Acute ischemic STROKE - from laboratory to the Patient's BED (STROKELABED): A translational approach to reperfusion injury. Study Protocol.

Cerebral edema (CE) and hemorrhagic transformation (HT) are frequent and unpredictable events in patients with acute ischemic stroke (AIS), even when an effective vessel recanalization has been achieved. These complications, related to blood-brain barrier (BBB) disruption, remain difficult to prevent or treat and may offset the beneficial effect of recanalization, and lead to poor outcomes. The aim of this translational study is to evaluate the association of circulating and imaging biomarkers with subsequent CE and HT in stroke patients with the dual purpose of investigating possible predictors as well as molecular dynamics underpinning those events and functional outcomes. Concurrently, the preclinical study will develop a new mouse model of middle cerebral artery (MCA) occlusion and recanalization to explore BBB alterations and their potentially harmful effects on tissue. The clinical section of the study is based on a single-center observational design enrolling consecutive patients with AIS in the anterior circulation territory, treated with recanalization therapies from October 1, 2015 to May 31, 2020. The study will employ an innovative evaluation of routine CT scans: in fact, we will assess and quantify the presence of CE and HT after stroke in CT scans at 24 h, through the quantification of anatomical distortion (AD), a measure of CE and HT. We will investigate the relationship of AD and several blood biomarkers of inflammation and extracellular matrix, with functional outcomes at 3 months. In parallel, we will employ a newly developed mouse model of stroke and recanalization, to investigate the emergence of BBB changes 24 h after the stroke onset. The close interaction between clinical and preclinical research can enhance our understanding of findings from each branch of research, enabling a deeper interpretation of the underlying mechanisms of reperfusion injury following recanalization treatment for AIS.

Quantitative EEG and prognosis for recovery in post-stroke patients: The effect of lesion laterality.

OBJECTIVE: There is emerging confidence that quantitative EEG (qEEG) has the potential to inform clinical decision-making and guide individualized rehabilitation after stroke, but consensus on the best EEG biomarkers is needed for translation to clinical practice. This study investigates the spatial qEEG spectral and symmetry distribution in patients with a left/right hemispheric stroke, to evaluate their side-specific prognostic power in post-acute rehabilitation outcome. METHODS: Resting-state 19-channel EEG recordings were collected with clinical information on admission to intensive inpatient rehabilitation (within 30 days post stroke), and six months post stroke. After preprocessing, spectral (Delta-to-Alpha Ratio, DAR) and symmetry (pairwise and hemispheric Brain Symmetry Index) features were extracted. Patients were divided into Affected Right and Left (AR/AL) groups, according to the location of their lesion. Within each group, DAR was compared between homologous electrode pairs and the pairwise difference between pairs was compared across pairs in the scalp. Then, the prognostic power of qEEG admission metrics was evaluated by performing correlations between admission metrics and discharge mBI values. RESULTS: Fifty-two patients with hemorrhagic or ischemic stroke (20 females, 38.5 %, median age 76 years [IQR = 22]) were included in the study. DAR was significantly higher in the affected hemisphere for both AR and AL groups, and, a higher frontal (to posterior) asymmetry was found independent of the side of the lesion. DAR was found to be a prognostic marker of 6-months modified Barthel Index (mBI) only for the AL group, while hemispheric asymmetry did not correlate with follow-up outcomes in either group. DISCUSSION: While the presence of EEG abnormalities in the affected hemisphere of a stroke is well recognized, we have shown that the extent of DAR abnormalities seen correlates with disability at 6 months post stroke, but only for left hemispheric lesions. Routine prognostic evaluation, in addition to motor and functional scales, can add information concerning neuro-prognostication and reveal neurophysiological abnormalities to be assessed during rehabilitation.

Trunk Control Test as a Main Predictor of the Modified Barthel Index Score at Discharge From Intensive Post-acute Stroke Rehabilitation: Results From a Multicenter Italian Study.

OBJECTIVES: To verify whether trunk control test (TCT) upon admission to intensive inpatient post-stroke rehabilitation, combined with other confounding variables, is independently associated with discharge mBI. DESIGN: Multicentric retrospective observational cohort study. SETTING: Two Italian inpatient rehabilitation units. PARTICIPANTS: A total of 220 post-stroke adult patients, within 30 days from the acute event, were consecutively enrolled. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: The outcome measure considered was the modified Barthel Index (mBI), one of the most widely recommended tools for assessing stroke rehabilitation functional outcomes. RESULTS: All variables collected at admission and significantly associated with mBI at discharge in the univariate analysis (TCT, mBI at admission, pre-stroke modified Rankin Scale [mRS], sex, age, communication ability, time from the event, Cumulative Illness Rating Scale, bladder catheter, and pressure ulcers) entered the multivariate analysis. TCT, mBI at admission, premorbid disability (mRS), communication ability and pressure ulcers (P<.001) independently predicted discharge mBI (adjusted R2=68.5%). Concerning the role of TCT, the model with all covariates and without TCT presented an R2 of 65.1%. On the other side, the model with the TCT only presented an R2 of 53.1%. Finally, with the inclusion of both TCT and all covariates, the model showed an R2 increase up to 68.5%. CONCLUSIONS: TCT, with other features suggesting functional/clinical complexity, collected upon admission to post-acute intensive inpatient stroke rehabilitation, independently predicted discharge mBI.

Predicting the functional outcome of intensive inpatient rehabilitation after stroke: results from the RIPS Study.

BACKGROUND: The complexity of stroke sequelae, the heterogeneity of outcome measures and rehabilitation pathways, and the lack of extensively validated prediction models represent a challenge in predicting stroke rehabilitation outcomes. AIM: To prospectively investigate a multidimensional set of variables collected at admission to inpatient post-stroke rehabilitation as potential predictors of the functional level at discharge. DESIGN: Multicentric prospective observational study. SETTING: Patients were enrolled in four Intensive Rehabilitation Units (IRUs). POPULATION: Patients were consecutively recruited in the period December 2019-December 2020 with the following inclusion criteria: aged 18+, with ischemic/haemorrhagic stroke, and undergoing inpatient rehabilitation within 30 days from stroke. METHODS: This is a multicentric prospective observational study. The rehabilitation pathway was reproducible and evidence-based. The functional outcome was disability in activities of daily living, measured by the modified Barthel Index (mBI) at discharge. Potential multidimensional predictors, assessed at admission, included demographics, event description, clinical assessment, functional and cognitive profile, and psycho-social domains. The variables statistically associated with the outcome in the univariate analysis were fed into a multivariable model using multiple linear regression. RESULTS: A total of 220 patients were included (median [IQR] age: 80 [15], 112 women, 175 ischemic). Median mBI was 26 (43) at admission and 62.5 (52) at discharge. In the multivariable analysis younger age, along with better functioning, fewer comorbidities, higher cognitive abilities, reduced stroke severity, and higher motor functions at admission, remained independently associated with higher discharge mBI. The final model allowed a reliable prediction of discharge functional outcome (adjusted R2=77.2%). CONCLUSIONS: The model presented in this study, based on easily collectable, reliable admission variables, could help clinicians and researchers to predict the discharge scores of the global functional outcome for persons enrolled in an evidence-based inpatient stroke rehabilitation program. CLINICAL REHABILITATION IMPACT: A reliable outcome prediction derived from standardized assessment measures and validated treatment protocols could guide clinicians in the management of patients in the subacute phase of stroke and help improve the planning of the rehabilitation individualized project.

Depressive Symptoms Moderate the Association Between Functional Level at Admission to Intensive Post-Stroke Rehabilitation and Effectiveness of the Intervention.

INTRODUCTION: Previous studies showed that depression acts as an independent factor in functional recovery after stroke. In a prospective cohort of patients admitted to intensive inpatient rehabilitation after a stroke, we aimed to test depression as a moderator of the relationship between the functional level at admission and the effectiveness of rehabilitation at discharge. METHODS: All patients admitted to within 30 days from an ischemic or hemorrhagic stroke to 4 intensive rehabilitation units were prospectively screened for eligibility to a multicenter prospective observational study. Enrolled patients underwent an evidence-based rehabilitation pathway. We used clinical data collected at admission (T0) and discharge (T1). The outcome was the effectiveness of recovery at T1 on the modified Barthel Index (proportion of achieved over potential functional improvement). Moderation analysis was performed by using the PROCESS macro for SPSS using the bootstrapping procedure. RESULTS: Of 278 evaluated patients, 234 were eligible and consented to enrolment; 81 patients were able to answer to the Hospital Anxiety and Depression Scale (HADS) and were included in this analysis. The relationship between the functional status at admission and rehabilitation effectiveness was significant only in persons with fewer depressive symptoms; depression (HADS cut-off score: 5.9) moderated this relationship (P = .047), independent from age and neurological impairment. CONCLUSIONS: Our results suggest that depression moderates between the functional status at admission and the functional recovery after post-stroke rehabilitation. This approach facilitates the identification of subgroups of individuals who may respond differently to stroke rehabilitation based on depression.

Correlates of participation six months after stroke in an Italian population: results from the RIPS (Post-Stroke Intensive Rehabilitation) Study.

BACKGROUND: Stroke survivors report physical, cognitive, and psychological impairments, with a consequent limitation of participation. Participation is the most context-related dimension of functioning, but the literature on participation in Italian stroke patients is scant. AIM: This study aimed to describe the recovery of participation six months after stroke with a validated Italian version of the Frenchay Activity Index (FAI) and to investigate potential correlates with higher participation scores. DESIGN: The study is a prospective observational study. SETTING: The cohort of patients was enrolled in four intensive inpatient rehabilitation units of IRCCS Fondazione Don Carlo Gnocchi Onlus, Florence, Italy. POPULATION: Adults addressing postacute intensive inpatient rehabilitation after an ischemic or hemorrhagic stroke occurred within 30 days from recruitment were prospectively enrolled. METHODS: Data were collected at admission to intensive inpatient rehabilitation, and a six-month follow-up. The primary outcome was participation, measured by a validated Italian version of the FAI; only patients whose data included both anamnestic FAI and FAI at six months follow-up were included in this analysis. The data were analyzed by univariate and multivariate linear regressions. RESULTS: A cohort of 105 patients (median age 78 years [interquartile range, IQR=21]; 46.7% males) with completed FAI at follow-up were included in this study. The sample reported a FAI median score of 28 (IQR=8) at admission (referred to the participation in the 3-6 months before the stroke) and 13 (IQR=20) at follow-up. All items were significantly affected, with the exception of reading and making trips. The multivariate regression for all patients with good participation before the stroke (N.=101), showed that 6 months after the stroke a higher FAI Score was independently associated with better functioning in activities of daily living (modified Barthel Index) (B=0.133; P=0.015), and absence of cognitive impairment (B=4.755; P=0.027); a lower stroke severity in the postacute phase (NIHSS B=-0.832; P=0.001) and a higher prestroke FAI Score (B=0.410; P=0.028) were also independently related to follow-up FAI Score. CONCLUSIONS: In our cohort of patients addressing postacute stroke rehabilitation, prestroke participation levels were on average good, while they were severely reduced six months after stroke for all the considered items except reading and making trips. Higher FAI at follow-up was independently associated with a higher functional level and no cognitive impairment at follow-up, with lower stroke severity in the postacute phase, as well as a higher anamnestic participation score. CLINICAL REHABILITATION IMPACT: Our results suggest that investigating prestroke participation may be highly relevant to predict, and possibly address, participation recovery after stroke.

Factors influencing trunk control recovery after intensive rehabilitation in post-stroke patients: a multicentre prospective study.

BACKGROUND: Trunk control plays a crucial role in the stroke rehabilitation, but it is unclear which factors could influence the trunk control after an intensive rehabilitation treatment. OBJECTIVES: To study which demographic, clinical and functional variables could predict the recovery of trunk control after intensive post-stroke inpatient rehabilitation. METHODS: Subjects with acute, first-ever stroke were enrolled and clinical and data were collected at admission and discharge. The primary outcome was considered the trunk control measured by the Trunk Control Test (TCT). The data were analyzed by a univariate and multivariate logistic regressions. RESULTS: Two hundred forty-one post-stroke patients were included. All baseline variables significantly associated to TCT at discharge in the univariate analysis (i.e. gender, NIHSS neglect item at admission, presence of several complexity markers, TCT total score at admission, NIHSS total score, pre-stroke modified Rankin Scale, Fugl-Meyer Assessment motor and sensitivity score) were entered in the multivariate analysis. The multivariate regression showed that age (p = .003), admission NIHSS total score (p = .001), admission TCT total score (p < .001) and presence of depression (p = .027) independently influenced the TCT total score at discharge (R2 = 61.2%). CONCLUSIONS: Age, admission neurological impairment (NIHSS total score), trunk control at the admission (TCT total score), and presence of depression independently influenced the TCT at discharge. These factors should be carefully assessed at the baseline to plan a tailoring rehabilitation treatment achieving the best trunk control performance at discharge.

Design and implementation of a Stroke Rehabilitation Registry for the systematic assessment of processes and outcomes and the development of data-driven prediction models: The STRATEGY study protocol.

Background: Stroke represents the second preventable cause of death after cardiovascular disease and the third global cause of disability. In countries where national registries of the clinical quality of stroke care have been established, the publication and sharing of the collected data have led to an improvement in the quality of care and survival of patients. However, information on rehabilitation processes and outcomes is often lacking, and predictors of functional outcomes remain poorly explored. This paper describes a multicenter study protocol to implement a Stroke rehabilitation Registry, mainly based on a multidimensional assessment proposed by the Italian Society of Physical and Rehabilitation Medicine (PMIC2020), in a pilot Italian cohort of stroke survivors undergoing post-acute inpatient rehabilitation, to provide a systematic assessment of processes and outcomes and develop data-driven prediction models of functional outcomes. Methods: All patients with a diagnosis of ischemic or haemorrhagic stroke confirmed by clinical assessment, admitted to intensive rehabilitation units within 30 days from the acute event, aged 18+, and providing informed consent will be enrolled. Measures will be taken at admission (T0), at discharge (T1), and at follow-up, 3 months (T2) and 6 months (T3) after the stroke. Assessment variables include anamnestic data, clinical and nursing complexity information and measures of body structures and function, activity and participation (PMIC2020), rehabilitation interventions, adverse events and discharge data. The modified Barthel Index will be our primary outcome. In addition to classical biostatistical analysis, learning algorithms will be cross-validated to achieve data-driven prognosis prediction models. Conclusions: This study will test the feasibility of a stroke rehabilitation registry in the Italian health context and provide a systematic assessment of processes and outcomes for quality assessment and benchmarking. By the development of data-driven prediction models in stroke rehabilitation, this study will pave the way for the development of decision support tools for patient-oriented therapy planning and rehabilitation outcomes maximization. Clinical tial registration: The registration on ClinicalTrials.gov is ongoing and under review. The identification number will be provided when the review process will be completed.

Translational Stroke Research Review: Using the Mouse to Model Human Futile Recanalization and Reperfusion Injury in Ischemic Brain Tissue.

The approach to reperfusion therapies in stroke patients is rapidly evolving, but there is still no explanation why a substantial proportion of patients have a poor clinical prognosis despite successful flow restoration. This issue of futile recanalization is explained here by three clinical cases, which, despite complete recanalization, have very different outcomes. Preclinical research is particularly suited to characterize the highly dynamic changes in acute ischemic stroke and identify potential treatment targets useful for clinical translation. This review surveys the efforts taken so far to achieve mouse models capable of investigating the neurovascular underpinnings of futile recanalization. We highlight the translational potential of targeting tissue reperfusion in fully recanalized mouse models and of investigating the underlying pathophysiological mechanisms from subcellular to tissue scale. We suggest that stroke preclinical research should increasingly drive forward a continuous and circular dialogue with clinical research. When the preclinical and the clinical stroke research are consistent, translational success will follow.

Critical issue on the extinction and inattention subtest of NIHSS scale: an analysis on post-acute stroke patients attending inpatient rehabilitation.

OBJECTIVES: This study aims to evaluate the diagnostic performance of NIHSS extinction and inattention item, compared to the results of the Oxford Cognitive Screen (OCS) heart subtest. Additionally, the possible role of the NIHSS visual field subtest on the NIHSS extinction and inattention subtest performance is explored and discussed. METHODS: We analysed scores on NIHSS extinction and inattention subtest, NIHSS visual field subtest, and OCS heart subtest on a sample of 118 post-stroke patients. RESULTS: Compared to OCS heart subtest, the results on NIHSS extinction and inattention subtest showed an accuracy of 72.9% and a moderate agreement level (Cohen's kappa = 0.404). Furthermore, a decrease in NIHSS accuracy detecting neglect (61.1%) was observed in patients with pathological scores in NIHSS visual field item. CONCLUSIONS: Extreme caution is recommended for the diagnostic performance of extinction and inattention item of NIHSS. Signs of neglect may not be detected by NIHSS, and may be confused with visual field impairment. TRIAL REGISTRATION: This study refers to an observational study protocol submitted to ClinicalTrials.gov with identifier: NCT03968627 . The name of the registry is "Development of a National Protocol for Stroke Rehabilitation in a Multicenter Italian Institution" and the date of the registration is the 30th May 2019.

Blood-brain barrier leakage and hemorrhagic transformation: The Reperfusion Injury in Ischemic StroKe (RISK) study.

BACKGROUND AND PURPOSE: In patients with acute ischemic stroke treated with reperfusion therapy we aimed to evaluate whether pretreatment blood-brain barrier (BBB) leakage is associated with subsequent hemorrhagic transformation (HT). METHODS: We prospectively screened patients with acute ischemic stroke treated with intravenous thrombolysis and/or endovascular treatment. Before treatment, each patient received computed tomography (CT), CT angiography, and CT perfusion. We assessed pretreatment BBB leakage within the ischemic area using the volume transfer constant (Ktrans ) value. Our primary outcome was relevant HT, defined as hemorrhagic infarction type 2 or parenchymal hemorrhage type 1 or 2. We evaluated independent associations between BBB leakage and HT using logistic regression, adjusting for age, sex, baseline stroke severity, Alberta Stroke Program Early CT Score (ASPECTS) ≥ 6, treatment type, and onset-to-treatment time. RESULTS: We enrolled 171 patients with available assessment of BBB leakage. The patients' mean (±SD) age was 75.5 (±11.8) years, 86 (50%) were men, and the median (interquartile range) National Institutes of Health Stroke Scale score was 18 (12-23). A total of 32 patients (18%) received intravenous thrombolysis, 102 (60%) underwent direct endovascular treatment, and 37 (22%) underwent both. Patients with relevant HT (N = 31;18%) had greater mean BBB leakage (Ktrans 0.77 vs. 0.60; p = 0.027). After adjustment in the logistic regression model, we found that BBB leakage was associated both with a more than twofold risk of relevant HT (odds ratio [OR] 2.50; 95% confidence interval [CI] 1.03-6.03 per Ktrans point increase; OR 2.34; 95% CI 1.06-5.17 for Ktrans values > 0.63 [mean BBB leakage value]) and with symptomatic intracerebral hemorrhage (OR 4.30; 95% CI 1.13-13.77 per Ktrans point increase). CONCLUSION: Pretreatment BBB leakage before reperfusion therapy was associated with HT, and may help to identify patients at risk of HT.

Acute Symptomatic Sinus Bradycardia in High-Dose Methylprednisolone Therapy in a Woman With Inflammatory Myelitis: A Case Report and Review of the Literature.

High dose corticosteroid therapy is widely used as attack therapy of inflammatory central nervous system disorders and can induce several adverse reactions. Bradycardia is an infrequent event after corticosteroids administration and is often asymptomatic. We report a case of a woman admitted to the neurological department of our hospital for paraesthesias of the lower limbs. She received adiagnosis of inflammatory myelitis and high dose corticosteroid therapy was prescribed. During the therapy she complained of chest tightness, dyspnoea, weakness and malaise. An electrocardiogram revealed sinus bradycardia. A significant increase in body weight, probably due to plasma volume expansion, was detected. Bradycardia and high blood pressure spontaneously resolved in few days. We provide a collection and a statistical analysis of literature data about steroid induced bradycardia. We found that higher total doses are associated with lower pulse rate and symptomatic bradycardia. Bradycardia is more frequent in older patients and those with underlying cardiac disease or with autonomic disturbance. However clinicians must be aware about the occurrence of symptomatic bradycardia in all patients who undergo high dose corticosteroid therapy, not only in those at risk, to early detect and treat this potentially dangerous condition.

Differentiation between Subtypes of Primary Progressive Aphasia by Using Cortical Thickness and Diffusion-Tensor MR Imaging Measures.

PURPOSE: To test a multimodal magnetic resonance (MR) imaging-based approach composed of cortical thickness and white matter (WM) damage metrics to discriminate between variants of primary progressive aphasia (PPA) that are nonfluent and/or agrammatic (NFVPPA) and semantic (SVPPA). MATERIALS AND METHODS: This study was approved by the local ethics committees on human studies, and written informed consent from all patients was obtained before their enrollment. T1-weighted and diffusion-tensor (DT) MR images were obtained from 13 NFVPPA patients, 13 SVPPA patients, and 23 healthy control participants. Cortical thickness and DT MR imaging indices from the long-associative and interhemispheric WM tracts were obtained. A random forest (RF) analysis was used to identify the image features associated with each clinical syndrome. Individual patient classification was performed by using receiver operator characteristic curve analysis with cortical thickness, DT MR imaging, and a combination of the two modalities. RESULTS RF analysis showed that the best markers to differentiate the two PPA variants at an individual patient level among cortical thickness and DT MR imaging metrics were diffusivity abnormalities of the left inferior longitudinal and uncinate fasciculi and cortical thickness measures of the left temporal pole and inferior frontal gyrus. A combination of cortical thickness and DT MR imaging measures (the so-called gray-matter-and-WM model) was able to distinguish patients with NFVPPA and SVPPA with the following classification pattern: area under the curve, 0.91; accuracy, 0.89; sensitivity, 0.92; specificity, 0.85. Leave-one-out analysis demonstrated that the gray matter and WM model is more robust than the single MR modality models to distinguish PPA variants (accuracy was 0.86, 0.73, and 0.68 for the gray matter and WM model, the gray matter-only model, and the WM-only model, respectively). CONCLUSION: A combination of structural and DT MR imaging metrics may provide a quantitative procedure to distinguish NFVPPA and SVPPA patients at an individual patient level. The discrimination accuracies obtained suggest that the gray matter and WM model is potentially relevant for the differential diagnosis of the PPA variants in clinical practice.