Patient-reported outcomes (PROs) are essential for understanding the effects of MS and its treatments on patients\' lives; they play an important role in multiple sclerosis (MS) research and practice. We present the protocol for an observational study to prospectively assess the effect of cladribine tablets on PROs and their correlation to disability and physical activity in adults with highly active relapsing MS switching from a first disease modifying drug (DMD) to cladribine tablets in routine clinical practice at study sites in Italy. The primary objective will be to evaluate changes from baseline in the impact of highly active MS on self-assessed physical functioning 52 weeks after the switch to cladribine tablets using the Multiple Sclerosis Impact Scale-29 (MSIS-29). Secondary objectives will include self-assessed psychological impact of highly active MS in daily life and general health after the switch to cladribine tablets as well as changes in cognitive function, anxiety, and depression symptoms. Additional PRO measures will include the Hospital Anxiety and Depression Scale (HADS), the EuroQoL 5-Dimension 5-Level (EQ-5D-5L), the Work Productivity and Activity Impairment Questionnaire: Multiple Sclerosis (WPAI:MS), and the Patient-Reported Outcomes Measurement Information System (PROMIS). Wearable devices will acquire activity data (step counts, walking speed, time asleep, and energy expenditure). Additional clinical, radiological, and laboratory data will be collected when available during routine management. The findings will complement data from controlled trials by providing insight from daily clinical practice into the effect of cladribine tablets on the patient\'s experience and self-assessed impact of treatment on daily life.

Serum neurofilament light chain (sNfL) levels have been proposed as a biomarker of the clinical activity, disability progression, and response to treatment of people with multiple sclerosis (PwMS); however, questions remain about its implementation in clinical practice. Ocrelizumab (OCR) has proven effective in improving clinical and radiological outcomes and reducing sNfL levels. This real-life study followed the sNfL levels of 30 PwMS treated for 12 months with OCR and evaluated the usefulness of this biomarker for their short-term prognosis, considering expanded disability status scale (EDSS), annualized relapse rate (ARR), radiological activity, and NEDA-3 values. OCR reduced ARR in 83% of PwMS and radiological activity in 80%. EDSS was maintained, while NEDA-3 was achieved in 70% at 12 months. OCR produced an early reduction in sNfL levels (at 3 months). At baseline, greater MRI-evaluated radiological activity was associated with higher sNfL levels. sNfL levels over the first 12 months of treatment did not predict a suboptimal response or sustained control of the disease. Longer-term studies are needed to explore the predictive usefulness of sNfL levels in PwMS treated with high-efficacy drugs.

BACKGROUND: As disease-modifying Alzheimer\'s (AD) treatments are becoming available, concerns have been raised that even high-income countries lack the diagnostic capacity to accurately identify eligible patients in a timely manner.
OBJECTIVE: We analyze how much NHS England would have to invest in capacity for AD specialists, biomarker testing with PET scans or CSF testing and MRI scans to reach G7 average levels and estimate the effect on wait times in the diagnostic process.
METHODS: Desk research and expert interviews for cost and capacity data. Markov model to estimate wait times.
METHODS: NHS England.
METHODS: AD specialists, and PET and MRI scanners per capita in G7 countries and wait times in England under different investment scenarios.
RESULTS: England has the lowest number of PET and MRI scanners and the second-lowest of AD specialists per capita among the G7 countries. An investment of GBP 14 billion over ten years would be needed to reach G7 average levels, of which 31%, 22%, 10%, 37% would be devoted to capacity for memory assessment services, PET scanning, CSF analysis, and MRI scanning, respectively. This investment would reduce estimated average wait times by around 87% between 2023 and 2032.
CONCLUSIONS: The NHS England has large gaps in diagnostic capacity for AD. Without substantial investments, AD patients in England would experience substantial wait times and avoidable disease progression.

BACKGROUND: Recent developments in blood biomarkers (BBM) have shown promising results in diagnosing amyloid pathology in Alzheimer\'s Disease (AD). However, information on how these BBMs can best be used in clinical settings to optimise clinical decision-making and long-term health outcomes for individuals with AD is still lacking.
OBJECTIVE: We aim to assess the potential value of BBM in AD diagnosis within the context of disease-modifying treatment (DMT).
METHODS: We developed a decision analytic model to evaluate the long-term health outcomes using BBM in AD diagnosis. We compared standard of care (SOC) diagnosis workflow to the integration of BBM as a (1) referral decision tool in primary health center (PHC) and (2) triaging tool for invasive CSF examination in specialist memory clinic (MC). We combined a decision tree and a Markov model to simulate the patient\'s diagnostic journey, treatment decisions following diagnosis and long-term health outcomes. Input parameters for the model were identified from published literature and registry data analysis. We conducted a cost-utility analysis from the societal perspective using a one-year cycle length and a 30-year (lifetime) horizon.
METHODS: We reported the simulated outcomes in the percentage of correct diagnosis, costs (in 2022 Euros), quality-adjusted life year (QALY), and incremental cost-effectiveness ratios (ICER) associated with each diagnosis strategy.
RESULTS: Compared to SOC, integrating BBM in PHC increased patient referrals by 8% and true positive AD diagnoses by 10.4%. The lifetime costs for individuals diagnosed with AD were € 249,685 and €250,287, and QALYs were 9.5 and 9.52 in SOC and PHC pathways, respectively. The cost increments were €603, and QALYs gained were 0.01, resulting in an ICER of €48,296. Using BBM in MC reduced the exposure to invasive CSF procedures and costs but also reduced true positive AD diagnoses and QALYs.
CONCLUSIONS: Using BBM at PHC to make referral decisions might increase initial diagnostic costs but can prevent high costs associated with disease progression, providing a cost-effective DMT is available, whereas using BBM in MC could reduce the initial evaluation cost but incur high costs associated with disease progression.

UNASSIGNED: Uncertainty about disproportionate impact on health care budgets limits implementation of early highly effective treatment (EHT) in multiple sclerosis (MS).
UNASSIGNED: To estimate cost-effectiveness of escalation versus EHT disease-modifying treatment (DMT) sequences.
UNASSIGNED: Using a health-economic approach, we analysed health benefits (relapse rate reduction, disability prevention), direct/indirect DMT and societal costs of escalation versus EHT DMT sequences. In scenario analyses, we allowed (1) earlier use of alemtuzumab (ALE) and (2) a single retreatment with cladribine (CLA).
UNASSIGNED: In our model, we showed that the ratio between costs and quality-adjusted life years (QALYs) for the most cost-effective EHT and escalation sequence results into a similar net health benefit with higher costs and also higher QALYs associated with an EHT versus escalation strategy. Earlier use of ALE is more cost-effective than in later lines, even when aggravating the impact of its side-effects tenfold. Retreatment with CLA was more cost-effective in both escalation and EHT sequences.
UNASSIGNED: Certain EHT sequences are equally cost-effective to escalation sequences and are likely to result in more health at uncertain additional costs. The favourable cost-benefit ratio of CLA and ALE suggests that a wider application of affordable highly effective therapies could promote the cost-effectiveness both EHT and escalation approaches.

Parkinson\'s disease (PD) has a long, heterogeneous, pre-diagnostic phase, during which pathology insidiously accumulates. Increasing evidence suggests that environmental and lifestyle factors in early life contribute to disease risk and progression. Thanks to the extensive study of this pre-diagnostic phase, the first prevention trials of PD are being designed. However, the highly heterogenous evolution of the disease across the life course is not yet sufficiently taken into account. This could hamper clinical trial success in the advent of biological disease definitions. In an interdisciplinary patient-clinician study group, we discussed how an approach that incorporates the lifetime evolution of PD may benefit the design of disease-modifying trials by impacting population, target and outcome selection. We argue that the timepoint of exposure to risk and protective factors plays a critical role in PD subtypes, influencing population selection. In addition, recent developments in differential disease mechanisms, aided by biological disease definitions, could impact optimal treatment targets. Finally, multimodal biomarker panels using this lifetime approach will likely be most sensitive as progression markers for more personalized trials. We believe that the lifetime evolution of PD should be considered in the design of clinical trials, and that such initiatives could benefit from more patient-clinician partnerships.

Disease-modifying therapies (DMTs) for multiple sclerosis (MS) reduce relapse frequency, magnetic resonance imaging (MRI) activity, and slow disability progression. Numerous DMTs are approved for relapsing forms of MS although real-world data on patient-reported outcomes (PROs) and quality of life (QoL) are needed to inform treatment choice. Immune reconstitution therapy with cladribine tablets is a highly effective treatment for relapsing MS (RMS). We present the protocol for an observational study to prospectively assess the effectiveness of cladribine tablets on clinical and MRI parameters as well as on PROs, including treatment satisfaction, QoL, sleep quality, self-perceived health, fatigue, and physical function. Enrolled patients at study sites in Italy will be adults with RMS (including relapsing-remitting and active secondary progressive MS) who are either treatment naïve or have received at least one first-line disease modifying DMT or no more than one second-line DMT. The primary objective will be change in global treatment satisfaction measured with the Treatment Satisfaction Questionnaire for Medication Version 1.4 approximately 24 months after initiating cladribine tablets in patients switching from previous DMTs. Secondary objectives will include global treatment satisfaction at earlier timepoints, will comprise treatment naïve patients, and will quantify treatment effectiveness and tolerability. We will also assess relapses, disability progression, MRI activity, and other PROs at approximately 12 and 24 months. The findings will provide insight from daily clinical practice into the patient\'s experience to complement data from controlled trials and inform treatment choice. EU PAS Registration Number EUPAS49334 filed 17/10/2022.

Despite the proven efficacy of the disease-modifying therapy (DMT) for multiple sclerosis (MS), the rates of non-adherence are frequently high. We aimed to evaluate the rate of non-adherence to the first DMT in Upper Egypt and identify different contributing factors. Out of 310 patients, ninety-seven adult patients with RRMS were recruited from three MS units located in Upper Egypt and were subjected to the following: complete clinical history, expanded disability status score (EDSS), Eight-item Morisky Medication Adherence Scale (MMAS-8), abbreviated Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9), Hamilton depression scale, Fatigue Severity Scale (FSS) and the Pittsburgh Sleep Quality Index (PSQI). According to MMAS-8 scores, 63 (64.9%) of patients were non-adherent to their first DMT. Non-adherent patients are more likely to have longer disease duration (p = 0.002), longer duration on first DMT (p = 0.030), first DMT-start date before 2019 (p = 0.040), and lower treatment satisfaction scores (p = 0.016). However, there was no significant relation with physical disability, depression, fatigue, or sleep quality. On the regression analysis model, a lower treatment satisfaction score was the only predictor of DMT non-adherence (p = 0.012). Despite expanding DMT options, non-adherence among MS patients in Upper Egypt is high. Treatment satisfaction with DMT is the only predictor of adherence among MS patients of Upper Egypt. Adherence and satisfaction with the prescribed DMT should be assessed carefully to maximize DMT benefits.

UNASSIGNED: To evaluate the safety of growth-friendly instrumentation for early-onset scoliosis (EOS) in patients with spinal muscular atrophy (SMA) type 1 who received disease-modifying treatment (DMT) and analyze short-term efficacy.
UNASSIGNED: Retrospective search was conducted between 2017 and 2023. Patients with genetically confirmed SMA type 1 who were surgically treated for spinal deformity and receiving DMTs (nusinersen, risdiplam, or onasemnogene abeparvovec) were included. SMA types 2 and 3 and patients who do not receive DMTs were excluded. Clinical and radiographic data were collected at preoperative, postoperative, and latest follow-up visits.
UNASSIGNED: Twenty-eight patients (mean follow-up: 16 months (range 2-41)) were included. The mean age at surgery was 60 months (range 29-96). Fifteen were treated with dual magnetically controlled growing rods (MCGR), four with unilateral MCGR and a contralateral guided growth system, three with Vertical Expandable Prosthetic Titanium Rib (VEPTR®) implants, five with self-distracting systems, and one with traditional dual growing rods. The mean amount of correction was 57% (44°± 17) for scoliosis and 83% (13°± 11) for pelvic obliquity. The mean T1-12 height gain during surgery was 31 mm (±16 mm), while the mean T1 S1 height gain was 51 mm (±24 mm), and instrumented growth was observed during follow-up. Five patients (18%) developed six serious adverse events: three surgical site infections, two anchor failures, and one rod fracture, and all required unplanned reoperations. No neurologic complication, difficulty during nusinersen injections, or respiratory decline was recorded.
UNASSIGNED: We report that spinal deformity in this population can be safely treated with growth-friendly instrumentation, with similar complication rates when compared with SMA type 2.

Myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS), and congenital myasthenic syndromes (CMS) represent an etiologically heterogeneous group of (very) rare chronic diseases. MG and LEMS have an autoimmune-mediated etiology, while CMS are genetic disorders. A (strain dependent) muscle weakness due to neuromuscular transmission disorder is a common feature. Generalized MG requires increasingly differentiated therapeutic strategies that consider the enormous therapeutic developments of recent years. To include the newest therapy recommendations, a comprehensive update of the available German-language guideline \'Diagnostics and therapy of myasthenic syndromes\' has been published by the German Neurological society with the aid of an interdisciplinary expert panel. This paper is an adapted translation of the updated and partly newly developed treatment guideline. It defines the rapid achievement of complete disease control in myasthenic patients as a central treatment goal. The use of standard therapies, as well as modern immunotherapeutics, is subject to a staged regimen that takes into account autoantibody status and disease activity. With the advent of modern, fast-acting immunomodulators, disease activity assessment has become pivotal and requires evaluation of the clinical course, including severity and required therapies. Applying MG-specific scores and classifications such as Myasthenia Gravis Activities of Daily Living, Quantitative Myasthenia Gravis, and Myasthenia Gravis Foundation of America allows differentiation between mild/moderate and (highly) active (including refractory) disease. Therapy decisions must consider age, thymic pathology, antibody status, and disease activity. Glucocorticosteroids and the classical immunosuppressants (primarily azathioprine) are the basic immunotherapeutics to treat mild/moderate to (highly) active generalized MG/young MG and ocular MG. Thymectomy is indicated as a treatment for thymoma-associated MG and generalized MG with acetylcholine receptor antibody (AChR-Ab)-positive status. In (highly) active generalized MG, complement inhibitors (currently eculizumab and ravulizumab) or neonatal Fc receptor modulators (currently efgartigimod) are recommended for AChR-Ab-positive status and rituximab for muscle-specific receptor tyrosine kinase (MuSK)-Ab-positive status. Specific treatment for myasthenic crises requires plasmapheresis, immunoadsorption, or IVIG. Specific aspects of ocular, juvenile, and congenital myasthenia are highlighted. The guideline will be further developed based on new study results for other immunomodulators and biomarkers that aid the accurate measurement of disease activity.