Impact of multiple sclerosis comorbidities on quality of life and job activity.

BACKGROUND: Multiple sclerosis (MS) is frequently accompanied by comorbid conditions. OBJECTIVES: This study aimed to determine the prevalence of key comorbid conditions in people with multiple sclerosis (pwMS) and assess their impact on quality of life and work-related activities. METHODS: A cross-sectional study involving 755 pwMS from two third-level Italian MS centers was conducted. Comorbidities were identified from medical records, and quality of life was assessed using the EQ-5D-3L questionnaire. Work-related challenges were evaluated using the Multiple Sclerosis Questionnaire for Job Difficulties (MSQ-Job). RESULTS: 53.8% of pwMS had at least one comorbidity. Hypertension, depression, and anxiety were the most prevalent. Comorbidity presence was associated with reduced quality of life scores in almost all EQ-5D-3L domains and greater job difficulties in all but one MSQ-Job domain. CONCLUSION: Comorbidities in pwMS are prevalent and have a profound influence on quality of life and work-related activities. This comprehensive study offers new insights into the role of comorbidities in MS within the Italian context, emphasizing the need for a multidisciplinary approach in MS management. Further research is crucial to deepen our understanding of these findings in the broader Italian MS community.

The administration of the paper and electronic versions of the Manual Ability Measure-36 (MAM-36) and Fatigue Severity Scale (FSS) is equivalent in people with multiple sclerosis.

BACKGROUND: The mobile device diffusion has increasingly highlighted the opportunity to collect patient-reported outcomes (PROs) through electronic patient-reported outcomes measurements (ePROMs) during the clinical routine. Despite the ePROMs promises and advantages, the equivalence when a PRO measure is moved from the original paper-and-pencil to the electronic version is still little investigated. This study aims at evaluating equivalence between PROMs and ePROMs self-administration in people with multiple sclerosis (PwMS); in addition, preference of self-administration type was evaluated. METHODS: The Manual Ability Measure-36 (MAM-36) and Fatigue Severity Scale (FSS) were selected for the equivalence test. The app ABOUTCOME was developed through a user-centered design approach to administer the questionnaires on tablet. Both paper-and-pencil and electronic versions were randomly self-administered. Intrarater reliability between both versions was evaluated through the intraclass correlation coefficient (ICC, excellent for values ≥ 0.75). RESULTS: Fifty PwMS (35 females) participated to the study (mean age: 54.7±11.0 years, disease course: 27 relapsing-remitting and 23 progressive; mean EDSS: 4.7±1.9; mean disease duration: 13.3±9.5 years). No statistically significant differences were found for the means total scores of MAM-36 (p = 0.61) and FSS (p = 0.78). The ICC value for MAM-36 and FSS was excellent (0.98 and 0.94, respectively). Most of participants preferred the tablet version (84%). CONCLUSION: The results of the study provide evidence about the equivalence between the paper-and-pencil and electronic versions of PROs administration. In addition, PwMS prefer electronic methods rather than paper because the information can be provided more efficiently and accurately. The results could be easily extended to other MS PROs.

[Registers as central real world data source: the experience of the Italian Multiple Sclerosis and Related Disorders Register]. / I registri come importante fonte di real world data: l'esperienza del Registro Italiano Sclerosi Multipla e Patologie Correlate.

Registers collecting data from clinical practice (real world data) have gained increasing interest in recent years in the scientific, administrative, and regulatory fields. The value of longitudinal data collection in deepening knowledge about a specific pathology and its healthcare complexity is increasingly recognized. This article describes the development, organizational structure, and technical characteristics of the Italian Multiple Sclerosis and Related Disorders Register (RISM). This multicentre and prospective study gathers demographic, clinical, and epidemiological data from the Italian population with multiple sclerosis and related diseases. The study, officially launched in 2015, but containing data collected since the 1990's, currently involves the active participation of 136 specialized clinical centres and more than 80,000 enrolled patients. The analysis of data in RISM allows for a detailed description of the characteristics of multiple sclerosis and related diseases, providing new insights useful for healthcare planning, cost evaluation, treatment efficacy and safety assessment, and scientific research studies. The main demographic and clinical data of enrolled patients are reported, with a focus on specific study cohorts. In a continuous effort to improve data quality, RISM has implemented specific quality indicators. Starting from the RISM experience, crucial aspects such as the institutional recognition of the disease register, the contribution that register can provide in pharmacovigilance studies, the organizational and management challenges, and privacy issues are discussed.

Job Retention by People With Disabilities: A Qualitative Study of the Perspectives of People With Multiple Sclerosis.

BACKGROUND: Multiple sclerosis (MS), because of its early age at onset, greatly impacts the working lives of those affected by it in ways linked to different factors, both professional and personal. It has been observed that only a small percentage (20-40%) of workers with MS retain their jobs after the diagnosis. When identifying factors determining job retention or loss in this setting, it is essential to consider the direct perspectives of people with MS (PwMS). METHODS: A qualitative study, based on the conduction of two focus groups, was conducted to explore the personal experiences of PwMS who work. RESULTS: The results show that there are numerous factors, both positive and negative, that can influence these people's ability to retain their jobs. The climate established in the workplace and the relationship between workers with MS and their colleagues were fundamentally important aspects, as was knowledge of the disease at the level of public opinion. CONCLUSIONS: Managing work is a complex undertaking for people with a disabling condition like MS. There needs to be greater awareness of the employment rights of PwMS. Improving these knowledge-based aspects could undoubtedly improve the quality of the working lives of PwM.

Occupational Physicians' Management of Workers With Multiple Sclerosis in Italy: Results From a Survey.

BACKGROUND: This study, conducted on a sample of Italian occupational physicians (OPs), aimed to gather data regarding professional activity and their needs in managing workers with multiple sclerosis. METHODS: A convenience sample of OPs recruited by e-mail invitation to the list of Italian Society of Occupational Medicine members was considered. A total of 220 OPs participated between July and October 2022. An ad hoc questionnaire was developed based on previous survey experiences. It investigated, among others, the characteristics of OP respondents, the evaluation of fitness for work issues, and the OP training and updating needs on multiple sclerosis and work. RESULTS: Ninety-one percent of OPs had to assess the fitness for work of workers with multiple sclerosis during their activity. Sixty-four percent experienced particular difficulties in issuing a fitness for work judgment. Regarding the level of knowledge on multiple sclerosis, 54% judged it sufficient. The "Assessment of fitness for work for the specific task" and the "Role of the OPs in identifying reasonable accommodations" were the most interesting training topics regarding MS management in work contexts chosen by the respondents. CONCLUSIONS: The interest in the work inclusion and job retention of people with disability, particularly the aspects linked to the Identification and implementation of reasonable accommodations, will require integration with the occupational safety and health protection system and will undoubtedly impact the OP's activities.

The economic impact of comorbidity in multiple sclerosis.

BACKGROUND: Comorbid conditions are common in people with multiple sclerosis (pwMS). They can delay diagnosis and negatively impact the disease course, progression of disability, therapeutic management, and adherence to treatment. OBJECTIVE: To quantify the economic impact of comorbidity in multiple sclerosis (MS), based on cost-of-illness estimates made using a bottom-up approach. METHODS: A retrospective study was carried out in two northern Italian areas. The socio-demographic and clinical information, including comorbidities data, were collected through ad hoc anonymous self-assessment questionnaire while disease costs (direct and indirect costs of disease and loss of productivity) were estimated using a bottom-up approach. Costs were compared between pwMS with and without comorbidity. Adjusted incremental costs associated with comorbidity were reported using generalized linear models with log-link and gamma distributions or two-part models. RESULTS: 51.0% of pwMS had at least one comorbid condition. Hypertension (21.0%), depression (15.7%), and anxiety (11.7%) were the most prevalent. PwMS with comorbidity were more likely to use healthcare resources, such as hospitalizations (OR = 1.21, p < 0.001), tests (OR = 1.59, p < 0.001), and symptomatic drugs and supplements (OR = 1.89, p = 0.012), and to incur non-healthcare costs related to investment (OR = 1.32, p < 0.001), transportation (OR = 1.33, p < 0.001), services (OR = 1.33, p < 0.001), and informal care (OR = 1.43, p = 0.16). Finally, they experienced greater productivity losses (OR = 1.34, p < 0.001) than pwMS without comorbidity. The adjusted incremental annual cost per patient due to comorbidity was €3,106.9 (13% of the overall costs) with MS disability found to exponentially affect annual costs. CONCLUSION: Comorbidity has health, social, and economic consequences for pwMS.

Data monitoring roadmap. The experience of the Italian Multiple Sclerosis and Related Disorders Register.

INTRODUCTION: Over the years, disease registers have been increasingly considered a source of reliable and valuable population studies. However, the validity and reliability of data from registers may be limited by missing data, selection bias or data quality not adequately evaluated or checked. This study reports the analysis of the consistency and completeness of the data in the Italian Multiple Sclerosis and Related Disorders Register. METHODS: The Register collects, through a standardized Web-based Application, unique patients. Data are exported bimonthly and evaluated to assess the updating and completeness, and to check the quality and consistency. Eight clinical indicators are evaluated. RESULTS: The Register counts 77,628 patients registered by 126 centres. The number of centres has increased over time, as their capacity to collect patients. The percentages of updated patients (with at least one visit in the last 24 months) have increased from 33% (enrolment period 2000-2015) to 60% (enrolment period 2016-2022). In the cohort of patients registered after 2016, there were ≥ 75% updated patients in 30% of the small centres (33), in 9% of the medium centres (11), and in all the large centres (2). Clinical indicators show significant improvement for the active patients, expanded disability status scale every 6 months or once every 12 months, visits every 6 months, first visit within 1 year and MRI every 12 months. CONCLUSIONS: Data from disease registers provide guidance for evidence-based health policies and research, so methods and strategies ensuring their quality and reliability are crucial and have several potential applications.

Work Difficulties in People with Multiple Sclerosis.

PURPOSE: This study identifies potential predictors of unemployment and describes specific work difficulties and their determinants in a subgroup of employed people with multiple sclerosis (PwMS). The specific work difficulties were evaluated using a validated tool that measures the impact of respondents' symptoms and of workplace features. METHODS: A cross-sectional study was carried out in Italy during 2021-2022. The subjects included were adults (18-65 years) with a diagnosis of MS, currently employed or unemployed. Logistic regression models were used to determine the association between each potential determinant and employment status, while linear regression models were used to determine the association between determinants and specific work difficulties. RESULTS: The main risk factors associated with a higher risk of being unemployed were being older, living in the South of Italy/islands, and having a higher disability level, while protective factors against unemployment were having a high level of education and 'stable' employment (an open-ended contract). Fatigue was found to be associated with all work difficulties analyzed; mood disorders emerged as the main predictors of mental health-related work difficulties; level of disability and comorbidity significantly impacted physical health-related ones, and a good quality of life was found to improve both workplace-related and mental health-related difficulties at work. CONCLUSION: Identifying the most significant difficulties is a crucial step in the development of vocational rehabilitation interventions tailored to maximize the ability of PwMS to handle their job-related duties and demands.

Work Barriers and Job Adjustments of People with Multiple Sclerosis: A Systematic Review.

Purpose The aim was to carry out a systematic review dedicated to describing the work barriers and the job adjustments that are particularly sensitive to people with Multiple Sclerosis (PwMS). Methods Four electronic databases (PubMed/MEDLINE, Scopus, SciVerse ScienceDirect, and Web of Science) were searched for peer-reviewed original articles reporting the barriers at work and/or the job adjustments used by PwMS. MS must have been diagnosed according to accepted international criteria at the time of the study and/or confirmed by a doctor. No time limits were set for the search. Articles that were published in English, Italian, Spanish, French, and Portuguese were accepted. Each article was screened by three experienced and trained investigators. The protocol was registered in PROSPERO (CRD42022299994). Results The initial systematic search yielded 104,228 results, of which 49 articles provided sufficient information and were considered suitable for inclusion in the study. Overall, the studies included 30283 participants with MS. Thirteen (27.1%) studies reported on barriers to work, 14 (29.2%) addressed reasonable adjustments and 21 (43.7%) assessed both outcomes. Job characteristics are the most important barriers for PwMS. Other reported barriers concern the work environment, social relationships at work, negative work events and lack of information. PwMS are more vulnerable to the need for adjustments at the workplace, being the management of the workload the most commonly used one. Conclusions PwMS are exposed to a wide variety of work barriers and job adjustments. Future studies are still highly encouraged on the topic.

Do patients' and referral centers' characteristics influence multiple sclerosis phenotypes? Results from the Italian multiple sclerosis and related disorders register.

BACKGROUND: Multiple sclerosis (MS) is characterized by phenotypical heterogeneity, partly resulting from demographic and environmental risk factors. Socio-economic factors and the characteristics of local MS facilities might also play a part. METHODS: This study included patients with a confirmed MS diagnosis enrolled in the Italian MS and Related Disorders Register in 2000-2021. Patients at first visit were classified as having a clinically isolated syndrome (CIS), relapsing-remitting (RR), primary progressive (PP), progressive-relapsing (PR), or secondary progressive MS (SP). Demographic and clinical characteristics were analyzed, with centers' characteristics, geographic macro-areas, and Deprivation Index. We computed the odds ratios (OR) for CIS, PP/PR, and SP phenotypes, compared to the RR, using multivariate, multinomial, mixed effects logistic regression models. RESULTS: In all 35,243 patients from 106 centers were included. The OR of presenting more advanced MS phenotypes than the RR phenotype at first visit significantly diminished in relation to calendar period. Females were at a significantly lower risk of a PP/PR or SP phenotype. Older age was associated with CIS, PP/PR, and SP. The risk of a longer interval between disease onset and first visit was lower for the CIS phenotype, but higher for PP/PR and SP. The probability of SP at first visit was greater in the South of Italy. DISCUSSION: Differences in the phenotype of MS patients first seen in Italian centers can be only partly explained by differences in the centers' characteristics. The demographic and socio-economic characteristics of MS patients seem to be the main determinants of the phenotypes at first referral.

The hidden information in patient-reported outcomes and clinician-assessed outcomes: multiple sclerosis as a proof of concept of a machine learning approach.

Machine learning (ML) applied to patient-reported (PROs) and clinical-assessed outcomes (CAOs) could favour a more predictive and personalized medicine. Our aim was to confirm the important role of applying ML to PROs and CAOs of people with relapsing-remitting (RR) and secondary progressive (SP) form of multiple sclerosis (MS), to promptly identifying information useful to predict disease progression. For our analysis, a dataset of 3398 evaluations from 810 persons with MS (PwMS) was adopted. Three steps were provided: course classification; extraction of the most relevant predictors at the next time point; prediction if the patient will experience the transition from RR to SP at the next time point. The Current Course Assignment (CCA) step correctly assigned the current MS course with an accuracy of about 86.0%. The MS course at the next time point can be predicted using the predictors selected in CCA. PROs/CAOs Evolution Prediction (PEP) followed by Future Course Assignment (FCA) was able to foresee the course at the next time point with an accuracy of 82.6%. Our results suggest that PROs and CAOs could help the clinician decision-making in their practice.

Italian validation of the Arm Function in Multiple Sclerosis Questionnaire (AMSQ).

INTRODUCTION: Arm and hand function deficits are commonly in people with multiple sclerosis (PwMS). The Arm Function in Multiple Sclerosis Questionnaire (AMSQ) is a novel self-administered instrument specifically developed to evaluate upper limb function in MS. The aim of this study was to translate and adapt the AMSQ into Italian and to assess its psychometric properties in PwMS. Validity (structural, construct, and known-groups) and reliability (internal consistency, test-retest, and measurement error) were assessed. MATERIALS AND METHODS: From June 2017 to February 2018, a prospective cohort of PwMS among those followed as outpatients at the Rehabilitation Services of the Italian Multiple Sclerosis Society (AISM) of Genoa, Padua, and Vicenza was involved in the study. Construct validity of AMSQ was determined by examining correlations with the Italian version of ABILHAND, Modified Fatigue Impact Scale (MFIS), and Functional Independence Measure (FIM). RESULTS: A total of 234 PwMS were enrolled. The mean AMSQ total score was 67.3 (SD = 38.4). Factor analysis results suggested one factor. As expected, moderate to high correlation coefficients were found between AMSQ and ABILHAND (- 0.79), MFIS (0.50) and its subsets, and FIM (- 0.60) and its subsets involving upper limb functioning. PwMS with higher EDSS reported worse total score of AMSQ than patients with low disability. The internal consistency of the 31 items was high (Cronbach's α, 0.98). Test-retest reliability, as measured with ICC, was 0.96 (95% IC, 0.93-0.98), and measurement error was about 8.3 points showing good reliability. DISCUSSION: AMSQ has been adapted and validated, it is a reliable questionnaire for Italian PwMS.

Self-assessment reliability in multiple sclerosis: the role of socio-demographic, clinical, and quality of life aspects.

INTRODUCTION: Several multiple sclerosis studies matching self- and physician assessment of disease course and disability show moderate and high agreement respectively. However, the role played by socio-demographic, clinical, and quality of life (QoL) factors was not much investigated. The study aims at exploring how self-/physician agreement could depend on these variables. MATERIALS AND METHODS: Participants were asked to report own disease course and disability according to preset categories. Kappa-value and confidence interval (CI) for disease course and two-way random interclass correlation coefficient (ICC) and CI for disability were calculated to evaluate self-/physician agreement. Χ2 was applied to examine whether other factors (gender, age, education, civil status, disease duration, fatigue, quality of life) had systematic effects. RESULTS: Data analysis on 203 participants indicated fair agreement (Kappa-value = 0.30; 95% CI 0.23-0.38) and no dependency on the categories of each variable for disease course. Satisfactory correlation was found for disability (ICC = 0.74; 95% IC 0.67-0.80), good agreement was found for almost all variable categories, and significant differences were observed for education (better agreement for higher levels), disease duration, fatigue and QoL (better agreement for worse conditions). DISCUSSION: Results seem to suggest that higher education and worse clinical and QoL conditions could engage the patient in developing more disease awareness and realistic self-perception and self-evaluation.

Disparity between perceived needs and service provision: a cross-sectional study of Italians with multiple sclerosis.

BACKGROUND: Assessing the coverage by public or private resources in meeting health-related and social-related needs may be useful for service planning and guide optimization of care, important especially in view of an increase in the prevalence of multiple sclerosis (MS). METHODS: An ad hoc questionnaire assessed satisfaction of health-related and social care-related needs in a cross-sectional study of 1014 people with MS identified through MS outpatient clinics and local branches and social media channels of the Italian MS Society. RESULTS: 87.1% and 79.8% of the responders had experienced at least one health-related or social-related need, respectively. The study demonstrated significant gaps between perceived needs and service provision. Rehabilitation, residential care, and psychological support were most frequently unsatisfied health-related needs, while the more commonly unmet social-related needs were financial support, elimination of architectural barriers, workplace adaptations, and career guidance. The multivariate analysis highlighted that the satisfaction of health-related needs was primarily associated with geographic area of residence. Social-related needs correlated with both clinical and sociodemographic aspects. CONCLUSION: The results provide insight into the range of interventions, care, and support people with MS report to be important to them at different points in their disease trajectory. More emphasis should be put on the inequitable distribution of NHS services in different geographic areas of Italy as well as on particularly fragile subgroups of the MS population (older individuals, and those with higher levels of disability) because the care of these individuals continues to be assumed by the family.

The Italian multiple sclerosis register.

The past decade has seen extraordinary increase in worldwide availability of and access to several large multiple sclerosis (MS) databases and registries. MS registries represent powerful tools to provide meaningful information on the burden, natural history, and long-term safety and effectiveness of treatments. Moreover, patients, physicians, industry, and policy makers have an active interest in real-world observational studies based on register data, as they have the potential to answer the questions that are most relevant to daily treatment decision-making. In 2014, the Italian MS Foundation, in collaboration with the Italian MS clinical centers, promoted and funded the creation of the Italian MS Register, a project in continuity with the existing Italian MS Database Network set up from 2001. Main objective of the Italian MS Register is to create an organized multicenter structure to collect data of all MS patients for better defining the disease epidemiology, improving quality of care, and promoting research projects in high-priority areas. The aim of this article is to present the current framework and network of the Italian MS register, including the methodology used to improve the quality of data collection and to facilitate the exchange of data and the collaboration among national and international groups.

Correction to: The Italian multiple sclerosis register.

Unfortunately in the original publication, the affiliation of the author Maria Pia Amato was incorrect. The author inadvertently missed out to include her second affiliation.

Randomized controlled trial of a home-based palliative approach for people with severe multiple sclerosis.

BACKGROUND: Evidence on the efficacy of palliative care in persons with severe multiple sclerosis (MS) is scarce. OBJECTIVE: To assess the efficacy of a home-based palliative approach (HPA) for adults with severe MS and their carers. METHODS: Adults with severe MS-carer dyads were assigned (2:1 ratio) to either HPA or usual care (UC). At each center, a multi-professional team delivered the 6-month intervention. A blind examiner assessed dyads at baseline, 3 months, and 6 months. Primary outcome measures were Palliative care Outcome Scale-Symptoms-MS (POS-S-MS) and Schedule for the Evaluation of Individual Quality of Life-Direct Weighting (SEIQoL-DW, not assessed in severely cognitively compromised patients). RESULTS: Of 78 dyads randomized, 76 (50 HPA, 26 UC) were analyzed. Symptom burden (POS-S-MS) significantly reduced in HPA group compared to UC ( p = 0.047). Effect size was 0.20 at 3 months and 0.32 at 6 months, and statistical significance was borderline in per-protocol analysis ( p = 0.062). Changes in SEIQoL-DW index did not differ in the two groups, as changes in secondary patient and carer outcomes. CONCLUSION: HPA slightly reduced symptoms burden. We found no evidence of HPA efficacy on patient quality of life and on secondary outcomes.

New insights into the burden and costs of multiple sclerosis in Europe: Results for Italy.

INTRODUCTION: In order to estimate the value of interventions in multiple sclerosis (MS) - where lifetime costs and outcomes cannot be observed - outcome data have to be combined with costs. This requires that cost data be regularly updated. OBJECTIVES AND METHODS: This study is part of a cross-sectional retrospective study in 16 countries collecting data on resource consumption and work capacity, health-related quality of life (HRQoL) and prevalent symptoms for patients with MS. Descriptive analyses are presented by level of severity, from the societal perspective, in EUR 2015. RESULTS: A total of 1010 patients (mean age = 45 years) participated in Italy. In total, 94% were below retirement age, and of these, 56% were employed. Employment was related to disability, and MS affected productivity at work in 77% of the patients. Overall, 96% and 65% of the patients experienced fatigue and cognitive difficulties as a problem, respectively. Mean utility and total annual costs were 0.735 and €22,900 at Expanded Disability Status Scale (EDSS) of 0-3, 0.534 and €40,100 at EDSS of 4-6.5, and 0.135 and €53,300 at EDSS of 7-9. The mean cost of a relapse was estimated to be €2600. CONCLUSION: This study illustrates the burden of MS on Italian patients and provides current data on MS that are important for the development of health policies.

Multiple sclerosis and rehabilitation: an overview of the different rehabilitation settings.

To date, a lack of accurate information about how the different rehabilitation settings are actually delivered to people with multiple sclerosis (PwMS) is still present. Here, we described how PwMS use the different rehabilitation settings in Italy. An observational retrospective study was designed and data collected through an anonymous questionnaire distributed attending MS clinical centers, rehabilitation units, or among PwMS affiliated to the Italian MS Society. We considered as settings: out-patient ambulatory therapy (OUT), hospitalized therapy (HOSP, in-patient and out-patient hospitalized therapy), and home-based therapy (HOME). One thousand six hundred eighty-six subjects at all disability levels were included in the analysis. A high number (53%, n = 890) did not receive rehabilitation care in the last 3 months before the interview. Main causes were probably due to organizational aspects and poor transports and road networks especially in Center and the Islands. The rehabilitation setting profile of the 796 subjects obtaining rehabilitation care consisted in 58.3% (n = 464) receiving only OUT setting, 9.4% (n = 75) only HOSP setting, and 21.7% (n = 173) only HOME setting. We observed a percentage of overlap among different rehabilitation settings: 3.9% (n = 31) OUT-HOME, 3.6% (n = 29) OUT-HOSP, 2.6% (n = 21) HOSP-HOME, and 0.4% (n = 3) OUT-HOME-HOSP. The physiotherapy was the treatment more common among different rehabilitation settings. Only in the in-patient hospitalized therapy setting, the patient received more frequently diversified treatment. Considering the results, the admission to rehabilitation care in Italy is still far from the standards outlined by the recent guidelines that hypothesize a multidisciplinary evaluation and a more individualized rehabilitation plan.

Endovascular treatment for acute ischemic stroke.

BACKGROUND: In patients with ischemic stroke, endovascular treatment results in a higher rate of recanalization of the affected cerebral artery than systemic intravenous thrombolytic therapy. However, comparison of the clinical efficacy of the two approaches is needed. METHODS: We randomly assigned 362 patients with acute ischemic stroke, within 4.5 hours after onset, to endovascular therapy (intraarterial thrombolysis with recombinant tissue plasminogen activator [t-PA], mechanical clot disruption or retrieval, or a combination of these approaches) or intravenous t-PA. Treatments were to be given as soon as possible after randomization. The primary outcome was survival free of disability (defined as a modified Rankin score of 0 or 1 on a scale of 0 to 6, with 0 indicating no symptoms, 1 no clinically significant disability despite symptoms, and 6 death) at 3 months. RESULTS: A total of 181 patients were assigned to receive endovascular therapy, and 181 intravenous t-PA. The median time from stroke onset to the start of treatment was 3.75 hours for endovascular therapy and 2.75 hours for intravenous t-PA (P<0.001). At 3 months, 55 patients in the endovascular-therapy group (30.4%) and 63 in the intravenous t-PA group (34.8%) were alive without disability (odds ratio adjusted for age, sex, stroke severity, and atrial fibrillation status at baseline, 0.71; 95% confidence interval, 0.44 to 1.14; P=0.16). Fatal or nonfatal symptomatic intracranial hemorrhage within 7 days occurred in 6% of the patients in each group, and there were no significant differences between groups in the rates of other serious adverse events or the case fatality rate. CONCLUSIONS: The results of this trial in patients with acute ischemic stroke indicate that endovascular therapy is not superior to standard treatment with intravenous t-PA. (Funded by the Italian Medicines Agency, ClinicalTrials.gov number, NCT00640367.).