To (1) identify clinical situations that may contribute to the experience of moral distress (MD) among professionals working with motor neuron disease (MND), (2) measure the occurrence and intensity of MD, and (3) explore associations with professional quality of life, turnover intention, and associated risk and/or protective factors. A cross-sectional online survey was distributed to healthcare professionals working in MND services across Europe. Data were analyzed using descriptive and inferential statistics. In total, 230 responses from professionals across 17 European countries were analyzed from the international survey. And 67% of respondents indicated that MD resonated with their experience of working with MND. Those who considered leaving or changing their position due to the challenges associated with caring for this patient population were also more likely to report resonance with MD (χ2 = 7.772, p = 0.020). The intensity of MD was associated with reduced professional quality of life (burnout [β = 0.106, p < 0.05], and secondary traumatic stress [β = 2.881, p < 0.001]). A total of 24 clinical scenarios were identified as potential contributors to experiences of MD in this population. Across all professional groups, service-/organization-level factors were the most common and distressing barriers to providing effective MND care. This study demonstrates that MD is experienced by healthcare professionals working with MND across Europe. MD was associated with reduced professional quality of life and increased intentions to leave or change positions, underscoring its potential implications for workforce retention and sustainability. The findings show that system/organization, patient/condition and family-level causes are the primary drivers of MD in this population. Future research should focus on evaluating the effectiveness of interventions designed to address these key drivers and mitigate the impact of MD among healthcare professionals working with MND.
People with dementia often need comprehensive support, depending on the stage of the disease, from both family members and healthcare professionals. Caring for a person with dementia can be stressful and impact the caregiver's health and wellbeing. Studies show that family caregivers of people with dementia frequently experience stress, depression, and reduced quality of life. We aimed to assess the association between the psychosocial intervention (DemTool) and caregiver wellbeing and quality of life among family caregivers of people with dementia. DemTool trial was a pragmatic, cluster-controlled trial. The intervention was delivered by primary care dementia coordinators across 30 Danish municipalities from 2020 to 2023, with 15 serving as the intervention group and 15 as treatment as usual. The primary outcome measures were the Neuropsychiatric Inventory Caregiver Distress Scale (NPI-D) and the European Quality of Life Visual Analog Scale (EQ VAS). Both measures were completed at baseline and follow-up, alongside secondary quality of life outcomes. To estimate group differences in primary and secondary outcomes, we applied analysis of variance (ANOVA) and analysis of covariance (ANCOVA). A total of 245 family caregivers were included in the study (181 in the intervention group and 64 in the treatment-as-usual group). Most participants were females caring for a spouse. Baseline scores for caregiver wellbeing and quality of life were similar across groups. The DemTool intervention was associated with a significant between-group difference in change from baseline in caregiver-related quality of life as measured by the Carer Experience Scale (CES), favoring the intervention. This was evident in the analysis adjusted for baseline scores (p = 0.05) and remained significant when further adjusting for caregiver-related covariates (p = 0.02). No statistically significant between-group differences were observed for the remaining wellbeing and quality-of-life outcomes. No effects of DemTool were found on traditional health-related quality-of-life outcomes. However, a positive association was found between the intervention and the CES, underlining the importance of selecting outcomes that are directly related to the targeted effects of the intervention. The study protocol was registered in the ClinicalTrials.gov system, registration number: NCT07355829.
Seizure freedom (SF) is widely recognized as a key goal in epilepsy treatment, yet its value is inconsistently defined, applied, and communicated in both clinical and research contexts. This lack of consensus limits the alignment of clinical care, trial design, and patient-centered outcomes. To generate expert consensus on the definition, relevance, and value of SF in epilepsy, and to inform its future integration into treatment guidelines, health policy, and economic evaluations. A three-round Delphi panel was conducted involving 28 stakeholders, including epileptologists, neurologists, patient advocacy representatives, nurses, and Health Economics and Outcomes Research (HEOR) experts from EU countries and the UK. Participants responded to structured questionnaires covering clinical, social, and economic aspects of seizure freedom. Consensus thresholds were pre-defined based on question type. High consensus was reached on the definition of SF as "no seizures for 1 year or more" and its importance as a primary endpoint in studies involving newly diagnosed patients and surgical interventions. In studies and clinical practice involving drug-resistant patients, consensus was also reached, on SF not being the sole primary endpoint. Patient-centered priorities, including improved quality of life, psychological well-being, and functional independence, were identified as key benefits of SF. Economic and societal impacts of uncontrolled seizures were also rated as highly significant and impactful. The Delphi panel findings highlight SF as a clinically meaningful, patient-prioritized, and economically valuable outcome. These insights should guide the standardization of SF definitions, support its broader use in health technology assessment (HTA), and inform shared decision-making in clinical practice in resource-rich environments in Europe.
Polytherapy in epilepsy is associated with a higher risk of adverse events, poorer adherence, and impaired quality of life. Thus, reducing concomitant antiseizure medications (ASMs) and/or using a newly added ASM such as cenobamate with only 1 other ASM (i.e., bitherapy) may improve tolerability. This post hoc analysis evaluated the impact of the number and type of concomitant ASMs on treatment-emergent adverse events (TEAEs) that occurred in the cenobamate C021 open-label clinical trial. Adjunctive cenobamate was initiated in adults (aged 18-70 years) with uncontrolled focal seizures who were taking 1 to 3 ASMs. The number and type of concomitant ASMs and the frequency, severity, and time to resolution of TEAEs were assessed. The most frequently reported (≥ 10%) TEAEs in the overall population (n = 1340) were somnolence, dizziness, fatigue, and headache. The percentage of patients with dizziness, somnolence, and fatigue increased with increasing numbers of concomitant ASMs, especially when combined with benzodiazepines, chiefly clobazam, and in patients taking ≥ 2 sodium channel blockers. Median time to resolution of frequently reported TEAEs was shorter in patients taking fewer concomitant ASMs, with the exception of fatigue. The proportion of patients experiencing more severe TEAEs (except for headache) also increased with increasing numbers of concomitant ASMs. Patients taking fewer concomitant ASMs reported better tolerability as evidenced by fewer and less severe AEs and faster time to resolution. These findings emphasize the importance of optimizing concomitant ASM regimens through dose adjustments, ASM substitution, and treatment simplification to improve tolerability.
Acute and chronic stressors contribute to neuropsychiatric disorders. However, the role of inflammatory dynamics around stress exposure remains unclear. Using TriNetX, an international electronic health records database, we examined how systemic inflammatory activity and its temporal dynamics relate to risk of mental illness and somatic symptoms. We compared 44,904 individuals with records of accidents and leukocytosis in the surrounding period with matched individuals with normal leukocyte counts, and performed analogous comparisons for socioeconomic and psychosocial stressors in cohorts of 100,855 individuals with leukocytosis and matched controls. To contrast dynamic with static inflammatory responses, we compared cohorts exhibiting leukocyte count changes with those maintaining persistently normal or elevated counts around stressor exposure. Incidence of psychiatric and somatic symptom diagnoses were evaluated within two years of the stressor. Following acute stressors, leukocytosis (compared with normal leukocyte counts) was associated with lower rates of anxiety disorders (Odds Ratio 0.88, 95% Confidence Interval 0.83-0.93), depression (0.92, 0.86-0.98), cognitive symptoms (0.86, 0.81-0.92) and several somatic symptoms, with similar reductions in anxiety (0.92, 0.88-0.95) and depression (0.92, 0.89-0.96) observed after chronic stressors. A dynamic inflammatory response was associated with the most favourable outcomes, with lower rates of anxiety, depression, cognitive difficulties, fatigue, and pain-related symptoms compared to persistently lower or higher inflammation, and lower rates of functional neurological disorder compared to low inflammation. Our findings suggest that patterns of inflammatory response to stressors are associated with diverse mental health and somatic outcomes, with transient immune activation showing a more favourable outcome profile.
Migraine imposes significant burden not only during acute attacks but also during headache-free interictal periods. Several patient-reported outcome measures (PROMs) have been used to assess this interictal burden, yet the quality of their measurement properties has not been systematically evaluated. To identify instruments used to assess interictal burden in migraine, evaluate their measurement properties using the COSMIN methodology, and synthesize the conceptual domains of interictal burden. A systematic search of MEDLINE, Embase, PsycINFO, CINAHL, and Web of Science Core Collection was conducted from database inception to 20 February 2026. Studies evaluating measurement properties of PROMs assessing interictal burden or migraine impact in migraine populations were eligible. The COSMIN risk-of-bias checklist and criteria for good measurement properties were applied. Findings were synthesized in accordance with PRISMA 2020. Among 29 included studies, three instruments were identified: the Migraine Interictal Burden Scale-4 (MIBS-4; 26 studies), the Eurolight questionnaire (1 study), and the Fear of Attacks Inventory (FAMI; 2 studies). Seven conceptual domains of interictal burden were identified: functional impairment, social and relational impact, psychological and emotional distress, cognitive dysfunction, sensory symptoms, physical symptoms, and behavioral modifications. Evidence of measurement properties was concentrated in construct validity (19 studies) and responsiveness (8 studies). Structural validity, internal consistency, test-retest reliability and content validity were sparsely evaluated. The MIBS-4 demonstrated consistent convergent and known-groups validity and sensitivity to change across preventive therapies, including CGRP-targeted treatments and onabotulinumtoxinA. The MIBS-4 is the most widely used instrument for assessing interictal burden. Despite encouraging evidence of construct validity and responsiveness, comprehensive psychometric studies addressing content and structural validity, reliability, and measurement error, alongside conceptual work towards broader interictal burden assessment, are needed. PROSPERO CRD420261296323; Clinical trial number: not applicable.
[18F]FDG PET/CT scan is sometimes performed as part of the diagnostic evaluation of non-compressive myelopathies, but the spinal cord lesion metabolism is not systematically evaluated. We aimed to investigate the diagnostic value of spinal cord lesion metabolism on [18F]FDG PET/CT for differentiating inflammatory myelitis from neurosarcoidosis and tumoral lesions. We conducted a retrospective cohort study of patients presenting with spinal cord lesions who underwent [18F]FDG PET/CT. Patients were classified as primary inflammatory myelitis, neurosarcoidosis, tumoral lesions, or other etiologies. PET/CT examinations were reviewed by a nuclear medicine physician, masked to final diagnosis, who assessed the presence of hypermetabolism (qualitative analysis) and measured lesion SUVmax, lesion-to-liver ratio, and level-standardized Z-score to account for physiological uptake variability (quantitative analysis). A total of 106 patients were included: 60 (56.6%) with inflammatory myelitis, 20 (18.9%) with neurosarcoidosis, 10 (9.4%) with tumoral lesions, and 16 (15.1%) with other etiologies. Hypermetabolism was found in 80.0% of tumoral lesions, 50.0% of neurosarcoidosis, and 23.3% of inflammatory myelitis. PET/CT showed good performance in differentiating inflammatory myelitis or neurosarcoidosis from tumoral lesions using qualitative analysis (hypermetabolism: sensitivity 0.77, specificity 0.80, and 0.50, respectively) and quantitative analysis (SUVmax: AUC 0.89 and 0.84, respectively). The performance of SUVmax for distinguishing inflammatory myelitis from neurosarcoidosis was low (AUC 0.55), but improved with the lesion-to-liver ratio (AUC 0.64) and level-standardized Z-score (AUC 0.65). Spinal cord hypermetabolism on [18F]FDG PET/CT demonstrated good performance for distinguishing tumoral lesions from inflammatory or neurosarcoidosis, but lower performance for differentiating inflammatory myelitis from neurosarcoidosis.
Reliable prediction of short-term mortality in status epilepticus (SE) can contribute to guide clinical decisions. Current prognostic systems achieve only acceptable predictive power and show lack of generalizability or poor calibration. We aimed to identify clinical predictors of short-term mortality in patients with nonhypoxic SE and develop a predictive score. This was a multicenter, multinational cohort study based on registry data. Participants were consecutive episodes of SE in participants aged 14 years or older from Modena (Italy) (derivation cohort) and in participants aged 18 years or older from Salzburg (Austria) (validation cohort). The predefined outcome was 30-day mortality after the onset of SE. Age, sex, level of consciousness before treatment, semiology of SE, level of disability at baseline before SE, etiology, and treatment refractoriness were assessed. Adjusted regression coefficients of each independent predictor were transformed to produce a points-based risk scoring system. The Italian cohort included 689 episodes, and the Austrian cohort comprised 569 episodes of SE. In the derivation cohort, the 30-day mortality rate was 27.3%. The independent risk factors were aged 75 years or older (odds ratio [OR] 5.52, 95% CI 3.45-8.83; p < 0.001), consciousness impairment (stuporous or comatose) before SE treatment (OR 1.76, 95% CI 1.09-2.82; p = 0.020), acute etiology due to primary CNS pathology (OR 2.60, 95% CI 1.60-4.23; p < 0.001), refractoriness to treatment (OR 6.40, 95% CI 3.91-10.46; p < 0.001), and disability before SE onset (OR 3.53, 95% CI 2.22-5.61; p < 0.001); remote etiology was independently associated with a lower likelihood of 30-day mortality (OR 0.28, 95% 0.13-0.61; p = 0.001). An integer-based scoring system termed Age, Consciousness, Aetiology, Refractoriness, Disability (ACARD) was developed by combining these independent predictors. In the validation cohort, the 30-day mortality rate was 11.6%. The area under the curve of the ACARD score was 0.864 (95% CI 0.836-0.891) in the derivation cohort and 0.845 (95% CI 0.801-0.888) in the validation cohort. Calibration plot indicated good fit of predicted and observed data in both cohorts. The ACARD score is a user-friendly tool developed to predict 30-day mortality after nonhypoxic SE. It has the potential to identify participants at high risk of short-term mortality and outperform the performance of other available scoring systems.
People with multiple sclerosis (pwMS) are rapidly aging, yet the clinical and functional profile of older individuals remains poorly characterized. Our study aimed to describe the demographic, clinical, cognitive, functional, and psychosocial features of pwMS aged ≥ 60 years in the Genoa province, and identify predictors of cognitive and motor decline. In this cross-sectional study, 109 pwMS aged 60-89 years were evaluated via structured telephone interviews. Collected variables included demographics, disability (SRDSS), mobility, comorbidities, dysphagia (DYMUS), pain (NRS, DN4), fatigue, urinary and fecal dysfunction, spasticity, cognitive function (Telephone-MoCA), depressive symptoms, and the level of independence. Multivariate logistic and ordered logistic regressions examined predictors of cognitive, motor, and clinical outcomes. An exploratory regression model estimated age-related cognitive and motor trajectories. Of the 109 participants (median age 71 years), 43 subjects were < 70 and 66 ≥ 70 years old. Participants showed high disability, widespread mobility limitation, fatigue (96%), urinary dysfunction (78%), and cognitive impairment (median MoCA 10). Older age was associated with worse cognition, greater dependence on instrumental activities of daily living, and higher dysphagia. In multivariate models, education predicted MoCA performance, and pain was independently associated with female sex and comorbidity burden. The age-trajectory model revealed a nonlinear acceleration of decline after 72-73 years, with cognition deteriorating earlier and faster than mobility. Aging pwMS exhibit a substantial multidimensional burden. Cognitive decline accelerates in advanced age and precedes motor deterioration, underscoring the need for early cognitive monitoring and integrated, geriatric-informed care strategies.
B-cell repopulation patterns in ocrelizumab treated patients with multiple sclerosis are highly variable between individuals, but the course of B-cell reoccurrence after subsequent doses within an individual is not yet determined. Our aim was to determine the intraindividual variability of CD19+ B-cell repopulation after each ocrelizumab dose when using CD19+ B-cell guided interval dosing. This was a prospective cohort study, as part of the ongoing BLOOMS trial, investigating participants randomised for B-cell guided interval dosing of ocrelizumab with ≥ 2 dosing intervals. Coefficients of variation were calculated for time from last ocrelizumab dose to first CD19+ B-cell measurement ≥ 0.01 × 109 cells/L. Seventy-five participants with a total of 209 B-cell guided intervals were included. Time from last dose to first appearance of CD19+ B-cell count ≥ 0.01 × 109 cells/L showed wide variability between individuals (20.6-72.1 weeks), but the median variation was 5.6% (IQR: 3.1-8.4) within an individual. This translated to a variation of 2 weeks per dosing interval on average. Time to CD19+ B-cell repopulation after each ocrelizumab dose is individually stable. This finding could pave the way for easier and more accessible future personalised interval dosing of B-cell depleting therapies if this stability is confirmed in long-term treatment.
Plasma phosphorylated tau (p-tau) biomarkers have improved the diagnosis of Alzheimer's disease (AD), but evidence in early-onset populations remains limited. We evaluated the diagnostic performance of plasma p-tau217 and p-tau181 levels in patients with early-onset AD (EOAD) and early-onset frontotemporal dementia (EOFTD). We analyzed 185 patients (EOAD = 150, EOFTD = 35) aged ≤ 65 years from the LEAF study (2021-2023). Plasma p-tau217, p-tau181, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) levels were measured by immunoassays. Both plasma p-tau217 (AUC = 0.831) and p-tau181 (AUC = 0.862) levels demonstrated high discriminative performance, with no significant difference between the two p-tau isoforms. P-tau levels were higher in patients with EOAD, whereas NfL levels were higher in EOFTD and were elevated in those with EOAD participants with severe hippocampal atrophy. Adding NfL, GFAP, and APOE ε4 status further improved the discriminative accuracy for differentiating EOAD from EOFTD. Plasma p-tau217 and p-tau181 are effective biomarkers for distinguishing biologically defined EOAD from EOFTD. Incorporating NfL, GFAP, and APOE ε4 status further enhances diagnostic accuracy.
Despite the therapeutic potential of canonical Wnt/β-catenin signaling activation in spinal cord injury (SCI), the development of Wnt-based therapeutic approaches is severely hampered by difficulties in Wnt ligand production, their high receptor cross-reactivity and the unspecificity of glycogen synthase kinase-3β inhibitors. Consequently, the generation of chimeric canonical Wnt surrogates that can overcome the previously detailed limitations has been of paramount importance for the development of Wnt-based therapeutic approaches, although their potential beneficial role in SCI has not been assessed to date. For this purpose, we have evaluated the effects exerted by the overexpression of the canonical Wnt surrogate scFv-Dkk1c in a clinically relevant model of SCI in critical injury-related aspects such as motor functional recovery, myelin preservation/loss, neuronal cell density, microglia/macrophage and astroglial reactivity, expression of markers related to astroglial and microglia/macrophage polarization, vascularization and descending serotonergic innervation. Briefly, we found that scFv-Dkk1c overexpression during the progression of SCI significantly improved motor functional recovery concomitant with changes in the SCI-associated microglia/macrophage reactivity, expression of markers related to microglia/macrophage polarization, astroglial reactivity and tissue vascularization, without affecting myelin preservation/loss, neuronal cell density, expression of markers related to astroglial polarization, NG2 + cell presence and descending serotonergic innervation. In conclusion, the present study provides experimental evidence for the potential role of the canonical Wnt surrogate scFv-Dkk1c in the context of SCI.
The global burden of age-associated diseases continues to grow. In particular, the accelerating impact of neurodegenerative diseases on individuals, communities and societies necessitates more effective approaches to diagnosis, prognosis and treatment of such disorders. Hence, the establishment of imaging biomarkers for early detection of disease, progression monitoring, and therapeutic evaluation is of utmost importance. Yet, despite the scientific consensus on the benefits of scientific collaboration and consequently medical innovation including biomarker development, substantial barriers for sharing neuroimaging data remain, demanding a transformation in how scientific data are generated, made accessible, re-used and valued. These barriers range from technical and infrastructural limitations to legal and motivational challenges that hinder widespread adoption of open science practices. Here, we present a comprehensive overview of the current landscape of brain imaging data sharing in neurodegenerative disease research. We explore the status of preregistration, data harmonization and storage standardization, legal compliance, and researcher incentives. We highlight best practices before, during and after data generation and the pressing need for a coordinated strategy regarding simplified and unified legal frameworks compliant with the General Data Protection Regulation of the European Union. Finally, we advocate for the establishment of an academic credit system designed to reward data stewardship. Only with a combined effort from researchers, stakeholders and funding agencies including a sustained infrastructure investment and community education, the field can fully overcome inertia and move towards much-desired open science, thereby fully leveraging shared data to improve patient outcomes and scientific discovery.
The optic nerve sheath expands with elevated intracranial pressure, and its diameter is a sensitive proxy measure. While 2D transorbital ultrasound is well-established for detecting elevated intracranial pressure (>20 mm Hg), it shows limited sensitivity to modest or gradual changes, potentially due to geometric assumptions and imaging misalignment. This study introduces freehand 3D ultrasound imaging of the optic nerve sheath to reduce measurement ambiguity and enhance the fidelity of optic nerve sheath assessment as a noninvasive marker of intracranial pressure. Twelve healthy participants (28.7 ± 8.2 y; 6 females) underwent freehand 3D optic nerve sheath imaging during 24 hours of normobaric hypoxia in an environmental chamber (FiO2 = 13.1%). Scans were acquired in a head-raised (30 degrees) position at baseline, 6, 12, and 24 hours. Cardiorespiratory parameters, cerebral blood flow, and end-tidal gases were recorded. In 6 participants, postural effects were also assessed at baseline. Nutrition and hydration were standardized to 75% of daily requirements. The optic nerve sheath's curved, noncircular shape makes the 2D diameter measurement of the sheath a geometric mismatch and an inadequate descriptor. Probe misalignments of 1.2 mm or 15 degrees led to 2D diameter errors (9%/18.7%) exceeding observer variability (2.6%/3.4%). Freehand 3D imaging was reproducible and yielded more informative metrics, including sheath area and thickness. Internal sheath thickness was more responsive to posture and hypoxia than internal 2D diameter (+31.5%, P = 0.01 vs +2.4%, P = 0.9; +8.2%, P = 0.04 vs +1.8%, P = 0.9). A time effect was observed for internal sheath thickness (P = 0.04), and both area and thickness correlated with internal carotid artery velocity (area: r = 0.9, P = 0.05; thickness: r = 0.8, P = 0.07), consistent with physiological expectations. By eliminating geometric assumptions and misalignment, freehand 3D ultrasound improves the fidelity and sensitivity of optic nerve sheath measurements at the bedside.
Inflammation plays a pivotal role in acute ischemic stroke (AIS), with neutrophil granulocytes acting as major contributors to the post-stroke immune response. Upon degranulation, neutrophils release matrix metalloproteinase-9 (MMP-9) and myeloperoxidase (MPO), both of which may influence functional outcomes following AIS. The aim of this study was to investigate the association between systemic levels of MMP-9 and MPO, functional outcome, and neutrophil counts in patients with moderate to severe AIS, with a focus on their pathophysiological relevance rather than standalone prognostic performance. This prospective single-center cohort study included patients with moderate to severe AIS in the anterior circulation (NIHSS score ≥ 6 points and /or indication for mechanical recanalization). Venous blood was sampled in order to assess plasma concentrations of MMP-9 via zymography as well as MPO plasma levels via ELISA. Furthermore, differential blood count was determined simultaneously to venous biomarker sampling. Poor outcome was defined as mRS score ≥ 3. Uni- and multivariable regression analyses were performed. Between 07/2020 and 09/2022 a total of 279 patients with blood samples taken up to 48 h after symptom onset with a median NIHSS score of 13 and a median age of 79 were included. Of these patients, 81.0% underwent mechanical recanalization and 42.7% received systemic thrombolytic therapy. Systemic MMP-9 and MPO plasma levels were significantly higher in patients with poor functional outcome compared to patients with good functional outcome at 3-months (MMP-9: 359.1 vs. 303.5 ng/ml, p = 0.0006; MPO: 27.0 vs. 19.2 ng/ml, p = 0.0010). Both biomarkers were associated with a poor outcome in unadjusted analyses [MMP-9: unadjusted OR = 15.63 (95% CI: 3.54-80.69), p = 0.0005; MPO: unadjusted OR = 4.02 (95% CI: 1.84-9.21), p = 0.0007]. In addition, MMP-9 and MPO concentrations correlated with neutrophil counts (MMP-9: r = 0.39, p < 0.0001; MPO: r = 0.31, p < 0.0001). In conclusion, systemic MMP-9 and MPO plasma concentrations are associated with functional outcome in patients with moderate to severe AIS and reflect neutrophil-driven inflammatory processes. Their value appears to lie in complementing established clinical predictors rather than serving as independent prognostic markers.
This survey aimed to investigate how physicians in Italy recognize, diagnose, and manage tardive dyskinesia (TD), as well as to assess and identify gaps in the current treatment approaches. A non-interventional cross-sectional online survey was conducted among Italian physicians who had managed patients with TD in the 1 year prior to the survey. The questionnaire explored physicians' demographics, clinical experience, diagnostic methods, treatment strategies, perceptions of TD impact, and health care resource utilization related to TD. Data were summarized descriptively. The survey included 70 psychiatrists and 30 movement disorder neurologists. Most patients presented with mild (49%) or moderate (35%) TD. Treatment strategies varied by TD severity; antipsychotic dose modification or switching was common, particularly to clozapine, quetiapine, and aripiprazole, whereas TD-specific add-on treatments such as tetrabenazine were rarely used (12% to 21% of physicians prescribed the treatment). Movement impairment was primarily assessed through patient or caregiver reports on quality-of-life impact, while standardized scales like the Abnormal Involuntary Movement Scale were underused, especially by psychiatrists. Physicians acknowledged significant challenges including a lack of highly effective treatments and an absence of specific Italian or European guidelines. TD was perceived as significantly affecting patients' physical and psychosocial functioning and increasing health care resource utilization. This study highlights variability and unmet needs in TD diagnosis and management among Italian specialists. Add-on treatments such as tetrabenazine are not considered standard of care in Italy due to lack of clinical practice guidelines, concerns around drug efficacy, adverse events, and overall treatment satisfaction.
Routinely collected health data are increasingly used to generate real-world evidence for therapeutic decision-making. Their use, however, depends on the expectations of multiple stakeholders. Clinicians require clinically interpretable analyses, pharmaceutical stakeholders need robust evidence on effectiveness and safety, patient advocacy groups emphasize transparency, privacy, and meaningful outcome measures, and statisticians focus on bias control, reproducibility, and methodological rigor. Without explicit consideration of these perspectives, analyses risk being fragmented, misaligned with end-user needs, or lacking transparency. Aligning these perspectives early in the design of routine data analyses therefore remains a central challenge. We developed a stakeholder-inclusive conceptual framework for modeling routine health data, through expert panel discussions, an interdisciplinary workshop and targeted literature examples. The synthesis focused on four stakeholder perspectives: clinicians, pharmaceutical industry, patient advocates, and statisticians. To illustrate how stakeholder priorities can be translated into analytical strategies, we reviewed selected applications of multistate models (MSMs) in routine health data settings. The conceptual framework links stakeholder-specific priorities, methodological requirements and identifies shared needs for analyses that are clinically meaningful, transparent, reproducible, and able to represent patient pathways, intermediate events, treatment trajectories, disease progression, safety outcomes, and patient-reported measures. While the framework is intended to be applicable across various analytical approaches MSMs are used here to illustrate how these diverse requirements can be operationalized in practice. They can capture longitudinal health processes, competing events, recurrent or intermediate states, and state-specific outcomes while retaining an interpretable graphical structure, and the reviewed examples show their applicability across different research questions using routine health data. Beyond specific methodological choices, clinical research relies fundamentally on statistical expertise. The framework also highlights that the statistician's role varies with the complexity of the research question, ranging from consultation on standard analyses to adaptation or development of advanced methods. The stakeholder-inclusive framework provides methodological guidance for designing analyses of routine health data that are clinically meaningful, scientifically rigorous, and socially acceptable. By aligning the research question with the intended perspective from the beginning, it supports more robust and transparent evidence generation, with multistate models serving as a flexible tool to operationalize this integration.
Chronic idiopathic axonal polyneuropathy (CIAP) is a common type of chronic polyneuropathy that often affects health-related quality of life. Currently, no patient-reported disease-specific outcome measure is available to assess functional deficit in patients with CIAP. The aim of this study was to construct a patient-reported Rasch-built interval scale for patients with CIAP. A historic prospective cohort study was conducted to develop a CIAP-specific Rasch-built overall disability scale (CIAP-RODS). The preliminary scale (pre-CIAP-RODS) comprised 196 items, including 146 activity and participation items selected from the World Health Organization International Classification of Functioning, Disability and Health and 50 expert-derived items formulated in collaboration with a CIAP patients advocacy group. Participants were patients with CIAP who were requested to score their perceived difficulty to perform each item as (0) unable to perform; (1) able to perform, but with difficulty; or (2) easily performed, without difficulty. For test-retest reliability studies, 150 participants completed the pre-CIAP-RODS twice with an interval of 2-4 weeks. The pre-CIAP-RODS was subjected to Rasch analyses (RUMM2030+) to develop the final CIAP-RODS, and external validity was assessed by examining associations with the European Quality of Life 5 Dimensions 3 Level Version (EQ-5D-3L). Of 551 eligible patients invited, 268 completed the pre-CIAP-RODS (mean age 72 years; 31% female; median disease duration 14 years). Patients with relevant comorbidities or newly identified risk factors of polyneuropathy were excluded. The pre-CIAP-RODS was subjected to Rasch analyses and did not meet the Rasch model expectations. In a systematic and stepwise manner, items were removed based on disordered thresholds, misfit statistics, local dependency, previously reported patient perceptions, and clinical applicability, resulting in a final 24-item CIAP-RODS that fulfilled Rasch model requirements. Test-retest reliability was good, internal validity was robust (person separation index 0.95), and significant associations between CIAP-RODS person location and EQ-5D-3L item scores indicated good discriminative external validity. The 24-item CIAP-RODS is a disease-specific interval measure developed for detection of activity and participation limitations in patients with CIAP. Use of the CIAP-RODS in future studies is recommended to evaluate longitudinal changes in the disease course. Further studies are needed to determine responsiveness and cross-cultural validity.
The burden of ischaemic stroke in Europe has evolved over recent decades, shaped by changes in prevention, acute care and population ageing. Understanding long-term trends in mortality and disability is essential for guiding policy and service planning. Using Global Burden of Disease (GBD) 2023 estimates, we analysed age-standardised disability-adjusted life years (DALYs), years of life lost (YLLs) and years lived with disability (YLDs) for ischaemic stroke across all European countries from 1990 to 2023. We estimated country-specific annual percentage changes (EAPCs), assessed non-linear trajectories, examined shifts in the fatal vs non-fatal composition of DALYs and synthesised trends using mixed-effects models and descriptive meta-analytic pooling. Disability-adjusted life year rates declined in every European country, with the steepest reductions in Central and Western Europe and more modest improvements in parts of Eastern and Southeastern Europe. Years of life lost declines closely paralleled DALY trends, indicating that falling premature mortality was the main driver of the overall reduction. Years lived with disability trends were smaller and more heterogeneous across countries. Mixed-effects modelling indicated average European EAPCs of -3.40% (95% CI, -3.74 to -3.05) for DALYs, -1.26% (-1.43 to -1.09) for YLLs and -3.86% (-4.26 to -3.46) for YLDs. Meta-analytic pooling of national patterns showed large declines in YLLs (random-effects EAPC -3.81%) relative to YLDs (-0.86%). Ischaemic stroke burden has fallen substantially across Europe, driven primarily by reductions in premature mortality. Slower progress in disability outcomes and persistent regional disparities highlight the need to strengthen long-term rehabilitation and address uneven improvements across the continent.