Time to Disability Milestones and Annualized Relapse Rates in NMOSD and MOGAD.

OBJECTIVE: To investigate accumulation of disability in neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein-antibody-associated disease (MOGAD) in a changing treatment landscape. We aimed to identify risk factors for the development of disability milestones in relation to disease duration, number of attacks, and age. METHODS: We analyzed data from individuals with NMOSD and MOGAD from the German Neuromyelitis Optica Study Group registry. Applying survival analyses, we estimated risk factors and computed time to disability milestones as defined by the Expanded Disability Status Score (EDSS). RESULTS: We included 483 patients: 298 AQP4-IgG+ NMOSD, 52 AQP4-IgG-/MOG-IgG- NMOSD patients, and 133 patients with MOGAD. Despite comparable annualized attack rates, disability milestones occurred earlier and after less attacks in NMOSD patients than MOGAD patients (median time to EDSS 3: AQP4-IgG+ NMOSD 7.7 (95% CI 6.6-9.6) years, AQP4-IgG-/MOG-IgG- NMOSD 8.7) years, MOGAD 14.1 (95% CI 10.4-27.6) years; EDSS 4: 11.9 (95% CI 9.7-14.7), 11.6 (95% lower CI 7.6) and 20.4 (95% lower CI 14.1) years; EDSS 6: 20.1 (95% CI 16.5-32.1), 20.7 (95% lower CI 11.6), and 37.3 (95% lower CI 29.4) years; and EDSS 7: 34.2 (95% lower CI 31.1) for AQP4-IgG+ NMOSD). Higher age at onset increased the risk for all disability milestones, while risk of disability decreased over time. INTERPRETATION: AQP4-IgG+ NMOSD, AQP4-IgG-/MOG-IgG- NMOSD, and MOGAD patients show distinctive relapse-associated disability progression, with MOGAD having a less severe disease course. Investigator-initiated research has led to increasing awareness and improved treatment strategies appearing to ameliorate disease outcomes for NMOSD and MOGAD. ANN NEUROL 2024;95:720-732.

Cognition in patients with myelin oligodendrocyte glycoprotein antibody-associated disease: a prospective, longitudinal, multicentre study of 113 patients (CogniMOG-Study).

BACKGROUND: Data on cognition in patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are limited to studies with small sample sizes. Therefore, we aimed to analyse the extent, characteristics and the longitudinal course of potential cognitive deficits in patients with MOGAD. METHODS: The CogniMOG-Study is a prospective, longitudinal and multicentre observational study of 113 patients with MOGAD. Individual cognitive performance was assessed using the Paced Auditory Serial Addition Task (PASAT), the Symbol Digit Modalities Test (SDMT) and the Multiple Sclerosis Inventory Cognition (MuSIC), which are standardised against normative data from healthy controls. Cognitive performance was assessed at baseline and at 1-year and 2-year follow-up assessments. Multiple linear regression was used to analyse demographic and clinical predictors of cognitive deficits identified in previous correlation analyses. RESULTS: At baseline, the study sample of MOGAD patients showed impaired standardised performance on MuSIC semantic fluency (mean=-0.29, 95% CI (-0.47 to -0.12)) and MuSIC congruent speed (mean=-0.73, 95% CI (-1.23 to -0.23)). Around 1 in 10 patients showed deficits in two or more cognitive measures (11%). No decline in cognition was observed during the 1-year and 2-year follow-up period. Cerebral lesions were found to be negatively predictive for SDMT (B=-8.85, 95% CI (-13.57 to -4.14)) and MuSIC semantic fluency (B=-4.17, 95% CI (-6.10 to -2.25)) test performance. CONCLUSIONS: Based on these data, we conclude that MOGAD patients show reduced visuomotor processing speed and semantic fluency to the extent that the disease burden includes cerebral lesions.

Apheresis therapies in MOGAD: a retrospective study of 117 therapeutic interventions in 571 attacks.

BACKGROUND: Incomplete attack remission is the main cause of disability in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Apheresis therapies such as plasma exchange and immunoadsorption are widely used in neuroimmunology. Data on apheresis outcomes in MOGAD attacks remain limited. METHODS: We retrospectively evaluated all apheresis treated attacks occurring in patients with MOGAD between 2008 and 2023 at 18 Neuromyelitis Optica Study Group centres. Treatment response was categorised as complete, partial or no remission. Preattack and follow-up Expanded Disability Status Scale (EDSS) and visual Functional System Scores (FSS) were used to calculate absolute outcomes (ΔEDSS/Δvisual FSS). Predictors of complete remission were analysed using a generalised linear mixed model. RESULTS: Apheresis was used for 117/571 (20.5%) attacks in 85/209 (40.7%) patients. Attacks with simultaneous optic neuritis and myelitis were treated more often with apheresis (42.4%, n=14) than isolated myelitis (25.2%, n=35), cerebral manifestation (21.0%, n=17) or isolated optic neuritis (17.6%, n=51). Apheresis was initiated as first-line therapy in 12% (4.5 (IQR 0-11) days after attack onset), second-line therapy in 62% (15 (IQR 6.75-31) days) and third-line therapy in 26% (30 (IQR 19-42) days). Complete remission was achieved in 21%, partial remission in 70% and no remission in 9% of patients. First-line apheresis (OR 2.5, p=0.040) and concomitant disease-modifying therapy (OR 1.5, p=0.011) were associated with complete remission. Both parameters were also associated with a favourable ΔEDSS. No differences in outcomes were observed between the apheresis types. CONCLUSION: Apheresis is frequently used in MOGAD attacks. An early start as first-line therapy and concomitant disease-modifying therapy predict full attack recovery.

Therapy challenges for NMOSD in a patient with HIV.

Neuromyelitis optica spectrum disorder (NMOSD) in people living with HIV (PLWH) is rare and its management can be difficult. Here we report a case of an HIV patient with bilateral vision loss, who was diagnosed with AQP4-IgG-positive NMOSD in 2020 during the COVID-19 pandemic. Rituximab treatment was initiated after attack therapy with corticosteroids and plasma exchange. NMOSD and HIV disease remained stable, but SARS-CoV-2 immune response after repeated vaccinations was insufficient. After switching immunotherapy due to the lack of vaccination response to satralizumab, peripheral B cells reoccurred and a humoral immune response was observed after reapplication of SARS-CoV-2 vaccination. This case illustrates the challenges associated with the treatment of NMOSD in PLWH.

The peer teachers' perception of intrinsic motivation and rewards.

Peer-assisted learning (PAL) is an educational method commonly applied in academic teaching. It is characterized by the interplay between peer teachers and learners who are at a similar academic level. Although it has been shown that peer teachers benefit from participating in PAL, little is known about their perception of motivation and rewards. Here we designed a questionnaire and measured the perception of intrinsic motivation and rewards of peer teachers from three different PAL programs. Overall, peer teachers were highly intrinsically motivated. The reward category Supporting Others was appreciated the most, followed by the reward categories Self-Improvement, Feedback, and Financial. The perception of rewards reflected the features of the three PAL programs. For example, the item "learning the teaching matter themselves" was most valued by peer teachers who were enrolled in a PAL program that deployed their peer teachers primarily to convey knowledge. In contrast, "actively shaping the teaching situation" was appreciated most by peer teachers of the PAL program that enables their peer teachers to conceive their teaching sessions independently. These findings go toward recommendations of the implementation and further development of PAL programs. If PAL programs clearly define their features and aims, they could specifically attract (and select) peer teachers and meet their needs as well as expectations, providing opportunities to gain knowledge and teaching experience. Ultimately, these PAL programs could better support the learners.

Peer teaching beyond the formal medical curriculum.

Peer-assisted learning (PAL) is nowadays commonly implemented in medical education. Mostly PAL is utilized to specifically support teaching within one subject or a specific curricular situation. Here, we present a large-scale peer teaching program that aims to address the individual student's learning needs. In addition, it provides a platform for students to participate in academic teaching. A retrospective data analysis was performed to reveal the program's development and acceptance. The program was implemented in 2008/09 with three tutorials conducted by 24 student tutors to support students preparing for reexaminations. Since then, the program has continuously grown. In 2015/16, 140 tutors conducted 52 tutorials, consisting of 2,750 lessons for 1,938 tutees. New tutorial categories were continuously introduced. In 2015/16, these encompassed tutorials that were held concomitantly to the formal curriculum, tutorials that exceeded the contents of the formal curriculum, tutorials for preparation for the state examination, and electives. Evaluations among the tutees revealed that 93.5% of the respondents rated the courses overall as "good" or "excellent" ( n = 13,489) in 2015/16. All elements of the peer teaching program are managed by one academic group. This encompasses the organization of tutorials, the quality management, and the qualification of tutors, including content-related supervision and didactic training. We conclude that the implementation of a large-scale peer teaching program can complement the formal curriculum. This might be beneficial for both tutors who can actively train their didactic and content-related competencies, and tutees who can autonomously consolidate and expand their knowledge.

Is there an immunological cross-reactivity of antibodies to the myelin oligodendrocyte glycoprotein and coronaviruses?

Recent reports indicated that myelin oligodendrocyte glycoprotein antibody-associated disease might be a rare complication after severe acute respiratory syndrome coronavirus 2 infection or vaccination. It is unclear whether this is an unspecific sequel of infection or vaccination or caused by possible immunological cross-reactivity of severe acute respiratory syndrome coronavirus 2 proteins and myelin oligodendrocyte glycoprotein. The aim of this study was therefore to elucidate whether there is an immunological cross-reactivity between severe acute respiratory syndrome coronavirus 2 spike or nucleocapsid proteins and myelin oligodendrocyte glycoprotein and to explore the relation of antibody responses against myelin oligodendrocyte glycoprotein and severe acute respiratory syndrome coronavirus 2 and other coronaviruses. We analysed serum samples from patients with severe acute respiratory syndrome coronavirus 2 infection and neurological symptoms with (myelin oligodendrocyte glycoprotein antibody-associated disease, n = 12) or without myelin oligodendrocyte glycoprotein-antibodies (n = 10); severe acute respiratory syndrome coronavirus 2 infection without neurological symptoms (n = 32); vaccinated patients with no history of severe acute respiratory syndrome coronavirus 2 infection and neurological symptoms with (myelin oligodendrocyte glycoprotein antibody-associated disease, n = 10) or without myelin oligodendrocyte glycoprotein-antibodies (n = 9); and severe acute respiratory syndrome coronavirus 2 negative/naïve unvaccinated patients with neurological symptoms with (myelin oligodendrocyte glycoprotein antibody-associated disease, n = 47) or without myelin oligodendrocyte glycoprotein-antibodies (n = 20). All samples were analysed for serum antibody responses to myelin oligodendrocyte glycoprotein, severe acute respiratory syndrome coronavirus 2, and other common coronaviruses (CoV-229E, CoV-HKU1, CoV-NL63 and CoV-OC43). Based on sample amount and antibody titres, 21 samples were selected for analysis of antibody cross-reactivity between myelin oligodendrocyte glycoprotein and severe acute respiratory syndrome coronavirus 2 spike and nucleocapsid proteins using affinity purification and pre-absorption. Whereas we found no association of immunoglobulin G and A myelin oligodendrocyte glycoprotein antibodies with coronavirus antibodies, infections with severe acute respiratory syndrome coronavirus 2 correlated with an increased immunoglobulin M myelin oligodendrocyte glycoprotein antibody response. Purified antibodies showed no cross-reactivity between severe acute respiratory syndrome coronavirus 2 spike protein and myelin oligodendrocyte glycoprotein. However, one sample of a patient with myelin oligodendrocyte glycoprotein antibody-associated disease following severe acute respiratory syndrome coronavirus 2 infection showed a clear immunoglobulin G antibody cross-reactivity to severe acute respiratory syndrome coronavirus 2 nucleocapsid protein and myelin oligodendrocyte glycoprotein. This patient was also seropositive for other coronaviruses and showed immunological cross-reactivity of severe acute respiratory syndrome coronavirus 2 and CoV-229E nucleocapsid proteins. Overall, our results indicate that an immunoglobulin G antibody cross-reactivity between myelin oligodendrocyte glycoprotein and severe acute respiratory syndrome coronavirus 2 proteins is rare. The presence of increased myelin oligodendrocyte glycoprotein-immunoglobulin M antibodies after severe acute respiratory syndrome coronavirus 2 infection may either be a consequence of a previous infection with other coronaviruses or arise as an unspecific sequel after viral infection. Furthermore, our data indicate that myelin oligodendrocyte glycoprotein-immunoglobulin A and particularly myelin oligodendrocyte glycoprotein-immunoglobulin M antibodies are a rather unspecific sequel of viral infections. Finally, our findings do not support a causative role of coronavirus infections for the presence of myelin oligodendrocyte glycoprotein-immunoglobulin G antibodies.

Early Neuroaxonal Damage in Neurologic Disorders Associated With GAD65 Antibodies.

OBJECTIVES: Neurodegeneration is considered a relevant pathophysiologic feature in neurologic disorders associated with antibodies against glutamic acid decarboxylase 65 (GAD65). In this study, we investigate surrogates of neuroaxonal damage in relation to disease duration and clinical presentation. METHODS: In a multicentric cohort of 50 patients, we measured serum neurofilament light chain (sNfL) in relation to disease duration and disease phenotypes, applied automated MRI volumetry, and analyzed clinical characteristics. RESULTS: In patients with neurologic disorders associated with GAD65 antibodies, we detected elevated sNfL levels early in the disease course. By contrast, this elevation of sNfL levels was less pronounced in patients with long-standing disease. Increased sNfL levels were observed in patients presenting with cerebellar ataxia and limbic encephalitis, but not in those with stiff person syndrome. Using MRI volumetry, we identified atrophy predominantly of the cerebellar cortex, cerebellar superior posterior lobe, and cerebral cortex with similar atrophy patterns throughout all clinical phenotypes. DISCUSSION: Together, our data provide evidence for early neuroaxonal damage and support the need for timely therapeutic interventions in GAD65 antibody-associated neurologic disorders.

Targeting the TCA cycle can ameliorate widespread axonal energy deficiency in neuroinflammatory lesions.

Inflammation in the central nervous system can impair the function of neuronal mitochondria and contributes to axon degeneration in the common neuroinflammatory disease multiple sclerosis (MS). Here we combine cell-type-specific mitochondrial proteomics with in vivo biosensor imaging to dissect how inflammation alters the molecular composition and functional capacity of neuronal mitochondria. We show that neuroinflammatory lesions in the mouse spinal cord cause widespread and persisting axonal ATP deficiency, which precedes mitochondrial oxidation and calcium overload. This axonal energy deficiency is associated with impaired electron transport chain function, but also an upstream imbalance of tricarboxylic acid (TCA) cycle enzymes, with several, including key rate-limiting, enzymes being depleted in neuronal mitochondria in experimental models and in MS lesions. Notably, viral overexpression of individual TCA enzymes can ameliorate the axonal energy deficits in neuroinflammatory lesions, suggesting that TCA cycle dysfunction in MS may be amendable to therapy.

Phagocyte-mediated synapse removal in cortical neuroinflammation is promoted by local calcium accumulation.

Cortical pathology contributes to chronic cognitive impairment of patients suffering from the neuroinflammatory disease multiple sclerosis (MS). How such gray matter inflammation affects neuronal structure and function is not well understood. In the present study, we use functional and structural in vivo imaging in a mouse model of cortical MS to demonstrate that bouts of cortical inflammation disrupt cortical circuit activity coincident with a widespread, but transient, loss of dendritic spines. Spines destined for removal show local calcium accumulations and are subsequently removed by invading macrophages or activated microglia. Targeting phagocyte activation with a new antagonist of the colony-stimulating factor 1 receptor prevents cortical synapse loss. Overall, our study identifies synapse loss as a key pathological feature of inflammatory gray matter lesions that is amenable to immunomodulatory therapy.

A method to investigate non-thermal effects of radio frequency radiation on pharmaceuticals with relevance to RFID technology.

A method is reported to accurately and precisely control temperature of a solution sample to investigate non-thermal effects of radio frequency radiation (RFR) on pharmaceuticals. This method utilizes a transverse electromagnetic (TEM) cell connected in series with a radiation source. The temperature of a sample under study, within the TEM cell, is regulated using a combination of a fiber-optic thermometer and thermo-electric cooler. It is shown that the sample temperature can be accurately controlled and maintained even under conditions where the RFR can increase the sample temperature via thermal mode. This methodology provides a well-controlled approach to investigate the non-thermal effects of RFR for a range of incident power intensities and frequencies and initial sample temperatures.