Adam Kirton

Safety of Transcranial Direct Current Stimulation: Evidence Based Update 2016.

This review updates and consolidates evidence on the safety of transcranial Direct Current Stimulation (tDCS). Safety is here operationally defined by, and limited to, the absence of evidence for a Serious Adverse Effect, the criteria for which are rigorously defined. This review adopts an evidence-based approach, based on an aggregation of experience from human trials, taking care not to confuse speculation on potential hazards or lack of data to refute such speculation with evidence for risk. Safety data from animal tests for tissue damage are reviewed with systematic consideration of translation to humans. Arbitrary safety considerations are avoided. Computational models are used to relate dose to brain exposure in humans and animals. We review relevant dose-response curves and dose metrics (e.g. current, duration, current density, charge, charge density) for meaningful safety standards. Special consideration is given to theoretically vulnerable populations including children and the elderly, subjects with mood disorders, epilepsy, stroke, implants, and home users. Evidence from relevant animal models indicates that brain injury by Direct Current Stimulation (DCS) occurs at predicted brain current densities (6.3-13 A/m(2)) that are over an order of magnitude above those produced by conventional tDCS. To date, the use of conventional tDCS protocols in human trials (≤40 min, ≤4 milliamperes, ≤7.2 Coulombs) has not produced any reports of a Serious Adverse Effect or irreversible injury across over 33,200 sessions and 1000 subjects with repeated sessions. This includes a wide variety of subjects, including persons from potentially vulnerable populations.

Contralesional repetitive transcranial magnetic stimulation for chronic hemiparesis in subcortical paediatric stroke: a randomised trial

BACKGROUND Arterial ischaemic stroke (AIS) can cause disabling hemiparesis in children. We aimed to test whether contralesional, inhibitory repetitive transcranial magnetic stimulation (rTMS) could affect interhemispheric inhibition to improve hand function in chronic subcortical paediatric AIS. METHODS Patients were eligible for this parallel, randomised trial if they were in the SickKids Childrens Stroke Program and had subcortical AIS more than 2 years previously, had transcallosal sparing, were more than 7 years of age, had hand motor impairment, had no seizures or dyskinesia, and were taking no drugs that alter cortical excitability. Patients were paired for age and weakness and were randomised within each pair to sham treatment or inhibitory, low-frequency rTMS over contralesional motor cortex (20 min, 1200 stimuli) once per day for 8 days. An occupational therapist did standardised tests of hand function at days 1 (baseline), 5, 10, and 17 (1 week post-treatment), and the primary outcomes were changes in grip strength and the Melbourne assessment of upper extremity function (MAUEF) between baseline and day 10. Patients, parents, and occupational therapists were blinded to treatment allocation. Analysis was per protocol. FINDINGS Ten patients with paediatric stroke were enrolled (median age 13.25 [IQR 10.08-16.78] years, mean time post-stroke 6.33 [SD 3.56] years): four with mild weakness, two with moderate weakness, and four with severe weakness. A repeated-measures ANOVA showed a significant interaction between time and the effect of treatment on grip strength (p=0.03). At day 10, grip strength was 2.28 (SD 1.01) kg greater than baseline in the rTMS group and 2.92 (1.20) kg less than baseline in the sham group (p=0.009). Benefits in mean grip strength persisted at day 17 (2.63 [0.56] kg greater than baseline with rTMS and 1.00 [0.70] kg less than baseline with sham treatment; p=0.01). Day 10 MAUEF score improved by more in the rTMS group than in the sham group (7.25 [3.8] vs 0.79 [1.3] points greater than baseline; p=0.002), but this benefit did not persist to day 17. Function of the unaffected hand remained stable. rTMS was well tolerated with no serious adverse events. INTERPRETATION Contralesional inhibitory rTMS was safe and feasible for patients with paediatric subcortical AIS, and seemed to improve hand function in patients with hemiparesis. Further studies are required to confirm the potential role of rTMS in paediatric neurorehabilitation. FUNDING Canadian Stroke Consortium; Canadian Institutes of Health Research; American Academy of Neurology Foundation; Alberta Heritage Foundation for Medical Research.

Symptomatic Neonatal Arterial Ischemic Stroke: The International Pediatric Stroke Study

BACKGROUND: Neonatal arterial ischemic stroke (AIS) has emerged as a leading cause of perinatal brain injury, cerebral palsy, and lifelong disability. The pathogenesis is poorly understood, which limits the development of treatment and prevention strategies. Multicenter studies must define epidemiology, risk factors, treatment practices, and outcomes to advance clinical trials and improve the adverse outcomes suffered by most survivors. METHODS: The International Pediatric Stroke Study is a global research initiative of 149 coinvestigators (30 centers in 10 countries). Patients with clinical and neuroimaging confirmation of symptomatic neonatal AIS were enrolled (2003–2007). Standardized, Web-based data entry collected clinical presentations, risk factors, investigations, treatments, and early outcomes. We examined predictors of infarct characteristics and discharge outcome by using multivariate logistic regression. RESULTS: Two hundred forty-eight neonates were studied (57% male, 10% premature). Most of them presented with seizure (72%) and nonfocal neurologic signs (63%). MRI was completed for 92% of the infants, although <50% had vascular imaging. Infarcts preferentially involved the anterior circulation and left hemisphere and were multifocal in 30%. Maternal health and pregnancies were usually normal. Neonates often required resuscitation (30%) and had systemic illnesses (23%). Cardiac and prothrombotic abnormalities were identified in <20% of the infants. Antithrombotic treatment was uncommon (21%) and varied internationally. Half (49%) of the infants had deficits at discharge, and data on their long-term outcomes are pending. CONCLUSIONS: Newborns with AIS are often systemically sick, whereas their mothers are usually healthy. Definitive causes for most neonatal AISs have not been established, and large-scale case-control studies are required to understand pathogenesis if outcomes are to be improved.

Presumed perinatal ischemic stroke: Vascular classification predicts outcomes

Perinatal stroke commonly causes childhood neurological morbidity. Presumed perinatal ischemic stroke (PPIS) defines children presenting outside a normal perinatal period with chronic, focal infarction on neuroimaging. Infarcts are assumed to represent arterial strokes, but recent evidence suggests the periventricular venous infarction (PVI) of infants born preterm may also occur in utero and present as PPIS. Using the largest published cohort, we aimed to define arterial and PVI PPIS syndromes and their outcomes.

Quantified Corticospinal Tract Diffusion Restriction Predicts Neonatal Stroke Outcome

Background and Purpose— Neonatal arterial ischemic stroke occurs in ≥1:4000 births. Many children experience motor deficits but acute predictors of outcome are lacking. Diffusion-weighted MRI changes in descending corticospinal tracts remote from arterial ischemic stroke may represent pre-Wallerian degeneration. We verify and quantify this signal and correlate it with motor outcome. Methods— Fourteen neonates with acute arterial ischemic stroke and ≥12 months follow-up with the Pediatric Stroke Outcome Measure were included. Quantitative measurements of descending corticospinal tracts diffusion-weighted MRI signal were developed using Image J software. Results— Ipsilesional descending corticospinal tract diffusion-weighted MRI signal was abnormal in 10 neonates with decreased apparent diffusion coefficients (P<0.001). Poor outcome correlated with: (1) percentage of peduncle (P=0.002); (2) length of descending corticospinal tracts P<0.001); and (3) volume of descending corticospinal tracts (P=0.002). None of: (1) any peduncle; (2) any posterior limb of the internal capsule; or (3) infarct volume correlated with outcome. All children without descending corticospinal tracts signal had normal outcome. Chronic Wallerian degeneration was seen in all children with hemiparesis. Software-assisted analysis was superior to visual inspection with excellent reliability (intra-class correlation coefficient ≥0.9). Conclusion— Descending corticospinal tracts diffusion-weighted MRI signal is predictive of motor outcome from neonatal arterial ischemic stroke. This accurate, reliable, and simple tool will impact decision making in acute neonatal stroke.

Advances in Perinatal Ischemic Stroke

Increasingly distinct patterns of focal ischemic injury in the fetal and perinatal brain are recognized. Improved classification has afforded advances in risk factor identification, pathophysiology hypotheses, outcome prediction, and potential avenues for intervention. Cerebrovascular occlusion leading to perinatal stroke may be arterial or venous, symptomatic or subclinical, and it can occur across multiple time frames. Distinguishing causative factors from mere associations represents a major challenge with important implications for studies of pathogenesis. The adverse outcomes suffered by most children highlight the need for further research. Reviewed here are the current understandings, recent advancements, and future directions for research in perinatal ischemic stroke.

Towards a Consensus-Based Classification of Childhood Arterial Ischemic Stroke

Background and Purpose— The implementation of uniform nomenclature and classification in adult arterial ischemic stroke (AIS) has been critical for defining outcomes and recurrence risks according to etiology and in developing risk-stratified treatments. In contrast, current classification and nomenclature in childhood AIS are often overlapping or contradictory. Our purpose was to develop a comprehensive consensus-based classification system for childhood AIS. Methods— Using a modified-Delphi method, members of the International Pediatric Stroke Study (IPSS) developed the Childhood AIS Standardized Classification And Diagnostic Evaluation (CASCADE) criteria. Two groups of pediatric stroke specialists from the IPSS classified 7 test cases using 2 methods each: (1) classification typical of the individual clinicians current clinical practice; and (2) classification based on the CASCADE criteria. Group 1 underwent in-person training in the utilization of the CASCADE criteria. Group 2 classified the same cases via an online survey, including definitions but without training. Inter-rater reliability (IRR) was assessed via multi-rater unweighted &kgr;-statistic. Results— In Group 1 (with training), IRR was improved using CASCADE criteria (&kgr;=0.78, 95% CI=[0.49, 0.94]), compared with typical clinical practice (&kgr;=0.40, 95% CI=[0.11, 0.60]). In Group 2 (without training), IRR was lower than among trained raters (&kgr;=0.61, 95% CI=[0.29, 0.77]), but higher than current practice (&kgr;=0.23, 95% CI=[0.03, 0.36]). Conclusions— A new, consensus-based classification system for childhood AIS, the CASCADE criteria, can be used to classify cases with good IRR. These preliminary findings suggest that the CASCADE criteria may be particularity useful in the setting of prospective multicenter studies in childhood-onset AIS, where standardized training of investigators is feasible.

Thrombolysis in Acute Childhood Stroke: Design and Challenges of the Thrombolysis in Pediatric Stroke Clinical Trial

Background: Although tissue plasminogen activator (tPA) has revolutionized the treatment of acute ischemic stroke in adults, no thrombolysis trials in childhood stroke have been conducted. Experience in adults cannot be applied to children due to fundamental age-related differences in coagulation systems, stroke pathophysiology and neuropharmacology. Obstacles to acute treatment trials in childhood stroke include delays in diagnosis and minimizing risk in a vulnerable population. Study Design: Thrombolysis in Pediatric Stroke (TIPS) is an international multicenter study to assess the safety of intravenous tPA within 0–3 h and intra-arterial tPA within 3–6 h of onset of arterial ischemic stroke in childhood. Through the International Pediatric Stroke Study, 30 international centers will enroll a total of 48 patients: 24 will be treated with intravenous tPA (0.6, 0.75, 0.9, and 1.0 mg/kg) using the classical dose-finding method, and 24 will be treated with intra-arterial tPA (maximum 0.2, 0.3, 0.4, and 0.5 mg/kg) using a Bayesian dose-finding method. Conclusion: The TIPS trial will be the first clinical trial exploring the safety and feasibility of systemic and local thrombolytic therapy in childhood stroke and the obstacles in conducting such a trial.

Canadian stroke best practice recommendations: Stroke rehabilitation practice guidelines, update 2015:

Stroke rehabilitation is a progressive, dynamic, goal-orientated process aimed at enabling a person with impairment to reach their optimal physical, cognitive, emotional, communicative, social and/or functional activity level. After a stroke, patients often continue to require rehabilitation for persistent deficits related to spasticity, upper and lower extremity dysfunction, shoulder and central pain, mobility/gait, dysphagia, vision, and communication. Each year in Canada 62,000 people experience a stroke. Among stroke survivors, over 6500 individuals access in-patient stroke rehabilitation and stay a median of 30 days (inter-quartile range 19 to 45 days). The 2015 update of the Canadian Stroke Best Practice Recommendations: Stroke Rehabilitation Practice Guidelines is a comprehensive summary of current evidence-based recommendations for all members of multidisciplinary teams working in a range of settings, who provide care to patients following stroke. These recommendations have been developed to address both the organization of stroke rehabilitation within a system of care (i.e., Initial Rehabilitation Assessment; Stroke Rehabilitation Units; Stroke Rehabilitation Teams; Delivery; Outpatient and Community-Based Rehabilitation), and specific interventions and management in stroke recovery and direct clinical care (i.e., Upper Extremity Dysfunction; Lower Extremity Dysfunction; Dysphagia and Malnutrition; Visual-Perceptual Deficits; Central Pain; Communication; Life Roles). In addition, stroke happens at any age, and therefore a new section has been added to the 2015 update to highlight components of stroke rehabilitation for children who have experienced a stroke, either prenatally, as a newborn, or during childhood. All recommendations have been assigned a level of evidence which reflects the strength and quality of current research evidence available to support the recommendation. The updated Rehabilitation Clinical Practice Guidelines feature several additions that reflect new research areas and stronger evidence for already existing recommendations. It is anticipated that these guidelines will provide direction and standardization for patients, families/caregiver(s), and clinicians within Canada and internationally.

Acute Corticospinal Tract Wallerian Degeneration Is Associated With Stroke Outcome

Background and Purpose— In children with stroke, poor motor outcome is associated with early Wallerian degeneration of the corticospinal tract that is seen on diffusion-weighted MRI. In this study we test the hypothesis that early diffusion changes also occur in the corticospinal tract (CST) of adults after stroke and that these lesions are associated with poor outcome. Methods— In this retrospective study, we assessed images from a serial MRI study of adults with acute middle cerebral/internal carotid artery stroke. MRI-negative TIA patients served as controls. Custom software measured signal along the CST on different sequences, including the apparent diffusion coefficient (ADC). Visual detection of abnormal signal by blinded neuroradiologists was also evaluated. We then determined associations between CST signal changes and 3-month motor outcome (NIHSS score). Results— Thirty-eight patients (20 stroke/18 control) were included. ADC measures were much more accurate than other MRI sequences for detection of degeneration in the CST. The ADC decreased in a time-dependent fashion in the CST of patients with poor motor outcome but not in those with good outcome. Changes in ADC were maximal at 7 days. Neuroradiologists could visually detect these changes with accuracy comparable to the software method. Conclusion— CST ADC decreases after acute stroke in patients with poor motor outcome and may represent early Wallerian degeneration. Recognition of this imaging marker may improve early outcome prediction and patient selection for rehabilitation and neuroprotection trials.