High‐resolution diffusion‐weighted imaging identifies ischemic lesions in a majority of transient ischemic attack patients

Transient ischemic attack (TIA) is defined as focal neurological deficit caused by ischemia resolving within 24 hours. In a secondary analysis of a large monocentric cohort of 446 TIA patients, we explored the frequency and determinants of diffusion-weighted imaging (DWI) lesions on high-resolution magnetic resonance imaging. Overall, 240 (54%) of all TIA patients presented with DWI lesions. These patients had higher National Institute of Health Stroke Scale and ABCD2 scores and presented more frequently with vessel occlusion and perfusion deficits, but had similar functional outcome at 3 months. Taken together, high-resolution DWI provides evidence of ischemic brain injury in the majority of TIA patients. ANN NEUROL 201

a clinical study protocol

Introduction The approved analgesic and anti-inflammatory drugs ibuprofen and indometacin block the small GTPase RhoA, a key enzyme that impedes axonal sprouting after axonal damage. Inhibition of the Rho pathway in a central nervous system-effective manner requires higher dosages compared with orthodox cyclooxygenase-blocking effects. Preclinical studies on spinal cord injury (SCI) imply improved motor recovery after ibuprofen/indometacin-mediated Rho inhibition. This has been reassessed by a meta-analysis of the underlying experimental evidence, which indicates an overall effect size of 20.2% regarding motor outcome achieved after ibuprofen/indometacin treatment compared with vehicle controls. In addition, ibuprofen/indometacin may also limit sickness behaviour, non-neurogenic systemic inflammatory response syndrome (SIRS), neuropathic pain and heterotopic ossifications after SCI. Consequently, ‘small molecule’-mediated Rho inhibition after acute SCI warrants clinical investigation. Methods and analysis Protocol of an investigator-initiated clinical open-label pilot trial on high-dose ibuprofen treatment after acute traumatic, motor-complete SCI. A sample of n=12 patients will be enrolled in two cohorts treated with 2400 mg/day ibuprofen for 4 or 12 weeks, respectively. The primary safety end point is an occurrence of serious adverse events, primarily gastroduodenal bleedings. Secondary end points are pharmacokinetics, feasibility and preliminary effects on neurological recovery, neuropathic pain and heterotopic ossifications. The primary safety analysis is based on the incidence of severe gastrointestinal bleedings. Additional analyses will be mainly descriptive and casuistic. Ethics and dissemination The clinical trial protocol was approved by the responsible German state Ethics Board, and the Federal Institute for Drugs and Medical Devices. The study complies with the Declaration of Helsinki, the principles of Good Clinical Practice and all further applicable regulations. This safety and pharmacokinetics trial informs the planning of a subsequent randomised controlled trial. Regardless of the result of the primary and secondary outcome assessments, the clinical trial will be reported as a publication in a peer-reviewed journal. Trial registration number NCT02096913; Pre-results

Acute Cerebrovascular Disease in the Young The Stroke in Young Fabry Patients Study

Background and Purpose-Strokes have especially devastating implications if they occur early in life; however, only limited information exists on the characteristics of acute cerebrovascular disease in young adults. Although risk factors and manifestation of atherosclerosis are commonly associated with stroke in the elderly, recent data suggests different causes for stroke in the young. We initiated the prospective, multinational European study Stroke in Young Fabry Patients (sifap) to characterize a cohort of young stroke patients. Methods-Overall, 5023 patients aged 18 to 55 years with the diagnosis of ischemic stroke (3396), hemorrhagic stroke (271), transient ischemic attack (1071) were enrolled in 15 European countries and 47 centers between April 2007 and January 2010 undergoing a detailed, standardized, clinical, laboratory, and radiological protocol. Results-Median age in the overall cohort was 46 years. Definite Fabry disease was diagnosed in 0.5% (95% confidence interval, 0.4%-0.8%; n=27) of all patients; and probable Fabry disease in additional 18 patients. Males dominated the study population (2962/59%) whereas females outnumbered men (65.3%) among the youngest patients (18-24 years). About 80.5% of the patients had a first stroke. Silent infarcts on magnetic resonance imaging were seen in 20% of patients with a first-ever stroke, and in 11.4% of patients with transient ischemic attack and no history of a previous cerebrovascular event. The most common causes of ischemic stroke were large artery atherosclerosis (18.6%) and dissection (9.9%). Conclusions-Definite Fabry disease occurs in 0.5% and probable Fabry disease in further 0.4% of young stroke patients. Silent infarcts, white matter intensities, and classical risk factors were highly prevalent, emphasizing the need for new early preventive strategies

SCISSOR-Spinal Cord Injury Study on Small molecule-derived Rho inhibition: a clinical study protocol

INTRODUCTION: The approved analgesic and anti-inflammatory drugs ibuprofen and indometacin block the small GTPase RhoA, a key enzyme that impedes axonal sprouting after axonal damage. Inhibition of the Rho pathway in a central nervous system-effective manner requires higher dosages compared with orthodox cyclooxygenase-blocking effects. Preclinical studies on spinal cord injury (SCI) imply improved motor recovery after ibuprofen/indometacin-mediated Rho inhibition. This has been reassessed by a meta-analysis of the underlying experimental evidence, which indicates an overall effect size of 20.2% regarding motor outcome achieved after ibuprofen/indometacin treatment compared with vehicle controls. In addition, ibuprofen/indometacin may also limit sickness behaviour, non-neurogenic systemic inflammatory response syndrome (SIRS), neuropathic pain and heterotopic ossifications after SCI. Consequently, 'small molecule'-mediated Rho inhibition after acute SCI warrants clinical investigation. METHODS AND ANALYSIS: Protocol of an investigator-initiated clinical open-label pilot trial on high-dose ibuprofen treatment after acute traumatic, motor-complete SCI. A sample of n=12 patients will be enrolled in two cohorts treated with 2400 mg/day ibuprofen for 4 or 12 weeks, respectively. The primary safety end point is an occurrence of serious adverse events, primarily gastroduodenal bleedings. Secondary end points are pharmacokinetics, feasibility and preliminary effects on neurological recovery, neuropathic pain and heterotopic ossifications. The primary safety analysis is based on the incidence of severe gastrointestinal bleedings. Additional analyses will be mainly descriptive and casuistic. ETHICS AND DISSEMINATION: The clinical trial protocol was approved by the responsible German state Ethics Board, and the Federal Institute for Drugs and Medical Devices. The study complies with the Declaration of Helsinki, the principles of Good Clinical Practice and all further applicable regulations. This safety and pharmacokinetics trial informs the planning of a subsequent randomised controlled trial. Regardless of the result of the primary and secondary outcome assessments, the clinical trial will be reported as a publication in a peer-reviewed journal

Inverse mismatch and lesion growth in small subcortical ischaemic stroke

OBJECTIVE: Infarction typically develops within the borders of an initial hypoperfused tissue. We prospectively investigated whether in small subcortical stroke patients infarct growth can occur beyond the margins of the affected vascular territories. METHODS: In 19 consecutive patients, stroke MRI was performed within 14 h after ictus, and at days 2 and 6 (± 1). Size of diffusion and perfusion disturbances were determined. Infarct volume measured on T2-weighted images on day 6 was considered as imaging endpoint. RESULTS: At the initial examination, the mean diffusion lesion [apparent diffusion coefficient (ADC) lesion size, 1.82 ± 1.2 ml] was larger (p = 0.0002) than the perfusion lesion [mean transit time (MTT) lesion size, 0.72 ± 0.69 ml]. Such an "inverse mismatch" (ADC lesion > MTT lesion) was present in 14/19 patients at baseline and in all patients on day 2. Final lesion volume at day 6 was 3.2 ± 1.6 ml which was larger than the initial perfusion deficit (p = 0.02). CONCLUSION: In small subcortical ischaemic stroke "inverse mismatch" is frequent and infarction develops beyond the initial perfusion disturbance. This indicates that cytotoxic processes probably triggered by the infarct core are a dominant mechanism for lesion growth. Areas with normal perfusion but which are threatened by cytotoxic damage developing over several days seem prime targets for neuroprotective therapy