ARR) before treatment (median [IQR] 2 [1-3] vs 1 [1-2], p = 0.023), and a trend toward shorter interrelapse intervals. Additional distinguishing features included higher frequencies of antinuclear antibody positivity, elevated CSF interleukin-6, and extensive enhancement of the optic nerve on MRI. Relapse burden correlated with visual acuity decline and retinal thinning. In MOG+ patients, monoclonal antibody therapy reduced the ARR (n = 21; 2 [1-3] vs 0 [0-2], p = 0.024), primarily driven by tocilizumab (n = 11; 2 [1-3] vs 0 [0-1], p = 0.023). In MOG- patients, rituximab and azathioprine showed a trend toward ARR reduction. CRION represents a heterogeneous syndrome encompassing distinct subgroups. Although MOG+ patients demonstrate higher disease activity, tocilizumab might represent a therapeutic option, though further validation is needed. Serologic testing is critical for treatment stratification and preventing relapses.

Disability trajectories in aquaporin-4 immunoglobulin G-seropositive neuromyelitis optica spectrum disorder (AQP4-IgG+ NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are primarily driven by attack-related damage. Confirmed disability worsening (CDW) independent of attacks has been described but occurs infrequently in AQP4-IgG+ NMOSD and MOGAD. Confirmed disability improvement (CDI) has not been evaluated in large cohorts. We determined the frequency of CDI and CDW independent of attacks and identified clinical factors associated with these outcomes in AQP4-IgG+ NMOSD and MOGAD. This retrospective, multicenter cohort study analyzed data from the German Neuromyelitis Optica Study Group (NEMOS) registry. Adult patients with AQP4-IgG+ NMOSD or MOGAD and longitudinal Expanded Disability Status Scale (EDSS) assessments were included. EDSS episodes were defined as periods with ≥3 EDSS assessments without attacks, obtained ≥90 days after attack. CDW and CDI were defined as sustained EDSS increase or decrease (≥1.5 for baseline EDSS 0; ≥1.0 for EDSS 1.0-5.5; ≥0.5 for EDSS ≥6.0) confirmed after at least 6 months. The primary outcomes were annualized CDI and CDW rates. Risk factors were assessed using multivariable Anderson-Gill regression models. A total of 338 EDSS episodes of 307 patients (n: 202/105, median age at EDSS change: 56/41 years, 88/49% female, both p < 0.001; AQP4-IgG+ NMOSD/MOGAD) were included. Adjusted annualized CDI and CDW rates did not differ between AQP4-IgG+ NMOSD (CDI: 0.083, 95% CI 0.029-0.233; CDW: 0.025, 95% CI 0.007-0.092) and MOGAD (CDI: 0.057, 95% CI 0.012-0.277; CDW: 0.036, 95% CI 0.002-0.513). In AQP4-IgG+ NMOSD, a lower number of prior attacks was associated with higher CDI rates (hazard ratio [HR] 0.89, 95% CI 0.82-0.97). Younger age was associated with increased CDI rates in both AQP4-IgG+ NMOSD and MOGAD (HR 0.96, 95% CI 0.94-0.99, for both). CDI and CDW independent of attacks, although rare, occur in AQP4-IgG+ NMOSD and MOGAD. The association between fewer prior attacks and higher CDI rates in AQP4-IgG+ NMOSD underscores the importance of early attack prevention. Limitations include the retrospective design, and the limited number of CDI and CDW events.

Background: Chronic relapsing inflammatory optic neuropathy (CRION) is a steroid-dependent form of optic neuritis with incompletely understood pathophysiology. The identification of myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) in a substantial patient subset has challenged the diagnostic and therapeutic management. The aim of this study was to investigate clinical profiles and treatment outcomes of patients with CRION, comparing MOG-IgG-positive (MOG+) and seronegative (MOG-) subgroups. Methods: Patients from six European tertiary centers fulfilling diagnostic criteria for CRION were included. All underwent cell-based autoantibody testing. Clinical outcomes (visual acuity, annualized relapse rate), laboratory and imaging findings (MRI, OCT), and treatment responses were retrospectively analyzed. Results: Sixty patients were included (median age 33 years; 70% female); 27 (45%) were MOG+. MOG+ CRION was associated with later onset, higher ARR before treatment (median [IQR] 2 [1-3] vs. 1 [1-2], p = 0.023), and a trend toward shorter inter-relapse intervals. Additional distinguishing features included higher frequencies of antinuclear antibody positivity, elevated CSF interleukin-6, and extensive optic neuritis on MRI. Relapse burden correlated with visual acuity decline and retinal thinning. In MOG+ patients, monoclonal antibody therapy reduced the ARR (n = 21; 2 [1-3] vs. 0 [0-2], p = 0.024), primarily driven by tocilizumab (n = 11; 2 [1-3] vs. 0 [0-1], p = 0.023). In MOG-patients, rituximab and azathioprine showed a trend toward ARR reduction. Conclusion: CRION represents a heterogeneous syndrome encompassing distinct subgroups. MOG+ patients demonstrate higher disease activity but respond favorably to tocilizumab. Serological testing is critical for treatment stratification and preventing relapses.

Neuromyelitis optica spectrum disorder (NMOSD) is a severe autoimmune disease mainly driven by aquaporin-4 antibodies (AQP4-IgG). During an attack, AQP4-IgG activates the complement system, leading to astrocyte destruction, inflammation, neuronal damage, and thus devastating and often irreversible neurologic deficits. Terminal complement inhibitors such as eculizumab and ravulizumab effectively prevent relapses, yet their therapeutic potential in stopping ongoing complement-mediated injury during acute attacks remains insufficiently explored. We conducted a multinational retrospective case series across NMOSD-specialized centers in 6 countries, analyzing 33 AQP4-IgG-positive patients (mean age: 48.1 years; 28 women) treated with component 5 (C5) inhibition during or shortly after acute relapse (mean 20.1 days from symptom onset; range 2-62). Eculizumab was used in 25 patients and ravulizumab in 8. Two additional patients were excluded because of delayed treatment initiation beyond 62 days. Lesion locations included myelitis (57.6%) and optic neuritis (30.3%). Expanded Disability Status Scale scores worsened from a pre-relapse median of 0 (interquartile range [IQR] 0-2) to a nadir of 6.5 (IQR 3.5-8), improving to 3.5 (IQR 3-6.5) at 1-3 months and 2.5 (IQR 2-6) at 6 months. All patients stabilized clinically; 20 continued C5 inhibition as attack-preventing therapy. Good, moderate, and poor/absent recovery were observed in 15, 11, and 7 patients, respectively. Earlier treatment was associated with better outcomes: treatment within 21 days yielded an odds ratio of 1.58 (95% CI 0.32-8.52) for good response. Plasma exchange was administered in 57.6% and was associated with higher overall response rates, but not with good response alone. These findings highlight the potential of complement inhibition as a treatment option for acute NMOSD attacks, particularly in patients with insufficient response to standard therapies. Given the absence of clinical worsening and the encouraging course observed in most of the patients, further investigation into the role of C5 inhibition in acute attack management is warranted. This retrospective case series provides Class IV evidence that the C5 complement inhibitors eculizumab or ravulizumab may improve disability in patients with NMOSD when given during or shortly after acute relapse.

Severe optic neuritis (ON) is a common clinical manifestation in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and neuromyelitis optica spectrum disorder (NMOSD). Given distinct prognoses and often the necessity of early plasma exchange in NMOSD, prompt differentiation is crucial. In this study, we investigated the utility of optical coherence tomography (OCT) in differentiating between first acute NMOSD-ON and MOGAD-associated optic neuritis (MOGAD-ON), as well as specific factors associated with disc edema. In this retrospective multicenter study, 111 adult patients with MOGAD or aquaporin-4 antibody-positive NMOSD who experienced a first ON and underwent OCT within 2 weeks of symptom onset were included from 14 centers across 8 countries. Peripapillary retinal nerve fiber layer (pRNFL) thickness in µm was analyzed, including the average of both eyes in cases of bilateral manifestation. Eighty-three patients with MOGAD (51 women; 124 ON eyes; bilateral ON 48.2%) and 28 with NMOSD (24 women; 36 ON eyes; bilateral ON 21.4%) were enrolled. A significant increase in pRNFL thickness (>2SD), suggestive of disc edema, was observed in 73.4% of MOGAD-ON eyes and 11.1% of NMOSD-ON eyes (p < 0.001). The pRNFL thickness cutoff of 117.5 µm provided 92.9% specificity and 71.1% sensitivity in distinguishing between MOGAD-ON and NMOSD-ON (area under the curve = 0.838). There was no association between pRNFL thickening and MOG-IgG titer (high vs low), body mass index, or the delay between ON onset and OCT. Simultaneous bilateral MOGAD-ON was associated with significantly more pronounced pRNFL thickening. Acute-stage OCT contributes to the rapid and accurate differentiation between MOGAD-ON and NMOSD-ON prior to antibody confirmation, which can be critical for timely therapeutic decisions.

Background/Objectives: Neuromyelitis Optica Spectrum disorder (NMOSD) is a rare, autoimmune disease of the central nervous system with a globally heterogeneous prevalence/ To estimate the prescription-based prevalence of NMOSD in Greece and determine the use of long-term immunotherapies and concomitant medications in these patients. Methods: We analyzed anonymized prescription records from the national prescription database, dating from 1 January 2017 to 1 May 2024. The administrative point prevalence of NMOSD in Greece on 1 January 2022 was calculated according to the national census conducted in late 2021. Results: We identified 219 cases of NMOSD and a 1:6.8 male-to-female ratio. The point prevalence on 1 January 2022 was 1.97 per 100,000, with the highest detected in the region of Crete, and the lowest in the regions of Eastern Macedonia and Thrace. The mean age of people with NMOSD on that date was 51.3 years old. Azathioprine was the most frequently prescribed maintenance immunotherapy, while antidepressants were the most common concomitant medications prescribed. Polypharmacy was observed in 28.9% of the identified cases. Conclusions: We hereby present the prescription drug use of people with NMOSD in Greece in the era just before the introduction of NMOSD-specific immunotherapy in Greece.

DNA damage is a major risk factor for the decline of neuronal functions with age and neurodegenerative diseases. The connection between DNA damage and neurodegeneration is extensively investigated, however, the mechanisms limiting the propagation of damaged DNA from highly replicative neural stem/progenitor cells (NSPCs) to post-mitotic neurons remains largely unknown. Here, we describe that enzymatic activity of the histone deacetylase sirtuin 1 (SIRT1) is important for the homologues recombination-dependent repair of double- stranded DNA breaks induced by etoposide. Furthemore, SIRT1 abolishes neuronal fate of murine NSPCs following induction of DNA damage. Pharmacological inhibition or genetic inactivation of SIRT1 rescues etoposide-mediated inhibition of neuronal differentiation in NSPCs and hippocampal slice cultures and promotes transcription of pro-neuronal genes. Inhibition of Ataxia-telangiectasia mutated (ATM), the central regulator of the DNA damage response, mimics the SIRT-dependent effect of DNA damage on neuronal differentiation, indicating that the ATM/SIRT1 axis inhibits formation of neuronal cells harbouring damaged DNA. These data are consistent with the role of SIRT1 in genome stability, healthy ageing and protection from the development of ageing-associated neurodegenerative diseases.