Association Between Stroke Severity and Serum Troponin in Acute Stroke.

Serum troponin is often elevated in patients with acute stroke and its mechanism is unknown. In a retrospective single-center cohort study, we evaluated the association between stroke severity and serum troponin in 187 patients with acute stroke using multivariable modified Poisson models. A one-point increase in the National Institutes of Health Stroke Scale (measure of stroke severity) was associated with a marginally higher serum troponin level in adjusted models (aIRR 1.03; 1.01-1.05, P = 0.001). The modest, yet potentially independent, association between stroke severity and serum troponins could suggest a neurogenic basis for a cardiac injury in patients with acute stroke.

Relative independence of upper limb position sense and reaching in children with hemiparetic perinatal stroke.

BACKGROUND: Studies using clinical measures have suggested that proprioceptive dysfunction is related to motor impairment of the upper extremity following adult stroke. We used robotic technology and clinical measures to assess the relationship between position sense and reaching with the hemiparetic upper limb in children with perinatal stroke. METHODS: Prospective term-born children with magnetic resonance imaging-confirmed perinatal ischemic stroke and upper extremity deficits were recruited from a population-based cohort. Neurotypical controls were recruited from the community. Participants completed two tasks in the Kinarm robot: arm position-matching (three parameters: variability [Varxy], contraction/expansion [Areaxy], systematic spatial shift [Shiftxy]) and visually guided reaching (five parameters: posture speed [PS], reaction time [RT], initial direction error [IDE], speed maxima count [SMC], movement time [MT]). Additional clinical assessments of sensory (thumb localization test) and motor impairment (Assisting Hand Assessment, Chedoke-McMaster Stroke Assessment) were completed and compared to robotic measures. RESULTS: Forty-eight children with stroke (26 arterial, 22 venous, mean age: 12.0 ± 4.0 years) and 145 controls (mean age: 12.8 ± 3.9 years) completed both tasks. Position-matching performance in children with stroke did not correlate with performance on the visually guided reaching task. Robotic sensory and motor measures correlated with only some clinical tests. For example, AHA scores correlated with reaction time (R = - 0.61, p < 0.001), initial direction error (R = - 0.64, p < 0.001), and movement time (R = - 0.62, p < 0.001). CONCLUSIONS: Robotic technology can quantify complex, discrete aspects of upper limb sensory and motor function in hemiparetic children. Robot-measured deficits in position sense and reaching with the contralesional limb appear to be relatively independent of each other and correlations for both with clinical measures are modest. Knowledge of the relationship between sensory and motor impairment may inform future rehabilitation strategies and improve outcomes for children with hemiparetic cerebral palsy.

Therapeutic Hypothermia in Acute Ischemic Stroke-a Systematic Review and Meta-Analysis.

PURPOSE OF REVIEW: Therapeutic hypothermia (TH) in stroke demonstrates robust neuroprotection in animals but clinical applications remain controversial. We assessed current literature on the efficacy of TH in ischemic stroke. RECENT FINDINGS: We conducted a meta-analysis comparing TH versus controls in studies published until June 2019. Controlled studies reporting on ≥ 10 adults with acute ischemic stroke were included. Primary outcome was functional independence (modified Rankin Scale [mRS] ≤ 2). Twelve studies (n = 351 TH, n = 427 controls) were included. Functional independence did not differ between groups (RR 1.17, 95% CI 0.93-1.46, random-effects p = 0.2). Five studies reported individual mRS outcomes and demonstrated a shift toward better outcome with TH (unadjusted cOR 1.57, 95% CI 1.01-2.44, p = 0.05). Overall complications were higher with TH (RR 1.18, 95% CI 1.06-1.32, p < 0.01). We did not observe an overall beneficial effect of TH in this analysis although some studies showed a shift toward better outcome. TH was associated with increased complications.

Assessment of bilateral motor skills and visuospatial attention in children with perinatal stroke using a robotic object hitting task.

BACKGROUND: While motor deficits are the hallmark of hemiparetic cerebral palsy, children may also experience impairments in visuospatial attention that interfere with participation in complex activities, including sports or driving. In this study, we used a robotic object hitting task to assess bilateral sensorimotor control and visuospatial skills in children with hemiparesis due to perinatal arterial ischemic stroke (AIS) or periventricular venous infarct (PVI). We hypothesized that performance would be impaired bilaterally and be related to motor behavior and clinical assessment of visuospatial attention. METHODS: Forty-nine children with perinatal stroke and hemiparetic cerebral palsy and 155 typically developing (TD) children participated in the study. Participants performed a bilateral object hitting task using the KINARM Exoskeleton Robot, in which they used virtual paddles at their fingertips to hit balls that fell from the top of the screen with increasing speed and frequency over 2.3 min. We quantified performance across 13 parameters including number of balls hit with each hand, movement speed and area, biases between hands, and spatial biases. We determined normative ranges of performance accounting for age by fitting 95% prediction bands to the TD children. We compared parameters between TD, AIS, and PVI groups using ANCOVAs accounting for age effects. Lastly, we performed regression analysis between robotic and clinical measures. RESULTS: The majority of children with perinatal stroke hit fewer balls with their affected arm compared to their typically developing peers. We also found deficits with the ipsilesional ("unaffected") arm. Children with AIS had greater impairments than PVI. Despite hitting fewer balls, we only identified 18% of children as impaired in hand speed or movement area. Performance on the Behavioral Inattention Test accounted for 21-32% of the variance in number of balls hit with the unaffected hand. CONCLUSIONS: Children with perinatal stroke-induced hemiparetic cerebral palsy may have complex bilateral deficits reflecting a combination of impairments in motor skill and visuospatial attention. Clinical assessments and interventions should address the interplay between motor and visuospatial skills.

Robotic assessment of rapid motor decision making in children with perinatal stroke.

BACKGROUND: Activities of daily living frequently require children to make rapid decisions and execute desired motor actions while inhibiting unwanted actions. Children with hemiparetic cerebral palsy due to perinatal stroke may have deficits in executive functioning in addition to motor impairments. The objective of this study was to use a robotic object hit and avoid task to assess the ability of children with hemiparetic cerebral palsy to make rapid motor decisions. METHODS: Forty-five children with hemiparetic cerebral palsy due to perinatal stroke and 146 typically developing children (both groups ages 6-19 years) completed a robotic object hit and avoid task using the Kinarm Exoskeleton. Objects of different shapes fell from the top of the screen with increasing speed and frequency. Children were instructed to hit two specific target shapes with either hand, while avoiding six distractor shapes. The number of targets and distractors hit were compared between children with hemiparetic cerebral palsy and typically developing children, accounting for age effects. We also compared performance to a simpler object hit task where there were no distractors. RESULTS: We found that children with hemiparetic cerebral palsy hit a greater proportion of total distractors compared to typically developing children, demonstrating impairments in inhibitory control. Performance for all children improved with age. Children with hemiparetic cerebral palsy hit a greater percentage of targets with each arm on the more complex object hit and avoid task compared to the simpler object hit task, which was not found in typically developing children. CONCLUSIONS: Children with hemiparetic cerebral palsy due to perinatal stroke demonstrated impairments in rapid motor decision making including inhibitory control, which can impede their ability to perform real-world tasks. Therapies that address both motor performance and executive functions are necessary to maximize function in children with hemiparetic cerebral palsy.

Corticospinal tract diffusion properties and robotic visually guided reaching in children with hemiparetic cerebral palsy.

Perinatal stroke is the leading cause of hemiparetic cerebral palsy (CP), resulting in life-long disability. In this study, we examined the relationship between robotic upper extremity motor impairment and corticospinal tract (CST) diffusion properties. Thirty-three children with unilateral perinatal ischemic stroke (17 arterial, 16 venous) and hemiparesis were recruited from a population-based research cohort. Bilateral CSTs were defined using diffusion tensor imaging (DTI) and four diffusion metrics were quantified: fractional anisotropy (FA), mean (MD), radial (RD), and axial (AD) diffusivities. Participants completed a visually guided reaching task using the KINARM robot to define 10 movement parameters including movement time and maximum speed. Twenty-six typically developing children underwent the same evaluations. Partial correlations assessed the relationship between robotic reaching and CST diffusion parameters. All diffusion properties of the lesioned CST differed from controls in the arterial group, whereas only FA was reduced in the venous group. Non-lesioned CST diffusion measures were similar between stroke groups and controls. Both stroke groups demonstrated impaired reaching performance. Multiple reaching parameters of the affected limb correlated with lesioned CST diffusion properties. Lower FA and higher MD were associated with greater movement time. Few correlations were observed between non-lesioned CST diffusion and unaffected limb function though FA was associated with reaction time (R = -0.39, p < .01). Diffusion properties of the lesioned CST are altered after perinatal stroke, the degree of which correlates with specific elements of visually guided reaching performance, suggesting specific relevance of CST structural connectivity to clinical motor function in hemiparetic children.

Bilateral reaching deficits after unilateral perinatal ischemic stroke: a population-based case-control study.

BACKGROUND: Detailed kinematics of motor impairment of the contralesional ("affected") and ipsilesional ("unaffected") limbs in children with hemiparetic cerebral palsy are not well understood. We aimed to 1) quantify the kinematics of reaching in both arms of hemiparetic children with perinatal stroke using a robotic exoskeleton, and 2) assess the correlation of kinematic reaching parameters with clinical motor assessments. METHODS: This prospective, case-control study involved the Alberta Perinatal Stroke Project, a population-based research cohort, and the Foothills Medical Center Stroke Robotics Laboratory in Calgary, Alberta over a four year period. Prospective cases were collected through the Calgary Stroke Program and included term-born children with magnetic resonance imaging confirmed perinatal ischemic stroke and upper extremity deficits. Control participants were recruited from the community. Participants completed a visually guided reaching task in the KINARM robot with each arm separately, with 10 parameters quantifying motor function. Kinematic measures were compared to clinical assessments and stroke type. RESULTS: Fifty children with perinatal ischemic stroke (28 arterial, mean age: 12.5 ± 3.9 years; 22 venous, mean age: 11.5 ± 3.8 years) and upper extremity deficits were compared to healthy controls (n = 147, mean age: 12.7 ± 3.9 years). Perinatal stroke groups demonstrated contralesional motor impairments compared to controls when reaching out (arterial = 10/10, venous = 8/10), and back (arterial = 10/10, venous = 6/10) with largest errors in reaction time, initial direction error, movement length and time. Ipsilesional impairments were also found when reaching out (arterial = 7/10, venous = 1/10) and back (arterial = 6/10). The arterial group performed worse than venous on both contralesional and ipsilesional parameters. Contralesional reaching parameters showed modest correlations with clinical measures in the arterial group. CONCLUSIONS: Robotic assessment of reaching behavior can quantify complex, upper limb dysfunction in children with perinatal ischemic stroke. The ipsilesional, "unaffected" limb is often abnormal and may be a target for therapeutic interventions in stroke-induced hemiparetic cerebral palsy.

Sensory tractography and robot-quantified proprioception in hemiparetic children with perinatal stroke.

Perinatal stroke causes most hemiparetic cerebral palsy, resulting in lifelong disability. We have demonstrated the ability of robots to quantify sensory dysfunction in hemiparetic children but the relationship between such deficits and sensory tract structural connectivity has not been explored. It was aimed to characterize the relationship between the dorsal column medial lemniscus (DCML) pathway connectivity and proprioceptive dysfunction in children with perinatal stroke. Twenty-nine participants (6-19 years old) with MRI-classified, unilateral perinatal ischemic stroke (14 arterial, 15 venous), and upper extremity deficits were recruited from a population-based cohort and compared with 21 healthy controls. Diffusion tensor imaging (DTI) defined DCML tracts and five diffusion properties were quantified: fractional anisotropy (FA), mean, radial, and axial diffusivities (MD, RD, AD), and fiber count. A robotic exoskeleton (KINARM) tested upper limb proprioception in an augmented reality environment. Correlations between robotic measures and sensory tract diffusion parameters were evaluated. Lesioned hemisphere sensory tracts demonstrated lower FA and higher MD, RD, and AD compared with the non-dominant hemisphere of controls. Dominant (contralesional) hemisphere tracts were not different from controls. Both arterial and venous stroke groups demonstrated impairments in proprioception that correlated with lesioned hemisphere DCML tract diffusion properties. Sensory tract connectivity is altered in the lesioned hemisphere of hemiparetic children with perinatal stroke. A correlation between lesioned DCML tract diffusion properties and robotic proprioceptive measures suggests clinical relevance and a possible target for therapeutic intervention. Hum Brain Mapp 38:2424-2440, 2017. © 2017 Wiley Periodicals, Inc.

Kinesthetic deficits after perinatal stroke: robotic measurement in hemiparetic children.

BACKGROUND: While sensory dysfunction is common in children with hemiparetic cerebral palsy (CP) secondary to perinatal stroke, it is an understudied contributor to disability with limited objective measurement tools. Robotic technology offers the potential to objectively measure complex sensorimotor function but has been understudied in perinatal stroke. The present study aimed to quantify kinesthetic deficits in hemiparetic children with perinatal stroke and determine their association with clinical function. METHODS: Case-control study. Participants were 6-19 years of age. Stroke participants had MRI confirmed unilateral perinatal arterial ischemic stroke or periventricular venous infarction, and symptomatic hemiparetic cerebral palsy. Participants completed a robotic assessment of upper extremity kinesthesia using a robotic exoskeleton (KINARM). Four kinesthetic parameters (response latency, initial direction error, peak speed ratio, and path length ratio) and their variabilities were measured with and without vision. Robotic outcomes were compared across stroke groups and controls and to clinical measures of sensorimotor function. RESULTS: Forty-three stroke participants (23 arterial, 20 venous, median age 12 years, 42% female) were compared to 106 healthy controls. Stroke cases displayed significantly impaired kinesthesia that remained when vision was restored. Kinesthesia was more impaired in arterial versus venous lesions and correlated with clinical measures. CONCLUSIONS: Robotic assessment of kinesthesia is feasible in children with perinatal stroke. Kinesthetic impairment is common and associated with stroke type. Failure to correct with vision suggests sensory network dysfunction.

Clinical characteristics and disease burden of African, Caribbean, and Black people with multiple sclerosis in Toronto, Canada.

BACKGROUND: Different racial and ethnic groups have demonstrated heterogeneity in the clinical course of multiple sclerosis(MS). OBJECTIVE: We aimed to evaluate disease characteristics in African, Caribbean, and Black people with MS(ACB-MS) followed at a single centre in Toronto, Canada. METHODS: ACB-MS were compared with age- and sex-matched people with MS (pwMS) of European descent(EUR-MS) identified through the clinic registry. RESULTS: 344 PwMS were included(n = 172 ACB-MS, n = 172 EUR-MS; mean age 43 years, 68 % female). Baseline mean Expanded disability status scale (EDSS) scores (ACB-MS 2.3 ± 2.3 vs. EUR-MS 2.2 ± 2.0, p = 0.38) and subsequent clinical and radiological measures of disease activity were similar between groups, including annualized relapse rate (ARR)(ACB-MS 0.47 ± 0.47 vs. EUR-MS 0.41 ± 0.34, p = 0.2) and most recent EDSS (ACB-MS 2.7 ± 2.2 vs. EUR-MS 2.3 ± 2.1, p = 0.10). However, the proportion of MRI brain demonstrating new disease activity was higher(37% vs. 26 %, p < 0.05) and disability progression greater in ACB-MS vs. EUR-MS(43% vs. 33 %,p < 0.05) but measures of disease severity including MS Severity Score(3.17 vs. 2.58, p = 0.3) and Progression Index(PI) (0.27 vs. 0.30, p = 0.5) were comparable. CONCLUSION: Disability progression was seen more commonly in ACB-MS, though clinical disease activity and severity were generally comparable between ACB-MS and EUR-MS patients in Toronto, Canada. These findings partially differ from prior studies demonstrating more overtly aggressive MS disease courses in Black and African American PwMS, necessitating further studies to understand how structural determinants of health drive these disparities.

Ozanimod for the treatment of relapsing forms of multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory disease that causes chronic neurological disability in young adults. Modulation of sphingosine 1-phosphate (S1P) receptors, a group of receptors that, among other things, regulate egression of lymphocytes from lymph nodes, has proven to be effective in treating relapsing MS. Fingolimod, the first oral S1P receptor modulator, has demonstrated potent efficacy and tolerability, but can cause undesirable side effects due to its interaction with a wide range of S1P receptor subtypes. This review will focus on ozanimod, a more selective S1P receptor modulator, which has recently received approval for relapsing MS. We summarize ozanimod's mechanism of action, and efficacy and safety from clinical trials that demonstrate its utility as another treatment option for relapsing MS.

Lay abstract There are increasing treatment options available for relapsing-remitting multiple sclerosis (MS). Ozanimod (ZEPOSIA) is a treatment that has recently received approval in many regions of the world for relapsing-remitting MS. Ozanimod acts on specific sphingosine 1-phosphate receptors, which are found in many tissues in the body, but also have known beneficial effects in MS. A robust clinical development program has demonstrated ozanimod's efficacy in reducing clinical and radiological measures of MS disease activity, making it a useful addition to the ever-increasing treatment armamentarium for relapsing MS.

Antiplatelet therapy for prevention of thromboembolic complications in coiling-only procedures for unruptured brain aneurysms.

BACKGROUND AND PURPOSE: Thromboembolic events are recognized complications of aneurysm coiling. OBJECTIVE: To identify any protective effects of antiplatelet therapy use before coiling of unruptured aneurysms. METHODS: We conducted a meta-analysis of clinical studies published up to February 2019. We included studies reporting symptomatic thromboembolic events (defined as clinical stroke or transient ischemic attacks) in patients who received antiplatelet therapy before coiling of unruptured aneurysms using unassisted coiling, balloon assistance, or multiple microcatheters. We excluded ruptured aneurysms and those treated with stent coiling or flow diverters. RESULTS: We identified 14 studies (2486 patients). All were single-center studies and four were prospective. In three studies with a control (no treatment) arm, the pooled risk ratio for symptomatic thromboembolic events with versus without antiplatelet therapy was 0.33 (95% CI 0.17 to 0.92, p= 0.035). The cumulative risk of symptomatic thromboembolic events with single antiplatelet agents was 5.0% '56/1122' (95% CI 1.6% to 8.4%, I283.63%), and with dual or multiple agents 2.7% '33/1237' (95% CI 1.0% to 3.0%, I239.9%). The incidence of diffusion lesions was reported in seven studies. It was 50.5% '96/190' (95% CI 7.3% to 93.9%, I294.4%) with single agents compared with 43.9% '196/446' (95% CI 25.9% to 61.9%, I273.4%) with dual or multiple agents. CONCLUSION: Periprocedural antiplatelet therapy was associated with a low symptomatic thromboembolic event after coiling-only for unruptured aneurysms. However, available evidence is of limited quality with significant heterogeneity, requiring evidence from randomized controlled trials.

Therapeutic Hypothermia in Patients with Malignant Ischemic Stroke and Hemicraniectomy-A Systematic Review and Meta-analysis.

BACKGROUND: Therapeutic hypothermia (TH) offers cerebral protection following ischemic stroke and may improve outcomes in conjunction with decompressive hemicraniectomy (DHC). We aimed to assess the effectiveness of TH in patients with malignant ischemic stroke and DHC. METHODS: We performed a meta-analysis in patients with malignant ischemic stroke undergoing DHC comparing TH versus normothermia in studies published up to August 2019. Included studies had ≥10 adults with acute ischemic stroke. Primary outcome was functional independence, and secondary outcomes included complications. Effect size was pooled and described by relative risk (RR) ratios and 95% confidence intervals (CIs). RESULTS: Five studies (n = 269 patients; n = 130 TH, n = 139 controls) were included, 4 of which were prospective (n = 2 randomized controlled trials). Median achieved body temperature of TH was 33.6°C (range 33°C-35°C). Median modified Rankin Scale at the study completion was similar between TH and controls (RR 1.08, 95% CI 0.56-2.07, P = 0.8). Three studies reported individual patient modified Rankin Scale outcomes demonstrated a shift toward worse outcomes with TH (unadjusted common odds ratio 1.74; 95% CI 1.05-2.88, P = 0.01). Overall complications were similar between groups (RR 1.20, 95% CI 0.70-2.05, random effects P = 0.5). A suggestion of higher mortality was seen in TH (RR 1.50, 95% CI 0.97-2.32, P = 0.07). CONCLUSIONS: Clinical and functional outcomes were not overall different between patients undergoing systemic TH and controls following DHC despite the shift toward worse outcomes with TH observed in some studies.

Therapeutic hypothermia: Applications in adults with acute ischemic stroke.

The advent of mechanical thrombectomy and increasing alteplase use have transformed the care of patients with acute ischemic stroke. Patients with major arterial occlusions with poor outcomes now have a chance of returning to independent living in more than half of the cases. However, many patients with these severe strokes suffer major disability despite these therapies. The search is ongoing for agents that can be combined with thrombectomy to achieve better recovery through halting infarct growth and mitigating injury after ischemic stroke. Several studies in animals and humans have demonstrated that therapeutic hypothermia (TH) offers potential to interrupt the ischemic cascade, reduce infarct volume, and improve functional independence. We performed a literature search to look up recent advances in the use of TH surrounding the science, efficacy, and feasibility of inducing TH in modern stroke treatments. While protocols remain controversial, there is a real opportunity to combine TH with the existing therapies to improve outcome in adults with acute ischemic stroke.

Robotic Quantification of Position Sense in Children With Perinatal Stroke.

Background Perinatal stroke is the leading cause of hemiparetic cerebral palsy. Motor deficits and their treatment are commonly emphasized in the literature. Sensory dysfunction may be an important contributor to disability, but it is difficult to measure accurately clinically. Objective Use robotics to quantify position sense deficits in hemiparetic children with perinatal stroke and determine their association with common clinical measures. Methods Case-control study. Participants were children aged 6 to 19 years with magnetic resonance imaging-confirmed unilateral perinatal arterial ischemic stroke or periventricular venous infarction and symptomatic hemiparetic cerebral palsy. Participants completed a position matching task using an exoskeleton robotic device (KINARM). Position matching variability, shift, and expansion/contraction area were measured with and without vision. Robotic outcomes were compared across stroke groups and controls and to clinical measures of disability (Assisting Hand Assessment) and sensory function. Results Forty stroke participants (22 arterial, 18 venous, median age 12 years, 43% female) were compared with 60 healthy controls. Position sense variability was impaired in arterial (6.01 ± 1.8 cm) and venous (5.42 ± 1.8 cm) stroke compared to controls (3.54 ± 0.9 cm, P < .001) with vision occluded. Impairment remained when vision was restored. Robotic measures correlated with functional disability. Sensitivity and specificity of clinical sensory tests were modest. Conclusions Robotic assessment of position sense is feasible in children with perinatal stroke. Impairment is common and worse in arterial lesions. Limited correction with vision suggests cortical sensory network dysfunction. Disordered position sense may represent a therapeutic target in hemiparetic cerebral palsy.

Position-Dependent Influence of the Three Trp Residues on the Membrane Activity of the Antimicrobial Peptide, Tritrpticin.

Antimicrobial peptides (AMPs) constitute promising candidates for the development of new antibiotics. Among the ever-expanding family of AMPs, tritrpticin has strong antimicrobial activity against a broad range of pathogens. This 13-residue peptide has an unusual amino acid sequence that is almost symmetrical and features three central Trp residues with two Arg residues near each end of the peptide. In this work, the role of the three sequential Trp residues in tritrpticin was studied in a systematic fashion by making a series of synthetic peptides with single-, double- and triple-Trp substitutions to Tyr or Ala. ¹H NMR and fluorescence spectroscopy demonstrated the ability of all of the tritrpticin-analog peptides to interact with negatively-charged membranes. Consequently, most tritrpticin analogs exhibited the ability to permeabilize synthetic ePC:ePG (egg-yolk phosphatidylcholine (ePC), egg-yolk phosphatidylglycerol (ePG)) vesicles and live Escherichia coli bacteria. The membrane perturbation characteristics were highly dependent on the location of the Trp residue substitution, with Trp6 being the most important residue and Trp8 the least. The membrane permeabilization activity of the peptides in synthetic and biological membranes was directly correlated with the antimicrobial potency of the peptides against E. coli. These results contribute to the understanding of the role of each of the three Trp residues to the antimicrobial activity of tritrpticin.