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- Early Mobilization Decision after an Acute Ischemic Stroke: Protocol for an Umbrella ReviewPublication . Fernandes, C; Sousa, JA; Bernardo-Castro, S; Silva, F; Donato, H; Sargento-Freitas, JIntroduction: Stroke is considered one of the greatest public health challenges worldwide, with the ischemic subtype being the most prevalent. Various acute stroke clinical guidelines recommend early rehabilitation interventions, including very early mobilization. However, despite the studies conducted in recent years regarding when to initiate mobilization after an acute stroke, there are few systematic and personalized protocols based on the factors for which patient mobilization should ideally be performed. We aim to conduct an umbrella review of systematic reviews and meta-analyses to study the early mobilization decision after an acute ischemic stroke in comparison with conventional care and correlate the different approaches with patient clinical outcomes.Methods and analysis: We will perform a systematic search on PubMed/MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Episte-monikos and Web of Science Core Collection databases. Retrieved studies will be independently reviewed by two authors and any discrepancies will be resolved by consensus or with a third reviewer. Reviewers will extract the data and assess the risk of bias in the selected studies. We will use the 16-item Assessment of Multiple Systematic Reviews 2 (AMSTAR2) checklist as the critical appraisal tool to assess cumulative evidence and risk of bias of the different studies. This will be the first umbrella review that compares early mobilization approaches in post-acute ischemic stroke. This study may help to define the optimal early mobilization strategy in stroke patients. PROSPERO registration number: CRD42023430494
- Early Mobilization Decision after an Acute Ischemic Stroke: Protocol for an Umbrella ReviewPublication . Fernandes, C; Sousa, JA; Bernardo-Castro, S; Silva, F; Donato, H; Sargento-Freitas, JIntroduction: Stroke is considered one of the greatest public health challenges worldwide, with the ischemic subtype being the most prevalent. Various acute stroke clinical guidelines recommend early rehabilitation interventions, including very early mobilization. However, despite the studies conducted in recent years regarding when to initiate mobilization after an acute stroke, there are few systematic and personalized protocols based on the factors for which patient mobilization should ideally be performed. We aim to conduct an umbrella review of systematic reviews and meta-analyses to study the early mobilization decision after an acute ischemic stroke in comparison with conventional care and correlate the different approaches with patient clinical outcomes. Methods and analysis: We will perform a systematic search on PubMed/MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Epistemonikos and Web of Science Core Collection databases. Retrieved studies will be independently reviewed by two authors and any discrepancies will be resolved by consensus or with a third reviewer. Reviewers will extract the data and assess the risk of bias in the selected studies. We will use the 16-item Assessment of Multiple Systematic Reviews 2 (AMSTAR2) checklist as the critical appraisal tool to assess cumulative evidence and risk of bias of the different studies. This will be the first umbrella review that compares early mobilization approaches in post-acute ischemic stroke. This study may help to define the optimal early mobilization strategy in stroke patients. PROSPERO registration number: CRD42023430494.
- CTA and CTP for Detecting Distal Medium Vessel Occlusions: A Systematic Review and Meta-analysisPublication . Sousa, JA; Sondermann, A; Bernardo-Castro, S; Varela, R; Donato, H; Sargento-Freitas, JBackground: The optimal imaging method for detecting distal medium vessel occlusions (DMVOs) remains undefined. Purpose: The objective of this study is to compare the diagnostic performance of CTA with CTP in detecting DMVOs. Data sources: We searched PubMed, EMBASE, Web of Science Core Collection, and Cochrane Central Register of Controlled Trials up to March 31, 2023 (PROSPERO: CRD42022344006). Study selection: A total of 12 studies reporting accuracy values of CTA and/or CTP were included, comprising 2607 patients with 479 cases (18.3%) of DMVOs. Data analysis: Pooled sensitivity and specificity of both imaging methods were compared using a random-effects model. Subgroup analyses were performed based on the technique used in CTA (multi or single-phase) and the subtype of DMVOs (M2-only vs. M2 and other DMVOs). We applied Quality Assessment of Diagnostic Accuracy (QUADAS-2) tool and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) quality assessment criteria. Data synthesis: CTA demonstrated significantly lower sensitivity compared to CTP in detecting DMVOs [0.74, 95%CI (0.63-0.82) vs. 0.89, 95% CI (0.82-0.93), P < 0.01]. When subgrouped into single-phase and multi-phase CTA, multi-phase CTA exhibited higher sensitivity for DMVO detection than single-phase CTA [0.91, 95%CI (0.85-0.94) vs. 0.64, 95%CI (0.56-0.71), P < .01], while reaching similar levels to CTP. The sensitivity of single-phase CTA substantially decreased when extending from M2 to other non-M2 DMVOs [0.74, 95%CI (0.63-0.83) vs. 0.61, 0.95%CI (0.53-0.68), P = .02]. Limitations: We identified an overall high risk of bias and low quality of evidence, attributable to the design and reference standards of most studies. Conclusions: Our findings highlight a significantly lower sensitivity of single-phase CTA compared to multi-phase CTA and CTP in diagnosing DMVOs.
- Diagnostic accuracy of CT angiography and CT perfusion imaging for detecting distal medium vessel occlusions: Protocol for a systematic review and meta-analysisPublication . Sousa, JA; Sondermann, A; Bernardo-Castro, S; Varela, R; Donato, H; Sargento-Freitas, JBackground: Distal medium vessel occlusions (DMVOs) represent 25-40% of all acute ischemic strokes (AIS). DMVO clinical syndromes are heterogenous, but as eloquent brain regions are frequently involved, they are often disabling. Since current intravenous fibrinolytic therapies may fail to recanalize up to two-thirds of DMVOs, endovascular treatment is progressively being considered in this setting. Nevertheless, the optimal imaging method for diagnosis remains to be defined. Stroke centers that use computed tomography as a routine stroke imaging approach rely on either isolated computed tomography angiography (CTA) or combined perfusion (CTP) studies. Despite a simplified non-CTP-dependent approach seeming reasonable for large vessel occlusion AIS diagnosis, CTP may still hold advantages for DMVOs workup. Therefore, this systematic review aims to compare the diagnostic performance of CTA and CTP in detecting DMVOs. Methods: We will perform a systematic search in PubMed, EMBASE, Web of Science Core Collection, and Cochrane Central Register of Controlled Trials. In addition, grey literature and ClinicalTrials.gov will be scanned. We will include any type of study that presents data on the diagnostic accuracy of CTA and/or CTP for detecting DMVOs. Two authors will independently review retrieved studies, and any discrepancies will be resolved by consensus or with a third reviewer. Reviewers will extract the data and assess the risk of bias in the selected studies. Data will be combined in a quantitative meta-analysis following the guidelines provided by the Cochrane Handbook for Systematic Reviews of Interventions. We will assess cumulative evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. Discussion: This will be the first systematic review and meta-analysis that compares two different imaging approaches for detecting DMVOs. This study may help to define optimal acute ischemic stroke imaging work-up. Trial registration: PROSPERO registration: CRD42022344006.
- Therapeutic Nanoparticles for the Different Phases of Ischemic StrokePublication . Bernardo-Castro, S; Albino, I; Barrera-Sandoval, ÁM; Tomatis, F; Sousa, JA; Martins, E; Simões, S; Lino, MM; Ferreira, L; Sargento-Freitas, JStroke represents the second leading cause of mortality and morbidity worldwide. Ischemic strokes are the most prevalent type of stroke, and they are characterized by a series of pathological events prompted by an arterial occlusion that leads to a heterogeneous pathophysiological response through different hemodynamic phases, namely the hyperacute, acute, subacute, and chronic phases. Stroke treatment is highly reliant on recanalization therapies, which are limited to only a subset of patients due to their narrow therapeutic window; hence, there is a huge need for new stroke treatments. Nonetheless, the vast majority of promising treatments are not effective in the clinical setting due to their inability to cross the blood-brain barrier and reach the brain. In this context, nanotechnology-based approaches such as nanoparticle drug delivery emerge as the most promising option. In this review, we will discuss the current status of nanotechnology in the setting of stroke, focusing on the diverse available nanoparticle approaches targeted to the different pathological and physiological repair mechanisms involved in each of the stroke phases.
- Pathophysiology of Blood–Brain Barrier Permeability Throughout the Different Stages of Ischemic Stroke and Its Implication on Hemorrhagic Transformation and RecoveryPublication . Bernardo-Castro, S; Sousa, JA; Brás, A; Cecília, C; Rodrigues, B; Almendra, L; Machado, C; Santo, G; Silva, F; Ferreira, L; Santana, I; Sargento-Freitas, JThe blood-brain barrier (BBB) is a dynamic interface responsible for maintaining the central nervous system homeostasis. Its unique characteristics allow protecting the brain from unwanted compounds, but its impairment is involved in a vast number of pathological conditions. Disruption of the BBB and increase in its permeability are key in the development of several neurological diseases and have been extensively studied in stroke. Ischemic stroke is the most prevalent type of stroke and is characterized by a myriad of pathological events triggered by an arterial occlusion that can eventually lead to fatal outcomes such as hemorrhagic transformation (HT). BBB permeability seems to follow a multiphasic pattern throughout the different stroke stages that have been associated with distinct biological substrates. In the hyperacute stage, sudden hypoxia damages the BBB, leading to cytotoxic edema and increased permeability; in the acute stage, the neuroinflammatory response aggravates the BBB injury, leading to higher permeability and a consequent risk of HT that can be motivated by reperfusion therapy; in the subacute stage (1-3 weeks), repair mechanisms take place, especially neoangiogenesis. Immature vessels show leaky BBB, but this permeability has been associated with improved clinical recovery. In the chronic stage (>6 weeks), an increase of BBB restoration factors leads the barrier to start decreasing its permeability. Nonetheless, permeability will persist to some degree several weeks after injury. Understanding the mechanisms behind BBB dysregulation and HT pathophysiology could potentially help guide acute stroke care decisions and the development of new therapeutic targets; however, effective translation into clinical practice is still lacking. In this review, we will address the different pathological and physiological repair mechanisms involved in BBB permeability through the different stages of ischemic stroke and their role in the development of HT and stroke recovery.
- Permeability of the blood-brain barrier through the phases of ischaemic stroke and relation with clinical outcome: protocol for a systematic reviewPublication . Bernardo-Castro, S; Donato, H; Ferreira, L; Sargento-Freitas, JIntroduction: Ischaemic stroke is the most prevalent type of stroke and is characterised by a myriad of pathological events triggered by a vascular arterial occlusion. Disruption of the blood-brain barrier (BBB) is a key pathological event that may lead to fatal outcomes. However, it seems to follow a multiphasic pattern that has been associated with distinct biological substrates and possibly contrasting outcomes. Addressing the BBB permeability (BBBP) along the different phases of stroke through imaging techniques could lead to a better understanding of the disease, improved patient selection for specific treatments and development of new therapeutic modalities and delivery methods. This systematic review will aim to comprehensively summarise the existing evidence regarding the evolution of the BBBP values during the different phases of an acute ischaemic stroke and correlate this event with the clinical outcome of the patient. Methods and analysis: We will conduct a computerised search on Medline, EMBASE, Cochrane Central Register of Controlled Trials, Scopus and Web of Science. In addition, grey literature and ClinicalTrials.gov will be scanned. We will include randomised controlled trials, cohort, cross-sectional and case-controlled studies on humans that quantitatively assess the BBBP in stroke. Retrieved studies will be independently reviewed by two authors and any discrepancies will be resolved by consensus or with a third reviewer. Reviewers will extract the data and assess the risk of bias of the selected studies. If possible, data will be combined in a quantitative meta-analysis following the guidelines provided by Cochrane Handbook for Systematic Reviews of Interventions. We will assess cumulative evidence using the Grading of Recommendations, Assessment, Development and Evaluation approach. Ethics and dissemination: Ethical approval is not needed. All data used for this work are publicly available. The result obtained from this work will be published in a peer-reviewed journal and disseminated in relevant conferences.
- Plasma exchange in severe acute relapses of multiple sclerosis - Results from a Portuguese cohortPublication . Correia, I; Ribeiro, JJ; Isidoro, L; Batista, S; Nunes, C; Macário, C; Borges, C; Tomaz, J; Sousa, LRelapses in Multiple Sclerosis (MS) are often associated with significant disability impairment which is resultant from poor response to corticosteroids. In such severe cases, plasma exchange (PLEX) may be used, although only a few studies with MS patients have been reported. Our objective was to evaluate the effectiveness of PLEX in severe relapses of MS. METHODS: Retrospective study of MS patients treated with PLEX in acute relapses. Data regarding EDSS, annualized relapse rate (ARR), treatment with corticosteroids, number of PLEX sessions, adverse events, and gadolinium enhancement in brain MRI were analysed. RESULTS: Included 46 patients, 76.09% female (n = 35) with mean age of 38.76 years and mean disease duration of 5.99 years, of which 84.78% had a Relapsing Remitting MS (n = 39), 15.22% Secondary Progressive MS (n = 7). The previous ARR was 1.1 and in 28.26% of the cases (n = 13) PLEX was used in the relapse that led to MS diagnosis. The majority of relapses had motor impairment (69.6%, n = 32), with a median EDSS increase of 1.5 points from baseline (maximum of 6.5) and higher than 1.5 points in 45.65% of cases (n = 21). Brain MRI was available in 69.57% of the cases (n = 32), and gadolinium enhancing lesions were present in 68.75% of cases (n = 22). Corticosteroids were used before PLEX in all patients for a mean of 6.09 days, without any immediate benefit in 41.30% of cases (n = 19), with the remaining cases showing only mild disability recovery. After a mean of 7.39 PLEX sessions, there was clinical benefit with complete EDSS recovery in 41.30% of patients (n = 19), and partial in 39.13% (n = 18). There were no adverse events related to PLEX in 89.13% of patients (n = 41) and in the remaining patients the reported adverse events included deep venous thrombosis (n = 1), anaemia (n = 1), fever (n = 1), hypoalbuminemia (n = 1) and arterial hypotension (n = 1). CONCLUSION: Our results support the use of PLEX in severe relapses unresponsive to corticosteroids, since it was an effective and relatively safe treatment for most of our patients.
- Apathy in multiple sclerosis: gender mattersPublication . Novo, AM; Batista, S; Tenente, J; Nunes, C; Macário, C; Sousa, L; Gonçalves, FApathy has been recognized as a frequent symptom in multiple sclerosis (MS) but uncertainty remains about its prevalence and clinical correlates. Therefore, the objective of this work was to assess the prevalence of apathy in patients with MS and to identify clinical and demographic correlates. A case-control study with 30 patients and 30 healthy controls matched for age, gender and education was performed. Apathy diagnosis was established using Robert et al.'s criteria. Additionally, apathy was assessed using the 10-item short version of the clinical-rated Apathy Evaluation Scale (AES-C-10). The Beck Depression Inventory (BDI), Modified Fatigue Impact Scale (MFIS), and Montreal Cognitive Assessment (MoCA) were used to evaluate depression, fatigue and cognitive impairment, respectively. Apathy prevalence in MS patients was 43.3%. Patients with MS had higher AES-C-10 scores than controls (13.9 vs. 12.0, p=0.015). Patients with apathy presented a higher proportion of males (53.8% vs. 11.8%, p=0.02), lower educational level (53.8% vs. 11.8% of patients with up to 9years of education), higher scores on cognitive dimension of MFIS (18.0 vs. 8.0, p=0.048) and BDI (13.0 vs. 7.0, p=0.035) and worse performance on MoCA (24.0 vs. 26.0, p=0.028). Gender was the only independent predictor of apathy, with men presenting a higher risk compared to women (OR: 9.62; 95%CI: 1.02-90.61; p=0.048). In conclusion, apathy is a common neuropsychiatric disorder in MS and it is probably underdiagnosed. Male patients seem to have an increased risk of apathy, and this finding may be related to the generally more unfavorable course of MS in men.
- Variations in multiple sclerosis practice within Europe - Is it time for a new treatment guideline?Publication . Marziniak, M; Ghorab, K; Kozubski, W; Pfleger, C; Sousa, L; Vernon, K; Zaffaroni, M; Meuth, SGIn the past 5 years, the combination of developments in diagnostic strategy and approval of new disease-modifying therapies has provided an opportunity to achieve dramatic improvements in patient outcomes in multiple sclerosis (MS). However, across Europe there are several factors that may prevent patients from receiving the best therapy at the appropriate time, and there is variation among countries in terms of which of these factors are most relevant. Here, we review current MS clinical practices in a number of countries in the European Union to identify differences regarding initiation of treatment in patients with clinically isolated syndrome or relapsing-remitting MS, and differences in the timing of treatment switch or escalation. While recognizing that policy is not static in any country, we believe that patients' interests would be better served if a European treatment guideline was developed. Such a guideline could both inform and be informed by national policies, facilitating the dissemination of best clinical practice internationally.