HLA dependency and possible clinical relevance of intrathecally synthesized anti-IgLON5 IgG4 in anti-IgLON5 disease.

Background: Anti-IgLON5 disease is a rare chronic autoimmune disorder characterized by IgLON5 autoantibodies predominantly of the IgG4 subclass. Distinct pathogenic effects were described for anti-IgLON5 IgG1 and IgG4, however, with uncertain clinical relevance. Methods: IgLON5-specific IgG1-4 levels were measured in 46 sera and 20 cerebrospinal fluid (CSF) samples from 13 HLA-subtyped anti-IgLON5 disease patients (six females, seven males) using flow cytometry. Intervals between two consecutive serum or CSF samplings (31 and 10 intervals, respectively) were categorized with regard to the immunomodulatory treatment active at the end of the interval, changes of anti-IgLON5 IgG1 and IgG4 levels, and disease severity. Intrathecal anti-IgLON5 IgG4 synthesis (IS) was assessed using a quantitative method. Results: The median age at onset was 66 years (range: 54-75), disease duration 10 years (range: 15-156 months), and follow-up 25 months (range: 0-83). IgLON5-specific IgG4 predominance was observed in 38 of 46 (83%) serum and 11 of 20 (55%) CSF samples. Anti-IgLON5 IgG4 levels prior clinical improvement in CSF but not serum were significantly lower than in those prior stable/progressive disease. Compared to IgLON5 IgG4 levels in serum, CSF levels in HLA-DRB1*10:01 carriers were significantly higher than in non-carriers. Indeed, IgLON5-specific IgG4 IS was demonstrated not only in four of five HLA-DRB1*10:01 carriers but also in one non-carrier. Immunotherapy was associated with decreased anti-IgGLON5 IgG serum levels. In CSF, lower anti-IgLON5 IgG was associated with immunosuppressive treatments used in combination, that is, corticosteroids and/or azathioprine plus intravenous immunoglobulins or rituximab. Conclusion: Our findings might indicate that CSF IgLON5-specific IgG4 is frequently produced intrathecally, especially in HLA-DRB1*10:01 carriers. Intrathecally produced IgG4 may be clinically relevant. While many immunotherapies reduce serum IgLON5 IgG levels, more intense immunotherapies induce clinical improvement and may be able to target intrathecally produced anti-IgLON5 IgG. Further studies need to confirm whether anti-IgLON5 IgG4 IS is a suitable prognostic and predictive biomarker in anti-IgLON5 disease.

Immunophenotyping in routine clinical practice for predicting treatment response and adverse events in patients with MS.

Background: Recent studies proposed cellular immunoprofiling as a surrogate for predicting treatment response and/or stratifying the occurrence of adverse events (AEs) in persons with multiple sclerosis (pwMS). However, applicability in real-world circumstances is not sufficiently addressed. Objective: We aimed to explore whether standard routine clinical leukocyte phenotyping before treatment initiation could help stratify patients according to treatment response or AEs in a real-world MS cohort. Methods: In this retrospective study, 150 pwMS were included, who had been newly initiated on a disease-modifying drug (DMD) and had been assessed for standard immunophenotyping before DMD initiation (baseline) and at least once during the following year. Multivariate models were used to assess an association of immune subsets and the association between immune cell profiles regarding treatment response and AEs. Results: We found that the composition of T cell subsets was associated with relapse activity, as an increased proportion of CD8+ lymphocytes at baseline indicated a higher likelihood of subsequent relapse (about 9% per 1% increase in CD8+ proportion of all CD3+ cells). This was particularly driven by patients receiving anti-CD20 therapy, where also EDSS worsening was associated with a higher number of CD8+ cells at baseline (3% increase per 10 cells). In the overall cohort, an increase in the proportion of NK cells was associated with a higher risk of EDSS worsening (5% per 1% increase). Occurrence of AEs was associated with a higher percentage of T cells and a lower number of percentual NKT cells at baseline. Conclusion: Immune cell profiles are associated with treatment response and the occurrence of AEs in pwMS. Hence, immunophenotyping may serve as a valuable biomarker to enable individually tailored treatment strategies in pwMS.

Role of Intragap States in Sensitized Sb-Doped Tin Oxide Photoanodes for Solar Fuels Production.

In view of developing photoelectrosynthetic cells which are able to store solar energy in chemical bonds, water splitting is usually the reaction of choice when targeting hydrogen production. However, alternative approaches can be considered, aimed at substituting the anodic reaction of water oxidation with more commercially capitalizable oxidations. Among them, the production of bromine from bromide ions was investigated long back in the 1980s by Texas Instruments. Herein we present optimized perylene-diimide (PDI)-sensitized antimony-doped tin oxide (ATO) photoanodes enabling the photoinduced HBr splitting with >4 mA/cm2 photocurrent densities under 0.1 W/cm2 AM1.5G illumination and 91 ± 3% faradaic efficiencies for bromine production. These remarkable results, among the best currently reported for the photoelectrochemical Br- oxidation by dye sensitized photoanodes, are strongly related to the occupancy extent of ATO's intragap (IG) states, generated upon Sb-doping, as demonstrated by comparing their performances with PDI-sensitized analogues on both undoped SnO2- and TiO2-passivated ATO scaffolds by means of (spectro)electrochemistry and electrochemical impedance spectroscopy. The architecture of the ATO-PDI photoanodic assembly was further modified via the introduction of a molecular iridium-based water oxidation catalyst, thus proving the versatility of the proposed hybrid interfaces as photoanodic platforms for photoinduced oxidations in PEC devices.

Clinical effectiveness of internet-based cognitive behavioral therapy for insomnia in routine secondary care: results of a randomized controlled trial.

Introduction: Delivering cognitive behavioral therapy for insomnia over the internet bears the advantage of accessibility and uptake to many patients suffering from chronic insomnia. In the current study, we aimed to investigate the effectiveness of internet-based cognitive behavioral therapy for insomnia (iCBT-I) in routine care. Materials and methods: We conducted a two-arm non-blinded randomized controlled trial with care as usual (CAU) as a control condition. Participants were recruited in a specialized outpatient sleep medicine department. Both arms had access to other healthcare resources, and the intervention group had access to the iCBT-I program for 2 months. The primary outcome was insomnia severity, measured by the Insomnia Severity Index (ISI). Secondary outcomes were fatigue severity, daytime sleepiness, affective symptoms, dysfunctional beliefs and attitudes about sleep, sleep locus of control, sleep hygiene, sleep efficiency (SE), sleep onset latency, wake time after sleep onset (WASO), and total sleep time (TST). Linear mixed models for repeated measures were used to analyze the longitudinal data at baseline, post-treatment, and after 3 months of follow-up. The trial was registered at www.clinicaltrials.gov (NCT04300218 21.04.2020). Results: The results showed a significant time*group interaction effect (p = 0.001) at post-treatment with between-group effect size (d = 0.51), indicating that the ISI decreased by a score of 3.8-fold in the iCBT-I group than in the CAU group. There was no significant difference in ISI between groups at follow-up. Regarding secondary outcomes, dysfunctional beliefs about sleep, SE, and WASO decreased significantly during treatment in the intervention group with between-group effect sizes d = 0.35, d = -0.51, and d = 0.47, respectively. At the follow-up, between-group effects on DBAS and SE remained significant: d = 0.36 and d = -0.63, respectively. For TST, we observed a significant time*group effect of d = -0.38 only after follow-up. Conclusion: Our findings suggest that iCBT-I has a significant effect on insomnia severity at post-treatment compared to CAU. iCBT-I further improved dysfunctional beliefs about sleep and improved subjective sleep characteristics, such as SE, WASO, and TST during 3 months after treatment. Clinical trial registration: www.clinicaltrials.gov, identifier (NCT04300218).

Comparison of the Working Alliance in Blended Cognitive Behavioral Therapy and Treatment as Usual for Depression in Europe: Secondary Data Analysis of the E-COMPARED Randomized Controlled Trial.

BACKGROUND: Increasing interest has centered on the psychotherapeutic working alliance as a means of understanding clinical change in digital mental health interventions in recent years. However, little is understood about how and to what extent a digital mental health program can have an impact on the working alliance and clinical outcomes in a blended (therapist plus digital program) cognitive behavioral therapy (bCBT) intervention for depression. OBJECTIVE: This study aimed to test the difference in working alliance scores between bCBT and treatment as usual (TAU), examine the association between working alliance and depression severity scores in both arms, and test for an interaction between system usability and working alliance with regard to the association between working alliance and depression scores in bCBT at 3-month assessments. METHODS: We conducted a secondary data analysis of the E-COMPARED (European Comparative Effectiveness Research on Blended Depression Treatment versus Treatment-as-usual) trial, which compared bCBT with TAU across 9 European countries. Data were collected in primary care and specialized services between April 2015 and December 2017. Eligible participants aged 18 years or older and diagnosed with major depressive disorder were randomized to either bCBT (n=476) or TAU (n=467). bCBT consisted of 6-20 sessions of bCBT (involving face-to-face sessions with a therapist and an internet-based program). TAU consisted of usual care for depression. The main outcomes were scores of the working alliance (Working Alliance Inventory-Short Revised-Client [WAI-SR-C]) and depressive symptoms (Patient Health Questionnaire-9 [PHQ-9]) at 3 months after randomization. Other variables included system usability scores (System Usability Scale-Client [SUS-C]) at 3 months and baseline demographic information. Data from baseline and 3-month assessments were analyzed using linear regression models that adjusted for a set of baseline variables. RESULTS: Of the 945 included participants, 644 (68.2%) were female, and the mean age was 38.96 years (IQR 38). bCBT was associated with higher composite WAI-SR-C scores compared to TAU (B=5.67, 95% CI 4.48-6.86). There was an inverse association between WAI-SR-C and PHQ-9 in bCBT (B=-0.12, 95% CI -0.17 to -0.06) and TAU (B=-0.06, 95% CI -0.11 to -0.02), in which as WAI-SR-C scores increased, PHQ-9 scores decreased. Finally, there was a significant interaction between SUS-C and WAI-SR-C with regard to an inverse association between higher WAI-SR-C scores and lower PHQ-9 scores in bCBT (b=-0.030, 95% CI -0.05 to -0.01; P=.005). CONCLUSIONS: To our knowledge, this is the first study to show that bCBT may enhance the client working alliance when compared to evidence-based routine care for depression that services reported offering. The working alliance in bCBT was also associated with clinical improvements that appear to be enhanced by good program usability. Our findings add further weight to the view that the addition of internet-delivered CBT to face-to-face CBT may positively augment experiences of the working alliance. TRIAL REGISTRATION: ClinicalTrials.gov NCT02542891, https://clinicaltrials.gov/study/NCT02542891; German Clinical Trials Register DRKS00006866, https://drks.de/search/en/trial/DRKS00006866; Netherlands Trials Register NTR4962, https://www.onderzoekmetmensen.nl/en/trial/25452; ClinicalTrials.Gov NCT02389660, https://clinicaltrials.gov/study/NCT02389660; ClinicalTrials.gov NCT02361684, https://clinicaltrials.gov/study/NCT02361684; ClinicalTrials.gov NCT02449447, https://clinicaltrials.gov/study/NCT02449447; ClinicalTrials.gov NCT02410616, https://clinicaltrials.gov/study/NCT02410616; ISRCTN Registry ISRCTN12388725, https://www.isrctn.com/ISRCTN12388725?q=ISRCTN12388725&filters=&sort=&offset=1&totalResults=1&page=1&pageSize=10; ClinicalTrials.gov NCT02796573, https://classic.clinicaltrials.gov/ct2/show/NCT02796573. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s13063-016-1511-1.

Different lymphocyte counts of multiple sclerosis patients treated with ofatumumab and ocrelizumab: A retrospective observational study.

Introduction: Patients with Multiple Sclerosis (pwMS) treated with anti-CD20 (cluster of differentiation) monoclonal antibodies (mAbs) such as ocrelizumab (OCR) and ofatumumab (OFA) show a reduction mainly of B-lymphocytes, but also other lymphocyte subsets can be affected by these treatments. There is limited data on differences between lymphocyte subset counts of pwMS after treatment initiation with OCR or OFA. Objective: To compare lymphocyte subset counts after treatment initiation in pwMS treated with OCR and OFA. Methods: We analyzed 22 pwMS initiated on OFA and 56 sex-, age- and MS course matched pwMS initiated on OCR from 2 prospectively collected observational MS databases (Bern [n: OFA 14, OCR 44] and Vienna [n: OFA 8, OCR 12]) statistically comparing lymphocyte subset counts (Mann Whitney Test). Results: We found that pwMS treated with OCR showed a stronger reduction of CD20 B-lymphocytes (P = .001), and a trend towards lower counts of CD8+ T cells (P = .056) compared to pwMS treated with OFA, whereas reduction of total lymphocyte, CD4+ lymphocyte and NK cell count was equally distributed between both treatments. Conclusion: Different effects on lymphocyte subpopulations appear to be present in pwMS after treatment initiation with different anti-CD20 mAbs. Further studies are needed to determine potential effects on anti-CD20 treatment efficacy as well as treatment associated risks such as failed vaccinations and infections.

Alemtuzumab treatment for multiple sclerosis in Austria: An observational long-term outcome study.

BACKGROUND/OBJECTIVE: Observational real-world study to analyze the clinical effects of alemtuzumab (ALEM) and subsequent disease-modifying therapy (DMT) usage in multiple sclerosis (MS). METHODS: Data retrieved from the Austrian MS treatment registry (AMSTR) included baseline (BL) characteristics (at ALEM start), annualized relapse rate (ARR), 6-month confirmed progression independent of relapse activity (PIRA; ≥ 0.5-point Expanded Disability Status Scale (EDSS) score increase), 6-month confirmed disability improvement (CDI; ≥ 0.5-point EDSS decrease), and safety outcomes until initiation of a subsequent DMT. The EDSS was re-baselined at 30 days from ALEM start (BL EDSS). RESULTS: Eighty-seven ALEM-treated patients (median age: 32 years, 72% female, 14% treatment-naïve) were followed for a median of 55 (interquartile range 31-68) months. We found significant reductions in the ARR from 1.16 before ALEM to 0.15 throughout Years 1-9 (p < 0.001). Subsequent DMTs were initiated in 19 patients (22%, 74% anti-CD20 monoclonal antibodies). At Year 5 (n = 53), more patients achieved CDI (58%, 95% confidence interval (CI) 45%-71%) than had experienced PIRA (14%, CI 7.5%-24%), and 58% remained relapse-free. Shorter MS duration (p < 0.001, hazard ratio (HR) 0.86 (CI 0.80-0.93)) and no previous high-efficacy treatment (p < 0.001, HR 5.16 (CI 2.66-10.0)) were the best predictors of CDI, while PIRA was associated with a higher number of previous DMTs (p = 0.04, HR 3.06, CI 1.05-8.89). We found no new safety signals. INTERPRETATION: ALEM had long-lasting beneficial effects on the ARR and disability improvement, especially when initiated early in the course of the disease. Only a subset of patients received subsequent DMTs.

Novel and emerging treatments to target pathophysiological mechanisms in various phenotypes of MS.

The objective is to comprehensively review on novel pharmacotherapies used in multiple sclerosis (MS) and the possibilities they may carry for therapeutic improvement. Specifically, we discuss pathophysiological mechanisms worth targeting in MS ranging from well-known targets such as autoinflammation and demyelination to more novel and advanced targets such as neuroaxonal damage and repair. To set the stage, a brief overview of clinical MS phenotypes is provided followed by a comprehensive recapitulation of both clinical and paraclinical outcomes available to assess the effectiveness of treatments in achieving these targets. Finally, we discuss various promising novel and emerging treatments including their respective hypothesized modes of action and currently available evidence from clinical trials. Significance Statement This comprehensive review discusses pathophysiological mechanisms worth targeting in multiple sclerosis. Various promising novel and emerging treatments including their respective hypothesized modes of action and currently available evidence from clinical trials are reviewed.

Consensus quality indicators for monitoring multiple sclerosis.

Multiple sclerosis (MS) as a chronic, degenerative autoimmune disease of the central nervous system has a longitudinal and heterogeneous course with increasing treatment options and risk profiles requiring constant monitoring of a growing number of parameters. Despite treatment guidelines, there is a lack of strategic and individualised monitoring pathways, including respective quality indicators (QIs). To address this, we systematically developed transparent, traceable, and measurable QIs for MS monitoring. Through literature review, expert discussions, and consensus-building, existing QIs were identified and refined. In a two-stage online Delphi process involving MS specialists (on average 53 years old and with 25 years of professional experience), the QIs were evaluated for content, clarity, and intelligibility, resulting in a set of 24 QIs and checklists to assess the quality of care. The final QIs provide a structured approach to document, monitor, and enhance the quality of care for people with MS across their treatment journey.

Managing multiple sclerosis in individuals aged 55 and above: a comprehensive review.

Multiple Sclerosis (MS) management in individuals aged 55 and above presents unique challenges due to the complex interaction between aging, comorbidities, immunosenescence, and MS pathophysiology. This comprehensive review explores the evolving landscape of MS in older adults, including the increased incidence and prevalence of MS in this age group, the shift in disease phenotypes from relapsing-remitting to progressive forms, and the presence of multimorbidity and polypharmacy. We aim to provide an updated review of the available evidence of disease-modifying treatments (DMTs) in older patients, including the efficacy and safety of existing therapies, emerging treatments such as Bruton tyrosine kinase (BTKs) inhibitors and those targeting remyelination and neuroprotection, and the critical decisions surrounding the initiation, de-escalation, and discontinuation of DMTs. Non-pharmacologic approaches, including physical therapy, neuromodulation therapies, cognitive rehabilitation, and psychotherapy, are also examined for their role in holistic care. The importance of MS Care Units and advance care planning are explored as a cornerstone in providing patient-centric care, ensuring alignment with patient preferences in the disease trajectory. Finally, the review emphasizes the need for personalized management and continuous monitoring of MS patients, alongside advocating for inclusive study designs in clinical research to improve the management of this growing patient demographic.

ENSEMBLE PLUS: final results of shorter ocrelizumab infusion from a randomized controlled trial.

INTRODUCTION: Ocrelizumab is an approved intravenously administered anti-CD20 antibody for multiple sclerosis (MS). The safety profile and patient preference for conventional versus shorter ocrelizumab infusions were investigated in the ENSEMBLE PLUS study. METHODS: ENSEMBLE PLUS was a randomized, double-blind substudy to the single-arm ENSEMBLE study (NCT03085810), comparing outcomes in patients with early-stage relapsing-remitting MS receiving ocrelizumab 600 mg over the approved 3.5-h (conventional) versus 2-h (shorter) infusion. The primary endpoint was the proportion of patients with infusion-related reactions (IRRs) following the first randomized dose (RD); the secondary endpoint included IRR frequency at subsequent RDs. RESULTS: At first RD, the number of patients with an IRR in the conventional (101/373; 27.1%) versus shorter (107/372; 28.8%) infusion group was similar (difference, stratified estimates [95% CI]: 1.9% [- 4.4, 8.2]). Most IRRs (conventional: 99.4%; shorter: 97.7%) were mild/moderate. IRR frequency decreased over the course of RDs; three patients discontinued from the shorter infusion arm but continued with conventional infusion. Overall, > 98% of IRRs resolved without sequelae in both groups. Pre-randomization throat irritation was predictive of future throat irritation as an IRR symptom. Adverse events (AEs) and serious AEs were consistent with the known ocrelizumab safety profile. On completion of ENSEMBLE PLUS, most patients chose to remain on (95%) or switch to (80%) shorter infusion. CONCLUSION: ENSEMBLE PLUS demonstrates the safety and tolerability of shorter ocrelizumab infusions. Most patients remained on/switched to shorter infusion after unblinding; IRRs did not strongly influence patient decisions. CLINICAL TRIALS REGISTRATION: Substudy of ENSEMBLE (NCT03085810). REGISTRATION: March 21, 2017.

Efficacy of an Internet- and Mobile-Based Intervention for Subclinical Anxiety and Depression (ICare Prevent) with Two Guidance Formats: Results from a Three-Armed Randomized Controlled Trial.

INTRODUCTION: Limited research exists on intervention efficacy for comorbid subclinical anxiety and depressive disorders, despite their common co-occurrence. Internet- and mobile-based interventions (IMIs) are promising to reach individuals facing subclinical symptoms. OBJECTIVE: This study aimed to evaluate the efficacy of a transdiagnostic and self-tailored IMI in reducing subclinical anxiety and depressive symptom severity with either individualized (IG-IMI) or automated (AG-IMI) guidance compared to a waitlist control group with care-as-usual access (WLC). METHODS: Participants included 566 adults with subclinical anxiety (GAD-7 ≥ 5) and/or depressive (CES-D ≥16) symptoms, who did not meet criteria for a full-syndrome depressive or anxiety disorder. In a three-arm randomized clinical trial, participants were randomized to a cognitive behavioral 7-session IMI plus booster session with IG-IMI (n = 186) or AG-IMI (n = 189) or WLC (n = 191). Primary outcomes included observer-rated anxiety (HAM-A) and depressive (QIDS) symptom severity 8 weeks after randomization assessed by blinded raters via telephone. Follow-up outcomes at 6 and 12 months are reported. RESULTS: Symptom severity was significantly lower with small to medium effects in IG-IMI (anxiety: d = 0.45, depression: d = 0.43) and AG-IMI (anxiety: d = 0.31, depression: d = 0.32) compared to WLC. No significant differences emerged between guidance formats in primary outcomes. There was a significant effect in HAM-A after 6 months favoring AG-IMI. On average, participants completed 85.38% of IG-IMI and 77.38% of AG-IMI. CONCLUSIONS: A transdiagnostic, self-tailored IMI can reduce subclinical anxiety and depressive symptom severity, but 12-month long-term effects were absent. Automated guidance holds promise for enhancing the scalability of IMIs in broad prevention initiatives.

Efficacy of an Internet-based self-help intervention with human guidance or automated messages to alleviate loneliness: a three-armed randomized controlled trial.

Loneliness is a prevalent and stigmatized phenomenon associated with adverse (mental) health outcomes. However, evidence-based interventions to alleviate loneliness are scarce. This randomized controlled trial (ClinicalTrials.gov-ID: NCT04655196) evaluated the efficacy of an internet-based cognitive behavioral self-help intervention (ICBT) to reduce loneliness by comparing two intervention groups with guidance or automated messages against a waitlist control group. Adults (N = 243) suffering from loneliness were recruited from the general public and then randomly assigned (2:2:1) to a 10-week ICBT with human guidance (GU) or automated messages (AM) or to a waitlist control group (WL). Loneliness, assessed with the UCLA-9, was the primary outcome. Outcomes were assessed at baseline and 10 weeks (post) and analyzed using mixed-effects models. The pooled intervention conditions resulted in lower loneliness scores at post-assessment than the WL (Cohen's d = 0.57, 95% CI [0.25; 0.89]) and reduced depressive symptoms, social anxiety, social avoidance behavior, and rejection sensitivity (d = 0.32-0.52). The GU group had lower loneliness scores at post-assessment than the AM group (d = 0.42, 95% CI [0.13; 0.70]). ICBT effectively alleviated loneliness, and guidance increased the reduction in loneliness compared to automated messages. Alleviating loneliness with ICBT further seems to reduce the overall burden of psychopathological symptoms.

Positive psychotic symptoms as a marker of clinical severity in a transdiagnostic sample of help-seeking adolescents.

The present study aimed to examine the association between the presence, number, and type of positive psychotic symptoms (PPS) and clinical severity in adolescent patients. Five hundred-six patients aged 11-17 years were assigned to either the noPPS (n = 341), the delusional beliefs only (del; n = 32), the hallucinations only (hall; n = 80), or the delusional beliefs and hallucinations (del&hall; n = 53) group. Generalized Structural Equation Modeling was applied to identify the best-fitting model representing clinical severity indicated by psychiatric diagnoses, depressivity, personality pathology, non-suicidal self-injury, suicide attempts, perceived stress, and psychosocial impairments, assessed by interviews and questionnaires. The groups were compared concerning the final model's factors. The final model consisted of three factors representing psychopathology and functional impairments, self-harming behavior, and perceived stress (BIC difference to reference model: 103.99). Participants with any PPS scored higher on all factors than the noPPS group (differences in SD: 0.49-1.48). Additionally, the del&hall group scored 1.31 SD higher on psychopathology and functional impairments than the hall group, and 1.16 SD higher on self-harming behavior compared to the del group. Finally, the hall group scored 0.84 SD higher on self-harming behavior than the del group, with no group differences in the other factors. In adolescent patients, the presence of PPS may represent a marker for a more severe form of mental disorder, with hallucinations being indicative of self-harming behavior. Early transdiagnostic assessment of PPS seems indicated as it may inform treatment in the context of clinical staging.

Pain sensitivity as a state marker and predictor for adolescent non-suicidal self-injury.

BACKGROUND: The pain analgesia hypothesis suggests that reduced pain sensitivity (PS) is a specific risk factor for the engagement in non-suicidal self-injury (NSSI). Consistent with this, several studies found reduced PS in adults as well as adolescents with NSSI. Cross-sectional studies in adults with borderline personality disorder (BPD) suggest that PS may (partially) normalize after remission or reduction of BPD symptoms. The objective of the present study was to investigate the development of PS over 1 year in a sample of adolescents with NSSI and to investigate whether PS at baseline predicts longitudinal change in NSSI. METHODS: N = 66 adolescents who underwent specialized treatment for NSSI disorder participated in baseline and 1-year follow-up assessments, including heat pain stimulation for the measurement of pain threshold and tolerance. Associations between PS and NSSI as well as BPD and depressive symptoms were examined using negative binomial, logistic, and linear regression analyses. RESULTS: We found that a decrease in pain threshold over time was associated with reduced NSSI (incident rate ratio = 2.04, p = 0.047) and that higher pain tolerance at baseline predicted lower probability for NSSI (odds ratio = 0.42, p = 0.016) 1 year later. However, the latter effect did not survive Holm correction (p = 0.059). No associations between PS and BPD or depressive symptoms were observed. CONCLUSION: Our findings suggest that pain threshold might normalize with a decrease in NSSI frequency and could thus serve as a state marker for NSSI.

General neurology: Current challenges and future implications.

BACKGROUND AND PURPOSE: In the coming decades, the world will face an increasing burden of neurological disorders (ND) and an urgent need to promote brain health. These challenges contrast with an insufficient neurological workforce in most countries, as well as decreasing numbers of general neurologists and neurologists attracted to work in general neurology (GN). This white paper aims to review the current situation of GN and reflect on its future. METHODS: The European Academy of Neurology (EAN) task force (TF) met nine times between November 2021 and June 2023. During the 2023 EAN annual meeting, attendees were asked to answer five questions concerning the future of GN. The document was sent for suggestions and eventually approval to the board and the presidents of the 47 national societies of the EAN. RESULTS: The TF first identified four relevant current and future challenges related to GN: (i) definition, (ii) practice, (iii) education, and (iv) research. The TF then identified seven initiatives to further develop GN at both the academic and community level. Finally, the TF formulated 16 recommendations to promote GN in the future. CONCLUSIONS: GN will remain essential in the coming decades to provide rapid, accessible, and comprehensive management of patients with ND that is affordable and cost-effective. There is also a need for research, education, and other initiatives aiming to facilitate improved working conditions, recognition, and prestige for those pursuing a career in GN.

Olfactory threshold as a biomarker of long-term relapse activity in multiple sclerosis.

BACKGROUND: Olfactory threshold (OT) is a marker of short-term inflammatory activity in multiple sclerosis (MS). OBJECTIVE: To investigate whether OT predicts long-term MS clinical disease course. METHODS: This was a 6-year prospective longitudinal study on MS patients at the MS clinic Innsbruck. Clinical visits assessing the occurrence of relapses, Expanded Disability Status Scale (EDSS) scores, and disease-modifying treatment (DMT), were conducted biannually. OT testing was performed at baseline (BL), year 1 (Y1), year 2 (Y2) and year 6 (Y6), using the threshold subscore of the "Sniffin' Sticks" test. Cognitive function was assessed by the Symbol Digit Modalities Test. RESULTS: Of 139 MS patients, 92 were eligible for Y6 follow-up. 68% experienced relapses, 53% EDSS worsening, 29% progression independent of relapse activity (PIRA) and 41% cognitive deterioration. OT scores were lower at BL, Y1 and Y2 in patients requiring DMT escalation. In multivariable analysis, higher OT scores at BL, Y1, Y2 and Y6 were associated with lower risk of relapse (hazard ratio, HR: 0.65-0.92) and EDSS worsening (HR: 0.86-0.89), while no associations were found for PIRA and cognitive deterioration. CONCLUSIONS: OT is a potential surrogate marker for long-term inflammatory disease activity and DMT failure in MS.

Sex impacts treatment decisions in multiple sclerosis.

BACKGROUND: Individual disease-modifying treatment (DMT) decisions might differ between female and male people with MS (pwMS). OBJECTIVE: To identify sex-related differences in DMT strategies over the past decades in a real-world setting. METHODS: In this cohort study, data from the Austrian Multiple Sclerosis Treatment Registry (AMSTR), a nationwide prospectively collected registry mandatory for reimbursement, were retrospectively analyzed. Of 4840 pwMS, those with relapsing-remitting MS, aged at least 18 years, who started DMT and had at least two clinical visits, were identified. At baseline, demographics, Expanded Disability Status Scale (EDSS) score, annualized relapse rate (ARR) in the prior 12 months and MRI lesion load were assessed. At follow-up, ARR, EDSS scores, and DMT were determined. RESULTS: A total of 4224 pwMS were included into the study and had a median of 10 (IQR 5-18) clinical visits over an observation period of 3.5 (IQR 1.5-6.1) years. Multivariable Cox regression analysis revealed that the probability of DMT escalation due to relapse activity was lower in female than male pwMS (HR 4.1 vs. 8.3 per ARR). Probability of discontinuing moderate-effective DMT was higher in female pwMS when they were younger (HR 1.03 per year), and lower in male pwMS at higher age (HR 0.92). Similarly, female pwMS were more likely to stop highly effective DMT than male pwMS (HR 1.7). Among others, the most frequent reason for DMT discontinuation was family planning in female pwMS. All sex-related effects were independent of disease activity, such as MRI lesion load, baseline ARR or EDSS. CONCLUSIONS: Real-world treatment decisions are influenced by sex-related aspects. Awareness of these associations should prevent unwarranted differences in MS care.

Early intensive versus escalation treatment in patients with relapsing-remitting multiple sclerosis in Austria.

OBJECTIVES: To compare the effectiveness of early intensive treatment (EIT) versus escalation treatment (ESC) in a nationwide observational cohort of almost 1000 people with relapsing-remitting multiple sclerosis (RRMS). MATERIALS AND METHODS: The EIT cohort started with alemtuzumab (AZM), cladribine (CLAD), fingolimod (FTY), natalizumab (NTZ), ocrelizumab (OCR), or ozanimod (OZA); whereas, the ESC cohort was escalated from dimethylfumarate (DMF) or teriflunomide (TERI) to AZM, CLAD, FTY, NTZ, OCR, or OZA within the Austrian MS Treatment Registry. Patients had to stay on therapy for at least 3 months and up to 16 years. The EIT cohort included 743 and the ESC cohort 227 RRMS patients. We used multinomial propensity scores for inverse probability weighting in generalized linear (GLM) and Cox proportional hazards models to correct for the bias of this non-randomized registry study. RESULTS: Estimated mean annualized relapse rates (ARR) were 0.09 for EIT and 0.4 for ESC patients. The incidence rate ratio (IRR) in the GLM model for relapses showed a decreased relapse probability of 78% for the EIT versus ESC cohort [IRR = 0.22, 95% CI (0.16-0.30), p < 0.001]. Analyzing the time to the first relapse by Cox regression, a hazard ratio (HR) of 0.17 [95% CI (0.13-0.22), p < 0.001] revealed a decreased risk of 83% for the EIT group. Regarding sustained Expanded Disability Status Scale (EDSS) progression for 12 weeks, a HR of 0.55 [95% CI (0.40-0.76), p < 0.001] showed a decreased probability of 45% for the EIT cohort. CONCLUSIONS: ESC treatment after DMF and TERI revealed a higher relapse and EDSS progression probability compared to EIT in Austrian RRMS patients. Therefore, an early intensive treatment should be started in patients with an active or highly active disease course.