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Hypothermia is a promising therapeutic strategy for severe vasospasm and other types of non-thrombotic cerebral ischemia, but its clinical application is limited by significant systemic side effects. We aimed to develop an intraventricular device for the controlled cooling of the cerebrospinal fluid, to produce a targeted hypothermia in the affected cerebral hemisphere with a minimal effect on systemic temperature. An intraventricular cooling device (acronym: V-COOL) was developed by in silico modelling, in vitro testing, and in vivo proof-of-concept application in healthy Wistar rats (n = 42). Cerebral cortical temperature, rectal temperature, and intracranial pressure were monitored at increasing flow rate (0.2 to 0.8 mL/min) and duration of application (10 to 60 min). Survival, neurological outcome, and MRI volumetric analysis of the ventricular system were assessed during the first 24 h. The V-COOL prototyping was designed to minimize extra-cranial heat transfer and intra-cranial pressure load. In vivo application of the V-COOL device produced a flow rate-dependent decrease in cerebral cortical temperature, without affecting systemic temperature. The target degree of cerebral cooling (− 3.0 °C) was obtained in 4.48 min at the flow rate of 0.4 mL/min, without significant changes in intracranial pressure. Survival and neurological outcome at 24 h showed no significant difference compared to sham-treated rats. MRI study showed a transient dilation of the ventricular system (+ 38%) in a subset of animals. The V-COOL technology provides an effective, rapid, selective, and safe cerebral cooling to a clinically relevant degree of − 3.0 °C.

Outcomes following endovascular thrombectomy (EVT) for large vessel occlusion stroke remain variable. Clinical predictors include presenting NIHSS and age, surrogate metrics of stroke severity and pre-stroke brain health, respectively. Imaging biomarkers can also predict outcome, but prognostic models typically only include biomarkers of acute stroke severity. This study aimed at exploring how incorporating both imaging biomarkers of stroke severity and brain frailty, automatically derived from routine imaging, impacts outcome prediction following successful EVT. In this single-center retrospective study of 215 patients presenting with anterior circulation stroke, we evaluated prognostic significance of automated analysis outputs from e-Stroke. Acute ischemic volume (AIV) and e-ASPECTS were used to define stroke severity. Cerebral atrophy was used as a marker of brain frailty. Models incorporating imaging biomarkers, clinical features, procedural factors, and combinations of these were evaluated using multivariate regression models predicting mRS 0-2 at 30 and 90-days, NIHSS improvement, mortality and sICH. Incorporation of brain atrophy into models negated the effect of age on patient outcome. The interaction of stroke severity with age was similar to that of infarct volume and brain atrophy. Models incorporating age, presenting NIHSS, AIV, atrophy, reperfusion status and time to recanalization outperformed clinical models at predicting NIHSS improvement (ROC AUC 0.81 and 0.57, respectively) and 90-day mRS. Combinations of imaging and clinical features were superior for predicting any outcome compared with clinical or imaging features in isolation. Models incorporating automated image analysis of acute infarct volume and atrophy outperform models based solely on clinical characteristics for predicting short- and long-term outcome following EVT. Atrophy as a marker of brain frailty is associated with poorer long-term outcomes and negates the effect of age in multivariate models. AIV tempers the effect of intervention on early neurological improvement. Better understanding the relationship between stroke severity and baseline health status may improve patient selection strategies for reperfusion therapies.

Neurological outcome after ischemic stroke depends on residual salvageable brain tissue at the time of recanalization. Head down tilt 15° (HDT15) was proven effective in reducing infarct size and improving functional outcome in rats with transient middle cerebral artery occlusion (t-MCAO) by increasing cerebral perfusion within the ischemic penumbra. In this pooled analysis, individual animal-level data from three experimental series were combined in a study population of 104 t-MCAO rats (45 in HDT15 group and 59 in flat position group). Co-primary outcomes were infarct size and functional outcome at 24 h in both groups. The secondary outcome was hemodynamic change induced by HDT15 in ischemic and non-ischemic hemispheres in a subgroup of animals. Infarct size at 24 h was smaller in HDT15 group than in flat position group (absolute mean difference 31.69 mm

Background and objective:In hyperacute ischaemic stroke, T2 of cerebral water increases with time. Quantifying this change may be informative of the extent of tissue damage and onset time. Our objective was to develop a user-unbiased method to measure the effect of cerebral ischaemia on T2 to study stroke onset time-dependency in human acute stroke lesions. Methods:Six rats were subjected to permanent middle cerebral occlusion to induce focal ischaemia, and a consecutive cohort of acute stroke patients (n=38) were recruited within 9 hours from symptom onset. T1-weighted structural, T2 relaxometry, and diffusion MRI for apparent diffusion coefficient (ADC) were acquired. Ischaemic lesions were defined as regions of lowered ADC. The median T2 difference (ΔT2) between lesion and contralateral non-ischaemic control region was determined by the newly-developed spherical reference method, and data compared to that obtained by the mirror reference method. Linear regressions and receiver operating characteristics (ROC) were compared between the two methods. Results:ΔT2 increases linearly in rat brain ischaemia by 1.9 ± 0.8 ms/h during the first 6 hours, as determined by the spherical reference method. In patients, ΔT2 linearly increases by 1.6 ± 1.4 and 1.9 ± 0.9 ms/h in the lesion, as determined by the mirror reference and spherical reference method, respectively. ROC analyses produced areas under the curve of 0.83 and 0.71 for the spherical and mirror reference methods, respectively. Conclusions:Data from the spherical reference method showed that the median T2 increase in the ischaemic lesion is correlated with stroke onset time in a rat as well as in a human patient cohort, opening the possibility of using the approach as a timing tool in clinics.

Introduction: Final infarct volume (FIV) is a commonly used imaging endpoint in stroke trials. The aim of this study was to investigate the potential of an automated masking pipeline (Brain Intensity AbNormality Classification Algorithm - BIANCA) on detecting ischemic stroke lesions of follow-up imaging on patients with acute ischemic stroke. Methods: Patients were retrospectively selected from a prospectively acquired mechanical thrombectomy (MT) database from January to July 2019, and were included if they had a follow-up magnetic resonance imaging DWI within 72h from procedure available. Masks were generated on B1000 imaging by clinical research stroke personnel and then compared with volumes delineated by a fully automated supervised method for lesion detection, based on a k-nearest neighbor (k-NN) algorithm. Results: Seventy patients were included. Human FIV measurements mean was comparable with BIANCA [67.7±73.2 vs 71.8±67 (p Conclusion: The automated masking pipeline measurement showed to behighlysimilar to a standardized protocol of FIV estimation at a busy neuroendovascular center and could be used in trials with large numbers of patients.

BACKGROUND: Head down tilt 15° (HDT15°), applied before recanalization, increases collateral flow and improves outcome in experimental ischemic stroke. For its simplicity and low cost, HDT15° holds considerable potential to be developed as an emergency treatment of acute stroke in the pre-hospital setting, where hemorrhagic stroke is the major mimic of ischemic stroke. In this study, we assessed safety of HDT15° in the acute phase of experimental intracerebral hemorrhage. METHODS: Intracerebral hemorrhage was produced by stereotaxic injection of collagenase in Wistar rats. A randomized non-inferiority trial design was used to assign rats to HDT15° or flat position (n=64). HDT15° was applied for 1 hour during the time window of hematoma expansion. The primary outcome was hematoma volume at 24 hours. Secondary outcomes were mass effect, mortality and functional deficit in the main study and acute changes of intracranial pressure, hematoma growth and cardiorespiratory parameters in separate sets of randomized animals (n=32). RESULTS: HDT15° achieved the specified criteria of non-inferiority for hematoma volume at 24 hours. Mass effect, mortality and functional deficit at 24 hours showed no difference in the two groups. HDT15° induced a mild increase in intracranial pressure with respect to the pre-treatment values (+ 2.91 +/- 1.76 mmHg). HDT15° had a neutral effect on MRI-based analysis of hematoma growth and cardiorespiratory parameters. CONCLUSIONS: Application of HDT15° in the hyperacute phase of experimental intracerebral hemorrhage does not worsen early outcome. Further research is needed to implement HDT15° as an emergency collateral therapeutic for acute stroke.

Objective To compare withdrawal of antiseizure medications (ASM) to continued treatment in newly diagnosed individuals achieving seizure freedom, and assess the risk of relapse and factors associated with relapse. Methods This is a multicenter retrospective cohort study with long-term follow-up. Patients with newly diagnosed epilepsy were identified from the medical records of 13 Italian epilepsy centers and followed up until the most recent visit or death. Seizure-free patients discontinuing treatment were compared to patients who maintained treatment for baseline characteristics. Treatment was stopped upon clinical judgment. The probability of relapse was calculated with the Kaplan–Meier method. Demographic, clinical, and instrumental variables associated with relapse were assessed with Cox proportional hazards models. Results One thousand and six patients aged 1 month to 72 years at diagnosis were enrolled and followed up for 17,892 person-years (median follow-up, 9.9 years). Three hundred and twenty patients (31.8%) underwent one or more treatment discontinuations. Factors associated with ASM withdrawal were younger age at remission and normal psychiatric examination. The probability of relapse after the first withdrawal was 16% at six months, 24% at 12 months, and 36%, 45%, and 53% at three, five, and ten years, respectively. The probability of remission after the first relapse was 59% at one month, 67%, 72, and 76% at three, six, and 12 months, respectively. Variables associated with relapse were age 14+ years, structural etiology, abnormal neuroimaging, ASM initiation after a single seizure, and symptomatic/cryptogenic epilepsy. Conclusions About one half of seizure-free patients stopping ASM relapse in 10 years. However, the possibility of remission after relapse is high, particularly in children and patients with idiopathic/cryptogenic epilepsy. Treatment deprescription might be encouraged at least in these patients.

Refractory status epilepticus (RSE) has been reported in 20%–30% of patients in coma after cardiac arrest,1 but aggressive and prolonged treatment of RSE in patients with favourable multimodal prognostic indicators might lead to 40%–50% survival and good neurological outcome.2 However, scarce data are available on chronic epilepsy after cardiac arrest, which may severely impair the quality of life in survivors. It is unclear whether these patients are at risk of epilepsy, and whether the occurrence of RSE in the acute phase increases such risk. We investigated the risk of epilepsy in a cohort of cardiac arrest survivors. ### Study design This is a retrospective cohort study approved by the Ethics Committee of San Gerardo Hospital, Monza, Italy, based on a previous prospective study.2 Between January 2011 and May 2016, consecutive adult patients with cardiac arrest treated with hypothermia (34°C), in coma for >24 hours, underwent simplified 4-channel continuous EEG monitoring (cEEG) started within 24 hours of event. If electrographic status epilepticus was detected, regardless of clinical manifestations, patients received an aggressive standardised treatment, according to our published protocol.2 ### Prognostic EEG patterns A multimodal prognostic approach was applied in all cases.3 Notably, no included patient received withdrawal of care, intended as active reduction of respiratory support or vasoactive drugs. Prognostic EEG patterns were identified by on-call epilepsy specialists on cEEG monitoring in the first 5 days after the event. EEG features were coded according to the ACNS classification for reactivity, continuity and generalised periodic discharges (GPDs),4 and to the Salzburg …

The apparent diffusion coefficient (ADC) of cerebral water, as measured by diffusion MRI, rapidly decreases in ischaemia, highlighting a lesion in acute stroke patients. The MRI T 2 relaxation time changes in ischaemic brain such that T 2 in ADC lesions may be informative of the extent of tissue damage, potentially aiding in stratification for treatment. We have developed a novel user-unbiased method of determining the changes in T 2 in ADC lesions as a function of clinical symptom duration based on voxel-wise referencing to a contralateral brain volume. The spherical reference method calculates the most probable pre-ischaemic T 2 on a voxel-wise basis, making use of features of the contralateral hemisphere presumed to be largely unaffected. We studied whether T 2 changes in the two main cerebral tissue types, i.e. in grey matter (GM) and white matter (WM), would differ in stroke. Thirty-eight acute stroke patients were accrued within 9 h of symptom onset and scanned at 3 T for 3D T 1-weighted, multi b-value diffusion and multi-echo spin echo MRI for tissue type segmentation, quantitative ADC and absolute T 2 images, respectively. T 2 changes measured by the spherical reference method were 1.94 ± 0.61, 1.50 ± 0.52 and 1.40 ± 0.54 ms h-1 in the whole, GM, and WM lesions, respectively. Thus, T 2 time courses were comparable between GM and WM independent of brain tissue type involved. We demonstrate that T 2 changes in ADC-delineated lesions can be quantified in the clinical setting in a user unbiased manner and that T 2 change correlated with symptom onset time, opening the possibility of using the approach as a tool to assess severity of tissue damage in the clinical setting.

Brain plasticity is a key mechanism for learning and recovery. A striking example of plasticity in the adult brain occurs following input loss, for example, following amputation, whereby the deprived zone is "invaded" by new representations. Although it has long been assumed that such reorganization leads to functional benefits for the invading representation, the behavioral evidence is controversial. Here, we investigate whether a temporary period of somatosensory input loss to one finger, induced by anesthetic block, is sufficient to cause improvements in touch perception ("direct" effects of deafferentation). Further, we determine whether this deprivation can improve touch perception by enhancing sensory learning processes, for example, by training ("interactive" effects). Importantly, we explore whether direct and interactive effects of deprivation are dissociable by directly comparing their effects on touch perception. Using psychophysical thresholds, we found brief deprivation alone caused improvements in tactile perception of a finger adjacent to the blocked finger but not to non-neighboring fingers. Two additional groups underwent minimal tactile training to one finger either during anesthetic block of the neighboring finger or a sham block with saline. Deprivation significantly enhanced the effects of tactile perceptual training, causing greater learning transfer compared with sham block. That is, following deafferentation and training, learning gains were seen in fingers normally outside the boundaries of topographic transfer of tactile perceptual learning. Our results demonstrate that sensory deprivation can improve perceptual abilities, both directly and interactively, when combined with sensory learning. This dissociation provides novel opportunities for future clinical interventions to improve sensation. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Cerebral collaterals are dynamically recruited after arterial occlusion and highly affect tissue outcome in acute ischemic stroke. We investigated the efficacy and safety of four pathophysiologically distinct strategies for acute modulation of collateral flow (collateral therapeutics) in the rat stroke model of transient middle cerebral artery (MCA) occlusion. A composed randomization design was used to assign rats (n = 118) to receive phenylephrine (induced hypertension), polygeline (intravascular volume load), acetazolamide (cerebral arteriolar vasodilation), head down tilt (HDT) 15° (cerebral blood flow diversion), or no treatment, starting 30 min after MCA occlusion. Compared to untreated animals, treatment with collateral therapeutics was associated with lower infarct volumes (62% relative mean difference; 51.57 mm3 absolute mean difference; p

Apparent diffusion coefficient (ADC) of cerebral water, as measured by diffusion MRI, rapidly decreases in ischaemia highlighting a lesion in acute stroke patients. The MRI T(2) relaxation time changes in ischaemic brain such that T(2) in ADC lesions may be informative of the extent of tissue damage, potentially aiding in stratification for treatment. We have developed a novel user-unbiased method of determining the changes in T(2) in ADC lesions as a function of clinical symptom duration based on voxel-wise referencing to a contralateral brain volume. The spherical reference method calculates the most probable pre-ischaemic T(2) on a voxel-wise basis, making use of features of the contralateral hemisphere presumed to be largely unaffected. We studied whether T(2) changes in the two main cerebral tissue types, i.e. in grey matter (GM) and white matter (WM), would differ in stroke. Thirty-eight acute stroke patients were accrued within 9 hours of symptom onset and scanned at 3T for 3D T1-weighted, multi b-value diffusion and multi-echo spin echo MRI for tissue type segmentation, quantitative ADC and absolute T(2) images, respectively. T(2) changes measured by the spherical reference method were 1.94 ± 0.61, 1.50 ± 0.52 and 1.40 ± 0.54 ms/hour in the whole, GM and WM lesions, respectively. Thus, T(2) time courses were comparable between GM and WM independent of brain tissue type involved. We demonstrate that T(2) changes in ADC-delineated lesions can be quantified in the clinical setting in a user unbiased manner and that T(2) change correlated with symptom onset time, opening the possibility of using the approach as a tool to assess severity of tissue damage in the clinical setting.

Bilateral absence of N20, elevated NSE levels and anoxic brain injury signs in neuroimaging, are noted as predictors of poor outcome in comatose patients after cardiac arrest (CA). We evaluated the association of various EEG patterns with these prognostic factors in comatose patients post AC. In our study, 166 patients with cardiac arrest in coma were stratified according to 4 independent EEG patterns: benign, RSE, generalized periodic discharges [GPDs], malignant non-epileptiform. NSE level > 68 ng/mL, bilateral absence of median nerve SEP and moderate to severe anoxic brain injury on neuroimaging, were considered indicators of poor prognosis. Of 166 patients that were included, a benign EEG pattern was recorded in 76 patients (45.8%); RSE occurred in 36 patients, a periodic pattern (GPDs) was seen in 13 patients (7.8%); and a malignant non epileptiform EEG pattern was recorded in 41 patients (24.7%). The four EEG patterns were highly associated with different prognostic indicators. Patients with benign EEG pattern and RSE showed lower NSE levels and were less likely to show bilateral absence N20 responses and severe anoxic brain injury on neuroimaging. On the other side, patients with GPDs and malignant pattern were associated more frequently with bilateral absence of N20 responses, higher NSE levels and severe anoxic brain injury on neuroimaging. These data show that the a benign EEG pattern and RSE without periodisms, may be a predictor of a good outcome and a more aggressive treatment may be indicated in this patients, given the possibility of a better prognosis.

ObjectiveTo investigate neurologic outcome of patients with cardiac arrest with refractory status epilepticus (RSE) treated with a standardized aggressive protocol with antiepileptic drugs and anesthetics compared to patients with other EEG patterns.MethodsIn the prospective cohort study, 166 consecutive patients with cardiac arrest in coma were stratified according to 4 independent EEG patterns (benign, RSE, generalized periodic discharges [GPDs], malignant nonepileptiform) and multimodal prognostic indicators. Primary outcomes were survival and cerebral performance category (CPC) at 6 months.ResultsRSE occurred in 36 patients (21.7%) and was treated with an aggressive standardized protocol as long as multimodal prognostic indicators were not unfavorable. RSE started after 3 ± 2.3 days after cardiac arrest and lasted 4.7 ± 4.3 days. A benign EEG pattern was recorded in 76 patients (45.8%); a periodic pattern (GPDs) was seen in 13 patients (7.8%); and a malignant nonepileptiform EEG pattern was recorded in 41 patients (24.7%). The 4 EEG patterns were highly associated with different prognostic indicators (low-flow time, clinical motor seizures, N20 responses, neuron-specific enolase, neuroimaging). Survival and good neurologic outcome (CPC 1 or 2) at 6 months were 72.4% and 71.1% for benign EEG pattern, 54.3% and 44.4% for RSE, 15.4% and 0% for GPDs, and 2.4% and 0% for malignant nonepileptiform EEG pattern, respectively.ConclusionsAggressive and prolonged treatment of RSE may be justified in patients with cardiac arrest with favorable multimodal prognostic indicators.

It has been proposed that metabolic markers of baseline brain oxygenation have a role to play in the early identification of the ischemic penumbra. Streamlined-qBOLD is a magnetic resonance imaging technique that does not require exogenous contrast. It is a refinement of the quantitative BOLD methodology that provides a simplified approach to mapping and quantifying baseline brain oxygenation related parameters (reversible transverse relaxation rate (R2′), deoxygenated blood volume (DBV) and deoxyhaemoglobin concentration ([dHb])) in a clinically relevant manner. Streamlined-qBOLD was applied to an exploratory cohort of acute stroke patients in a serial imaging study. Detailed voxel-level analysis was used to quantify the metabolic profile of ischaemic tissue on presentation and investigate these metrics in relation to tissue outcome. Individual patient examples illustrate the appropriate interpretation of R2′, DBV and [dHb] in acute stroke and demonstrate the ability of this method to deliver regional information related to oxygen metabolism in the ischaemic tissue. Regional analysis confirms that R2′, DBV and [dHb] vary between regions of ischaemia with different tissue outcomes.

SummaryObjective Rate, reasons, and predictors of antiepileptic drug (AED) discontinuation were investigated in a well-defined cohort of people with epilepsy to verify efficacy and tolerability of treatment up to 20 years from treatment initiation. Methods The history of AED usage in children and adults with epilepsy registered with 123 family physicians in an area of Northern Italy between 2000 and 2008 was recorded. Cumulative probabilities of AED withdrawal for specific reasons were estimated using cumulative incidence functions. The probabilities of withdrawing for terminal remission, and of achieving sustained remission while still on treatment, were also evaluated. The roles of sex, age at diagnosis, seizure types, duration at diagnosis, and syndrome were assessed with hazard ratios and 95% confidence intervals. Results Seven hundred thirty-one of 747 individuals were treated with one or more AEDs during the disease course. The three commonest drugs were valproate, carbamazepine, and phenobarbital. Reported reasons for AED withdrawal were, in decreasing order, terminal remission, ineffectiveness, and adverse events. The probability of withdrawing the first AED for terminal remission was 1.0% at 1 year and increased to 20.0% at 20 years. Corresponding rates were 2.9% and 12.6% for ineffectiveness and 0.5% and 3.3% for adverse events. Reasons for withdrawal varied with individuals’ age, sex, disease characteristics, and drugs. Significance The initial AED given was retained in the majority of cases. Terminal remission, lack of efficacy, and adverse effects were, in decreasing order, the commonest reasons for AED discontinuation. Withdrawal could be predicted by age at diagnosis, sex, and clinical characteristics and varies among drugs.

Refractory status epilepticus (RSE) occurs in up to 30% of patients following resuscitation after cardiac arrest. The impact of aggressive treatment of postanoxic RSE on long-term neurological outcome remains uncertain. We investigated neurological outcome of cardiac arrest patients with RSE treated with a standardized aggressive protocol with antiepileptic drugs and anesthetics, compared with patients with other electroencephalographic (EEG) patterns. A prospective cohort of 166 consecutive patients with cardiac arrest in coma was stratified according to four independent EEG patterns (benign; RSE; generalized periodic discharges (GPDs); malignant nonepileptiform) and multimodal prognostic indicators. Primary outcomes were survival and cerebral performance category (CPC) at 6 months. Refractory status epilepticus occurred in 36 patients (21.7%) and was treated with an aggressive standardized protocol as long as multimodal prognostic indicators were not unfavorable. Refractory status epilepticus started after 3 ± 2.3 days after cardiac arrest and lasted 4.7 ± 4.3 days. A benign electroencephalographic patterns was recorded in 76 patients (45.8%), a periodic pattern (GPDs) in 13 patients (7.8%), and a malignant nonepileptiform EEG pattern in 41 patients (24.7%). The four EEG patterns were highly associated with different prognostic indicators (low flow time, clinical motor seizures, N20 responses, neuron-specific enolase (NSE), neuroimaging). Survival and good neurological outcome (CPC 1 or 2) at 6 months were 72.4% and 71.1% for benign EEG pattern, 54.3% and 44.4% for RSE, 15.4% and 0% for GPDs, and 2.4% and 0% for malignant nonepileptiform EEG pattern, respectively. Aggressive and prolonged treatment of RSE may be justified in cardiac arrest patients with favorable multimodal prognostic indicators. This article is part of the Special Issue “Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures"

BACKGROUND: Excessively long clamping time and suboptimal position of stitches can influence the anastomosis patency and the clinical outcome in cerebral bypass surgery. Coronary intravascular micro-shunts could represent an innovative solution for neurosurgical bypass, but the hemodynamic properties of these devices should be extensively studied before their translational application. We created an experimental in-vivo model and we analyzed the blood flow and pressure modification induced by the micro-shunt. METHODS: After laparotomy, an intravascular micro-shunt was placed into the aorta of 8 adult rats, simulating a neurosurgical setting in which the shunt is temporary placed inside the receiving cerebral vessel. A fiber-optic pressure sensor was placed in the femoral artery and the blood pressure continuously recorded during the procedure. Using an ultrasound vascular probe, blood flow velocity in aorta was measured at baseline and both proximally and distally to the shunt. RESULTS: After shunt positioning, no significant decrease in blood pressure was observed (mean value 68.57 versus 80.00 mmHg; P=0.48). Distal aortic blood flow, expressed as peak systolic velocity, showed a significant decrease after shunt positioning (mean value 51.88 versus 86.88 cm/sec; P=0.04), with a mean residual blood flow of 63%. Blood flow values recorded immediately upstream to the shunt did not differ from baseline. CONCLUSIONS: This is the first in-vivo experimental study concerning the hemodynamic properties of an intravascular micro-shunt. Our results demonstrate that this device provides a considerable blood out-flow without significant changes in blood pressure, suggesting that specific neurosurgical micro-shunts might be developed.

International audience; High variability in infarct size is common in experimental stroke models and affects statistical power and validity of neuroprotection trials. The aim of this study was to explore cerebral collateral flow as a stratification factor for the prediction of ischemic outcome. Transient intraluminal occlusion of the middle cerebral artery was induced for 90 min in 18 Wistar rats. Cerebral collateral flow was assessed intra-procedurally using multi-site laser Doppler flowmetry monitoring in both the lateral middle cerebral artery territory and the borderzone territory between middle cerebral artery and anterior cerebral artery. Multi-modal magnetic resonance imaging was used to assess acute ischemic lesion (diffu-sion-weighted imaging, DWI), acute perfusion deficit (time-to-peak, TTP), and final ischemic lesion at 24 h. Infarct volumes and typology at 24 h (large hemispheric versus basal ganglia infarcts) were predicted by both intra-ischemic collateral perfusion and acute DWI lesion volume. Collateral flow assessed by multi-site laser Doppler flowmetry correlated with the corresponding acute perfusion deficit using TTP maps. Multi-site laser Doppler flowmetry monitoring was able to predict ischemic outcome and perfusion deficit in good agreement with acute MRI. Our results support the additional value of cerebral collateral flow monitoring for outcome prediction in experimental ischemic stroke, especially when acute MRI facilities are not available.

Background and purpose Seizures in most people with epilepsy remit but prognostic markers are poorly understood. There is also little information on the long-term outcome of people who fail to achieve seizure control despite the use of two antiepileptic drugs (drug resistance). Methods People with a validated diagnosis of epilepsy in whom two antiepileptic drugs had failed were identified from primary care records. All were registered with one of 123 family physicians in an area of northern Italy. Remission (uninterrupted seizure freedom lasting 2 years or longer) and prognostic patterns (early remission, late remission, remission followed by relapse, no remission) were determined. Results In all, 747 individuals (381 men), aged 11 months to 94 years, were followed for 11 045.5 person-years. 428 (59%) were seizure-free. The probability of achieving 2-year remission was 18% at treatment start, 34% at 2 years, 45% at 5, 52% at 10 and 67% at 20 years (terminal remission, 60%). Epilepsy syndrome and drug resistance were the only independent predictors of 2- and 5-year remission. Early remission was seen in 101 people (19%), late remission in 175 (33%), remission followed by relapse in 85 (16%) and no remission in 166 (32%). Treatment response was the only variable associated with differing prognostic patterns. Conclusion The long-term prognosis of epilepsy is favourable in most cases. Early seizure remission is not invariably followed by terminal remission and seizure outcome varies according to well-defined patterns. Prolonged seizure remission and prognostic patterns can be predicted by broad syndromic categories and the failure of two antiepileptic drugs.

Drug-resistant epilepsy (DRE) is defined by the International League Against Epilepsy as a failure of adequate trials of two tolerated, appropriately chosen, and used antiepileptic drugs to achieve sustained seizure freedom. Our aim was to calculate the following: (1) the prevalence of active epilepsy and DRE in a well-defined population of Northern Italy and (2) the proportion of incident cases developing DRE. The study population (146,506; year 2008) resided in the province of Lecco, Northern Italy. The medical records of 123 general practitioners were reviewed to identify patients with epilepsy, diagnosed by a neurologist during the period 2000-2008. The point prevalence of active epilepsy and DRE was calculated on December 31, 2008. A total of 747 prevalent patients with epilepsy, 684 patients with active epilepsy, and 342 incident cases were identified. The frequency of DRE was 15.6% (107/684) of all active epilepsies and 10.5% (36/342) of incident cases. The point prevalence was 0.73 per 1000. The standardized prevalence of DRE was 0.7 per 1000 (Italian population) and 0.8 per 1000 (world population). Our data indicate that 1/6 patients with active epilepsy in the general population has DRE, and 1/10 patients with newly diagnosed epilepsy will develop DRE within nine years from the diagnosis.

International audience; Intracranial collaterals are dynamically recruited after arterial occlusion and are emerging as a strong determinant of tissue outcome in both human and experimental ischemic stroke. The relationship between collateral flow and ischemic penumbra remains largely unexplored in pre-clinical studies. The aim of the present study was to investigate the pattern of collateral flow with regard to penumbral tissue after transient middle cerebral artery (MCA) occlusion in rats. MCA was transiently occluded (90min) by intraluminal filament in adult male Wistar rats (n=25). Intracranial collateral flow was studied in terms of perfusion deficit and biosignal fluctuation analyses using multi-site laser Doppler monitoring. Molecular penumbra was defined by topographical mapping and quantitative signal analysis of Heat Shock Protein 70kDa (HSP70) immunohistochemistry. Functional deficit and infarct volume were assessed 24h after ischemia induction. The results show that functional performance of intracranial collaterals during MCA occlusion inversely correlated with HSP70 immunoreactive areas in both the cortex and the striatum, as well as with infarct size and functional deficit. Intracranial collateral flow was associated with reduced areas of both molecular penumbra and ischemic core and increased areas of intact tissue in rats subjected to MCA occlusion followed by reperfusion. Our findings prompt the development of collateral therapeutics to provide tissue-saving strategies in the hyper-acute phase of ischemic stroke prior to recanalization therapy.

Statins have since long been reported to exert acute neuroprotection in experimental stroke models. However, crucial questions still need to be addressed as far as the timing of their cerebral effects after intravascular administration and the role played by the blood brain barrier (BBB) crossing properties. We tested the effects of an hydrophilic statin (pravastatin, 100 nM), which poorly crosses BBB under physiological conditions. Pravastatin was administered either 90 min before or immediately after transient middle cerebral artery occlusion in the in vitro isolated Guinea pig brain preparation. A multi-modal outcome assessment was performed, through electrophysiological and cerebral vascular tone recordings, MAP-2 immunohistochemistry, BBB evaluation via ZO-1/FITC-albumin analysis, AKT and ERK activation and whole-cell antioxidant capacity. Pravastatin pre-ischemic administration did not produce any significant effect. Pravastatin post-ischemic administration significantly prevented MAP-2 immunoreactivity loss in ischemic areas, increased ERK phosphorylation in the ischemic hemisphere and enhanced whole-cell antioxidant capacity. Electrophysiological parameters, vascular tone and AKT signaling were unchanged. In all tested ischemic brains, ZO-1 fragmentation and FITC albumin extravasation was observed, starting 30 min from ischemia onset, indicating loss of BBB integrity. Our findings indicate that the rapid anti-ischemic effects of intravascular pravastatin are highly dependent on BBB increased permeability after stroke.

The translational potential of pre-clinical stroke research depends on the accuracy of experimental modeling. Cerebral perfusion monitoring in animal models of acute ischemic stroke allows to confirm successful arterial occlusion and exclude subarachnoid hemorrhage. Cerebral perfusion monitoring can also be used to study intracranial collateral circulation, which is emerging as a powerful determinant of stroke outcome and a possible therapeutic target. Despite a recognized role of Laser Doppler perfusion monitoring as part of the current guidelines for experimental cerebral ischemia, a number of technical difficulties exist that limit its widespread use. One of the major issues is obtaining a secure and prolonged attachment of a deep-penetration Laser Doppler probe to the animal skull. In this video, we show our optimized system for cerebral perfusion monitoring during transient middle cerebral artery occlusion by intraluminal filament in the rat. We developed in-house a simple method to obtain a custom made holder for twin-fibre (deep-penetration) Laser Doppler probes, which allow multi-site monitoring if needed. A continuous and prolonged monitoring of cerebral perfusion could easily be obtained over the intact skull.