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Lyme borreliosis (LB) and tick-borne encephalitis (TBE) are important tick-borne diseases in Europe. This study aimed to investigate the seroreactivity against Borrelia burgdorferi and TBE virus (TBEV) in tick-infested individuals in North Macedonia and Serbia. Serum samples were collected from tick-infested individuals and from healthy individuals in the same regions. Samples were tested for anti- Borrelia IgG reactivity and TBEV-neutralizing antibodies. Results showed higher seroreactivity against Borrelia antigens in patients and healthy donors from Novi Sad compared to those from the Skopje region. However, there was no statistically significant difference between tick-infested patients and healthy donors within each region. No TBEV-neutralizing antibodies were detected in participants from Novi Sad or in the control groups, except for one person from North Macedonia who had a moderate TBEV-neutralizing reaction. The study highlights the need for improved surveillance and diagnostic capabilities for LB and TBE in these regions. It also suggests the potential existence of TBEV foci in North Macedonia. The findings provide a complementary understanding of the LB and TBE epidemiology in the studied regions; however, further research is needed to investigate the presence and distribution of Borrelia spp. and TBEV in ticks to assess the significance of detected seroreactivity.

Background: Both greater retinal neurodegenerative pathology and greater cardiovascular burden are seen in people with multiple sclerosis (pwMS). Studies also describe multiple extracranial and intracranial vascular changes in pwMS. However, there have been few studies examining the neuroretinal vasculature in MS. Our aim is to determine differences in retinal vasculature between pwMS and healthy controls (HCs) and to determine the relationship between retinal nerve fiber layer (RNFL) thickness and retinal vasculature characteristics. Methods: A total of 167 pwMS and 48 HCs were scanned using optical coherence tomography (OCT). Earlier OCT scans were available for 101 pwMS and 35 HCs for an additional longitudinal analysis. Segmentation of retinal vasculature was performed in a blinded manner in MATLAB's optical coherence tomography segmentation and evaluation GUI (OCTSEG) software. Results: PwMS has fewer retinal blood vessels when compared to HCs (35.1 vs. 36.8, p = 0.017). Over the 5.4 year follow up, and when compared to HCs, pwMS has a significant decrease in number of retinal vessels (average loss of -3.7 p = 0.007). Moreover, the total vessel diameter in pwMS does not change when compared to the increase in vessel diameter in the HCs (0.06 vs. 0.3, p = 0.017). Only in pwMS is there an association between lower RNFL thickness and fewer retinal vessel number and smaller diameter (r = 0.191, p = 0.018 and r = 0.216, p = 0.007). Conclusions: Over 5 years, pwMS exhibit significant retinal vascular changes that are related to greater atrophy of the retinal layers.

Background: Persons with neuroinflammatory diseases (pwNID) treated with potent immunosuppressives are at risk of severe COVID-19 outcomes and reduced vaccine seroconversion. We aimed at determining the real-world efficacy of tixagevimab and cilgavimab (Evusheld™) in immunosuppressed pwNID in preventing breakthrough COVID-19 infections., Methods: 31 immunosuppressed pwNID were followed for 6 months after administration of tixagevimab and cilgavimab as a prophylactic COVID-19 medication (January 2022-July 2022). Only pwNID treated with anti-CD20 monoclonal antibodies and sphingosine-1-phosphate modulators were considered eligible for the study. A control group of 126 immunosuppressed pwNID (38 seropositive and 88 seronegative after SARS-CoV-2 vaccination) were included. Breakthrough COVID-19 infections rate and their severity was determined over the follow-up., Results: The pwNID treated with tixagevimab and cilgavimab had more comorbidities when compared with the total and seronegative pwNID control group (54.8% vs. 30.2% vs. 27.3%, p = 0.02 and p = 0.005, respectively). After a 6-month follow-up, significantly lower numbers of pwNID treated with tixagevimab and cilgavimab had breakthrough COVID-19 when compared with the control pwNID group (6.5% vs. 34.1%, p = 0.002) and seronegative control pwNID group (6.5% vs. 38.6%, p < 0.001). All COVID-19 infections in Evusheld-treated pwNID were mild, whereas 9/43 COVID-19 infections in the control group were moderate/severe. No side effects to tixagevimab and cilgavimab were recorded., Conclusion: In pwNID treated with immunosuppressive therapies, tixagevimab and cilgavimab (Evusheld™) significantly reduced the numbers and severity of breakthrough COVID-19 infections during the Omicron (BA.2-BA.5 variants) wave.

Background: To determine the effect of disease-modifying therapies (DMT) on humoral postvaccine seroconversion, long-term humoral response, and breakthrough COVID-19 infections in persons with multiple sclerosis (PwMS) and other neuroinflammatory disorders. Methods: A total of 757 PwMS and other neuroinflammatory disorders were recruited in two MS centers and vaccinated with one of the FDA-approved vaccines (BNT162b2, mRNA-1273, Ad26.COV2.S). The primary outcomes are the rate of humoral postvaccine seroconversion and anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) immunoglobulin G (IgG) differences between patients on different DMTs. Secondary measures include breakthrough infections and humoral response after six months. Other outcomes include differences in vaccine response between SARS-CoV-2 vaccines and the effects of age and comorbidities on the vaccine response. Results: A total of 465 (68.4%) PwMS and 55 (74.3%) patients with neuroinflammatory diseases were seropositive at 4−12 weeks after vaccination. A significant difference in seroconversion based on the DMT used at the time of vaccination (p < 0.001) was observed, with the lowest rates seen in patients treated with anti-CD20 antibodies (23.2%) and sphingosine-1-phosphate modulators (S1P) (30.8%). In seropositive patients, there was a significant decrease in anti-SARS IgG from mean 20.0 to 4.7 at six months (p = 0.004). Thirty-nine patients had breakthrough infection, but only two seronegative patients required hospitalization. mRNA vaccines resulted in significantly greater seroconversion compared to Ad26.COV2.S (p < 0.001). Older age and presence of cardiovascular comorbidities were associated with lower anti-SARS IgG (p = 0.021 and p = 0.003, respectively) Conclusions: PwMS and neuroinflammatory disorders treated with anti-CD20 and S1P medications have lower humoral response after anti-SARS-CoV-2 vaccination, even after booster dose. Waning of the humoral response puts vaccinated PwMS at a greater risk of COVID-19 breakthrough.

Aqueduct of Sylvius (AoS) cerebrospinal fluid flow can be quantified using phase-contrast (PC) Magnetic Resonance Imaging. The software used for AoS segmentation might affect the PC-derived measures. We analyzed AoS PC data of 30 people with multiple sclerosis and 19 normal controls using three software packages, and estimated cross-sectional area (CSA), average and highest AoS velocity (Vmean and Vmax), flow rate and volume. Our aims were to assess the repeatability and reproducibility of each PC-derived measure obtained with the various software packages, including in terms of group differentiation. All the variables had good repeatability, except the average Vmean, flow rate and volume obtained with one software package. Substantial to perfect agreement was seen when evaluating the overlap between the AoS segmentations obtained with different software packages. No variable was significantly different between software packages, with the exception of Vmean diastolic peak and CSA. Vmax diastolic peak differentiated groups, regardless of the software package. In conclusion, a clinical study should preliminarily evaluate the repeatability in order to interpret its findings. Vmax seemed to be a repeatable and reproducible measure, since the pixel with its value is usually located in the center of the AoS, and is thus unlikely be affected by ROI size.

Both perfusion-weighted imaging (PWI) measures and serum neurofilament light (sNfL) chain levels have been independently associated with disability in multiple sclerosis (MS) patients. This study aimed to determine whether these measures are correlated to each other or independently describe different MS processes. For this purpose, 3T MRI dynamic susceptibility contrast (DSC)-PWI and single-molecule assay (Simoa)-based sNfL methods were utilized when investigating 86 MS patients. The perfusion measures of mean transit time (MTT), cerebral blood volume (CBV), and cerebral blood flow (CBF) were derived for the normal-appearing whole brain (NAWB), the normal-appearing white matter (NAWM), the gray matter (GM), the deep GM (DGM), and the thalamus. The normalized CBV and CBF (nCBV and nCBV) were calculated by dividing by the corresponding NAWM measure. Age- and sex-adjusted linear regression models were used to determine associations between the DSC-PWI and sNfL results. False discovery rate (FDR)-adjusted p -values < 0.05 were considered statistically significant. A greater age and thalamic MTT were independently associated with higher sNfL levels ( p < 0.001 and p = 0.011) and explained 36.9% of sNfL level variance. NAWM MTT association with sNfL levels did not survive the FDR correction. In similar models, a lower thalamic nCBF and nCBV were both associated with greater sNfL levels ( p < 0.001 and p = 0.022), explaining 37.8% and 44.7% of the variance, respectively. In conclusion, higher sNfL levels were associated with lower thalamic perfusion.

Background : Multiple sclerosis (MS) is a chronic neuroinflammatory and neurodegenerative disease that is associated with multiple environmental factors. Among suspected susceptibility events, studies have questioned the potential role of overt viral and bacterial infections, including the Epstein Bar virus (EBV) and human endogenous retroviruses (HERV). Furthermore, the fast development of immunomodulatory therapies further questions the efficacy of the standard immunization policies in MS patients. Topics reviewe d: This narrative review will discuss the potential interplay between viral and bacterial infections and their treatment on MS susceptibility and disease progression. In addition, the review specifically discusses the interactions between MS pathophysiology and vaccination for hepatitis B, influenza, human papillomavirus, diphtheria, pertussis, and tetanus (DTP), and Bacillus Calmette-Guerin (BCG). Data regarding potential interaction between MS disease modifying treatment (DMT) and vaccine effectiveness is also reviewed. Moreover, HERV-targeted therapies such as GNbAC1 (temelimab), EBV-based vaccines for treatment of MS, and the current state regarding the development of T-cell and DNA vaccination are discussed. Lastly, a reviewing commentary on the recent 2019 American Academy of Neurology (AAN) practice recommendations regarding immunization and vaccine-preventable infections in the settings of MS is provided. Conclusion: There is currently no sufficient evidence to support associations between standard vaccination policies and increased risk of MS. MS patients treated with immunomodulatory therapies may have a lower benefit from viral and bacterial vaccination. Despite their historical underperformance, new efforts in creating MS-based vaccines are currently ongoing. MS vaccination programs follow the set back and slow recovery which is widely seen in other fields of medicine., Competing Interests: D.J. has nothing to declare. B.W-G. received honoraria as a speaker and as a consultant for Biogen Idec, Teva Pharmaceuticals, EMD Serono, Novartis, Genentech and Mallickrodt. B.W-G. received research funds from Biogen Idec, Teva Pharmaceuticals, EMD Serono, Novartis, Genentech and Mallinckrodt. M. R. received research funding or consulting fees from the National Multiple Sclerosis Society, the Department of Defense, the National Institutes of Health, National Science Foundation and Otuska Pharmaceutical Development. M.G.D. has received research grant support from Novartis and Keystone Heart. R. Z. received personal compensation from EMD Serono, Genzyme-Sanofi, Celgene and Novartis for speaking and consultant fees. He received financial support for research activities from Genzyme-Sanofi, Novartis, Celgene, Mapi Pharma, Keystone Heart and Protembis. None of the disclosures are related to this manuscript.