Relationship between onset-to-door time and door-to-thrombolysis time: a pooled analysis of 10 dedicated stroke centers

BACKGROUND AND PURPOSE Inverse relationship between onset-to-door time (ODT) and door-to-needle time (DNT) in stroke thrombolysis was reported from various registries. We analyzed this relationship and other determinants of DNT in dedicated stroke centers. METHODS Prospectively collected data of consecutive ischemic stroke patients from 10 centers who received IV thrombolysis within 4.5 hours from symptom onset were merged (n=7106). DNT was analyzed as a function of demographic and prehospital variables using regression analyses, and change over time was considered. RESULTS In 6348 eligible patients with known treatment delays, median DNT was 42 minutes and kept decreasing steeply every year (P<0.001). Median DNT of 55 minutes was observed in patients with ODT ≤30 minutes, whereas it declined for patients presenting within the last 30 minutes of the 3-hour time window (median, 33 minutes) and of the 4.5-hour time window (20 minutes). For ODT within the first 30 minutes of the extended time window (181-210 minutes), DNT increased to 42 minutes. DNT was stable for ODT for 30 to 150 minutes (40-45 minutes). We found a weak inverse overall correlation between ODT and DNT (R(2)=-0.12; P<0.001), but it was strong in patients treated between 3 and 4.5 hours (R(2)=-0.75; P<0.001). ODT was independently inversely associated with DNT (P<0.001) in regression analysis. Octogenarians and women tended to have longer DNT. CONCLUSIONS DNT was decreasing steeply over the last years in dedicated stroke centers; however, significant oscillations of in-hospital treatment delays occurred at both ends of the time window. This suggests that further improvements can be achieved, particularly in the elderly.

The time window for generation of dendritic spikes by coincidence of action potentials and EPSPs is layer specific in somatosensory cortex

The precise timing of events in the brain has consequences for intracellular processes, synaptic plasticity, integration and network behaviour. Pyramidal neurons, the most widespread excitatory neuron of the neocortex have multiple spike initiation zones, which interact via dendritic and somatic spikes actively propagating in all directions within the dendritic tree. For these neurons, therefore, both the location and timing of synaptic inputs are critical. The time window for which the backpropagating action potential can influence dendritic spike generation has been extensively studied in layer 5 neocortical pyramidal neurons of rat somatosensory cortex. Here, we re-examine this coincidence detection window for pyramidal cell types across the rat somatosensory cortex in layers 2/3, 5 and 6. We find that the time-window for optimal interaction is widest and shifted in layer 5 pyramidal neurons relative to cells in layers 6 and 2/3. Inputs arriving at the same time and locations will therefore differentially affect spike-timing dependent processes in the different classes of pyramidal neurons.

Safety of endovascular treatment beyond the 6-h time window in 205 patients

Background and purpose Intra-arterial treatment (IAT) is effective when performed within 6 h of symptom onset in selected stroke patients (‘T < 6H’). Its safety and efficacy is unclear when the patient has had symptoms for more than 6 h (‘T > 6H’) or for an unknown time (unclear-onset stroke, UOS), or woke up with a stroke (wake-up stroke, WUS). In this study we compared the safety of IAT in these four patient groups. Methods Eight-hundred and fifty-nine patients treated with IAT were enrolled. The main outcome parameters were clinical outcome [excellent: modified Rankin Scale (mRS) 0 or 1; or favorable: mRS 0–2] or mortality 3 months after treatment. Further outcome parameters were the rates of vessel recanalization, and cerebral and systemic hemorrhage. Results Six-hundred and fifty-four patients were treated before (T < 6H) and 205 after 6 h or an unknown time (128 T > 6H, 55 WUS and 22 UOS). NIHSS scores were higher in UOS patients than in T < 6H patients, vertebrobasilar occlusion was more common in T > 6H and UOS patients, and middle cerebral artery occlusions less common in T > 6H than in T < 6H patients. Other baseline characteristics were similar. There was no significant difference in clinical outcome and the rate of hemorrhage in multivariable regression analysis. Conclusions Clinical outcome of our four groups of patients was similar with no increase of hemorrhage rates in patients treated after awakening, after an unknown time or more than 6 h. Our preliminary data suggest that treatment of such patients may be performed safely. If confirmed in randomized trials, this would have major clinical implications.

Time window for recanalization in basilar artery occlusion: Speculative synthesis.

Basilar artery occlusion (BAO) is one of the most devastating forms of stroke and few patients have good outcomes without recanalization. Most centers apply recanalization therapies for BAO up to 12-24 hours after symptom onset, which is a substantially longer time window than the 4.5 hours used in anterior circulation stroke. In this speculative synthesis, we discuss recent advances in BAO treatment in order to understand why and under which circumstances longer symptom duration might not necrotize the brainstem and turn therapeutic attempts futile. We raise the possibility that distinct features of the posterior circulation, e.g., highly developed, persistent collateral arterial network, reverse filling of the distal basilar artery, and delicate plasma flow siding the clot, might sustain brittle patency of brainstem perforators in the face of stepwise growth of the thrombus. Meanwhile, the tissue clock characterizing the rapid necrosis of a typical anterior circulation penumbra will not start. During this perilous time period, recanalization at any point would salvage the brainstem from eventual necrosis caused by imminent reinforcement and further building up of the clot.

[Acute occlusions of cerebral arterial vessels - intravenous versus intraarterial thrombolysis]

In selected stroke patients intravenous thrombolysis and/or endovascular therapies lead to a significant reduction of long term disabilities. In case of no contraindications, patients with acute ischemic stroke, which arrive within the time window on the emergency unit, should receive thrombolysis consequently and current data indicate that patients with a severe acute ischemic stroke and a proximal cerebral arterial vessel occlusion (i. e. main stem of the arteria cerebri media, posterior, maybe also anterior, arteria carotis interna and basilaris) should preferentially be treated endovascularly, patients with a peripheral cerebral arterial vessel occlusion (i. e. main branch of the arteria cerebri media, anterior and posterior) and mild symptoms with intravenous thrombolysis.

Reasons to withhold intra-arterial thrombolysis in clinical practice

BACKGROUND: In selected stroke centers intra-arterial thrombolysis (IAT) is used for the treatment of acute stroke patients presenting within 6 hours of symptom onset. However, data about eligibility of acute stroke patients for IAT in clinical practice are very scarce. METHODS: We collected prospectively data on indications advising for or against IAT of 230 consecutive stroke patients in a tertiary stroke center. RESULTS: 76 patients (33.0%) presented within 3 hours, 69 (30%) between 3 and 6 hours of symptom onset and 85 (37%) later than 6 hours. Arteriography was performed in 71 patients (31%) and IAT in 46 (20%). In 11 patients no or only peripheral branch occlusions were seen on arteriography and therefore IAT was not performed. In 9 patients the ICA was occluded and barred IAT and in five anatomical or technical difficulties made IAT impossible. 72 patients presenting within 6 hours did not undergo arteriography and thrombolysis, mostly because of mild (n = 44) or rapidly improving neurological deficits (n = 13). Other reasons to withhold IAT were CT and/or clinical findings suggesting lacunar stroke due to small vessel occlusion (n = 7), limiting comorbidty (n = 7) and baseline international normalized ratio > 1.7 (n = 1). CONCLUSIONS: A third of the patients underwent diagnostic arteriography and one fifth received IAT. The most important reasons to withhold thrombolysis were presentation beyond the 6 hours time window and mild or rapidly improving symptoms.

Delayed diagnosis of acute ischemic stroke in children - a registry-based study in Switzerland

QUESTIONS UNDER STUDY/PRINCIPLES: After arterial ischemic stroke (AIS) an early diagnosis helps preserve treatment options that are no longer available later. Paediatric AIS is difficult to diagnose and often the time to diagnosis exceeds the time window of 6 hours defined for thrombolysis in adults. We investigated the delay from the onset of symptoms to AIS diagnosis in children and potential contributing factors.

[Mechanical Thrombectomy for Acute Ischemic Stroke.]

The therapy of acute ischemic stroke aims at fast recanalization of the occluded brain vessel. In contrast to intravenous thrombolysis (IVT), endovascular approaches yield higher recanalization rates especially in large vessel occlusions. Mechanical thrombectomy with the Merci Retriever received FDA approval in 2004 as an adjunct to IVT or in the case of failed recanalization after IVT. The time window for treatment is 8 h from stroke onset. However, the recanalization rate was 55 %, still leaving space for further improvement. In addition to the Merci Retriever, the Penumbra System received FDA approval in 2008. The newest endovascular approach comprising retrievable intracranial stents results in an increased recanalization rate exceeding 90 % and has markedly reduced the time to recanalization. On the other hand, the complication rate has not increased yet. These promising results suggest a combined therapy for acute ischemic stroke. In a first step IVT can be started independently of the size of the treating hospital and in a next step the patient is transferred to a neuroradiological center. If vessel occlusion persists, additional endovascular recanalization is performed (bridging concept). Patients who don't qualify for IVT are candidates for mechanical thrombectomy up to 8 h after stroke onset.

Parameter-free extraction of the functional network topology from intracranial EEG recordings: a time-resolved study of graph properties in focal onset seizures

Rationale: Focal onset epileptic seizures are due to abnormal interactions between distributed brain areas. By estimating the cross-correlation matrix of multi-site intra-cerebral EEG recordings (iEEG), one can quantify these interactions. To assess the topology of the underlying functional network, the binary connectivity matrix has to be derived from the cross-correlation matrix by use of a threshold. Classically, a unique threshold is used that constrains the topology [1]. Our method aims to set the threshold in a data-driven way by separating genuine from random cross-correlation. We compare our approach to the fixed threshold method and study the dynamics of the functional topology. Methods: We investigate the iEEG of patients suffering from focal onset seizures who underwent evaluation for the possibility of surgery. The equal-time cross-correlation matrices are evaluated using a sliding time window. We then compare 3 approaches assessing the corresponding binary networks. For each time window: * Our parameter-free method derives from the cross-correlation strength matrix (CCS)[2]. It aims at disentangling genuine from random correlations (due to finite length and varying frequency content of the signals). In practice, a threshold is evaluated for each pair of channels independently, in a data-driven way. * The fixed mean degree (FMD) uses a unique threshold on the whole connectivity matrix so as to ensure a user defined mean degree. * The varying mean degree (VMD) uses the mean degree of the CCS network to set a unique threshold for the entire connectivity matrix. * Finally, the connectivity (c), connectedness (given by k, the number of disconnected sub-networks), mean global and local efficiencies (Eg, El, resp.) are computed from FMD, CCS, VMD, and their corresponding random and lattice networks. Results: Compared to FMD and VMD, CCS networks present: *topologies that are different in terms of c, k, Eg and El. *from the pre-ictal to the ictal and then post-ictal period, topological features time courses that are more stable within a period, and more contrasted from one period to the next. For CCS, pre-ictal connectivity is low, increases to a high level during the seizure, then decreases at offset. k shows a ‘‘U-curve’’ underlining the synchronization of all electrodes during the seizure. Eg and El time courses fluctuate between the corresponding random and lattice networks values in a reproducible manner. Conclusions: The definition of a data-driven threshold provides new insights into the topology of the epileptic functional networks.

Factors that determine penumbral tissue loss in acute ischaemic stroke

The goal of acute stroke treatment with intravenous thrombolysis or endovascular recanalization techniques is to rescue the penumbral tissue. Therefore, knowing the factors that influence the loss of penumbral tissue is of major interest. In this study we aimed to identify factors that determine the evolution of the penumbra in patients with proximal (M1 or M2) middle cerebral artery occlusion. Among these factors collaterals as seen on angiography were of special interest. Forty-four patients were included in this analysis. They had all received endovascular therapy and at least minimal reperfusion was achieved. Their penumbra was assessed with perfusion- and diffusion-weighted imaging. Perfusion-weighted imaging volumes were defined by circular singular value decomposition deconvolution maps (Tmax > 6 s) and results were compared with volumes obtained with non-deconvolved maps (time to peak > 4 s). Loss of penumbral volume was defined as difference of post- minus pretreatment diffusion-weighted imaging volumes and calculated in per cent of pretreatment penumbral volume. Correlations between baseline characteristics, reperfusion, collaterals, time to reperfusion and penumbral volume loss were assessed using analysis of covariance. Collaterals (P = 0.021), reperfusion (P = 0.003) and their interaction (P = 0.031) independently influenced penumbral tissue loss, but not time from magnetic resonance (P = 0.254) or from symptom onset (P = 0.360) to reperfusion. Good collaterals markedly slowed down and reduced the penumbra loss: in patients with thrombolysis in cerebral infarction 2 b-3 reperfusion and without any haemorrhage, 27% of the penumbra was lost with 8.9 ml/h with grade 0 collaterals, whereas 11% with 3.4 ml/h were lost with grade 1 collaterals. With grade 2 collaterals the penumbral volume change was -2% with -1.5 ml/h, indicating an overall diffusion-weighted imaging lesion reversal. We conclude that collaterals and reperfusion are the main factors determining loss of penumbral tissue in patients with middle cerebral artery occlusions. Collaterals markedly reduce and slow down penumbra loss. In patients with good collaterals, time to successful reperfusion accounts only for a minor fraction of penumbra loss. These results support the hypothesis that good collaterals extend the time window for acute stroke treatment.

Optimizing the success of cell transplantation therapy for stroke

Stem cell transplantation has evolved as a promising experimental treatment approach for stroke. In this review, we address the major hurdles for successful translation from basic research into clinical applications and discuss possible strategies to overcome these issues. We summarize the results from present pre-clinical and clinical studies and focus on specific areas of current controversy and research: (i) the therapeutic time window for cell transplantation; (ii) the selection of patients likely to benefit from such a therapy; (iii) the optimal route of cell delivery to the ischemic brain; (iv) the most suitable cell types and sources; (v) the potential mechanisms of functional recovery after cell transplantation; and (vi) the development of imaging techniques to monitor cell therapy.

Counterbalancing effects of competition for resources and facilitation against grazing in alpine snowbed communities

Alpine snowbeds are habitats where the major limiting factors for plant growth are herbivory and a small time window for growth due to late snowmelt. Despite these limitations, snowbed vegetation usually forms a dense carpet of palatable plants due to favourable abiotic conditions for plant growth within the short growing season. These environmental characteristics make snowbeds particularly interesting to study the interplay of facilitation and competition. We hypothesised an interplay between resource competition and facilitation against herbivory. Further, we investigated whether these predicted neighbour effects were species-specific and/or dependent on ontogeny, and whether the balance of positive and negative plant–plant interactions shifted along a snowmelt gradient. We determined the neighbour effects by means of neighbour removal experiments along the snowmelt gradient, and linear mixed model analyses. The results showed that the effects of neighbour removal were weak but generally consistent among species and snowmelt dates, and depended on whether biomass production or survival was considered. Higher total biomass and increased fruiting in removal plots indicated that plants competed for nutrients, water, and light, thereby supporting the hypothesis of prevailing competition for resources in snowbeds. However, the presence of neighbours reduced herbivory and thereby also facilitated survival. For plant growth the facilitative effects against herbivores in snowbeds counterbalanced competition for resources, leading to a weak negative net effect. Overall the neighbour effects were not species-specific and did not change with snowmelt date. Our finding of counterbalancing effects of competition and facilitation within a plant community is of special theoretical value for species distribution models and can explain the success of models that give primary importance to abiotic factors and tend to overlook interrelations between biotic and abiotic effects on plants.

Gadolinium diethylenetriaminepentaacetate enhancement kinetics in the menisci of asymptomatic subjects: a first step towards a dedicated dGEMRIC (delayed gadolinium-enhanced MRI of cartilage)-like protocol for biochemical imaging of the menisci

It was our aim to investigate the gadolinium diethylenetriaminepentaacetate (Gd-DTPA(2-) ) enhancement kinetics in the menisci of the knee joint over a prolonged period of time. Six asymptomatic volunteers (four men and two women; mean age, 25 ± 2.4 years) were enrolled. Sagittal, T(1) -weighted, spin-echo MR sequences of the right knee joint were obtained at 3 T. Imaging was performed before (baseline), 1 h after and in half-hour intervals up to 9 h after the intravenous administration of 0.2 mmol/kg of Gd-DTPA(2-) . To measure the rates of contrast enhancement relative to the baseline, regions of interest that covered the anterior and posterior horns of the medial and lateral meniscus were defined on each of two adjacent sections, and enhancement curves were constructed. An enhancement peak between 2.5 and 4.5 h after Gd-DTPA(2-) administration was observed, and analysis of variance also revealed no significant difference (p=0.94), in terms of enhancement, within this time interval. Pair-wise, post hoc testing also revealed no significant differences between 2.5 and 3, 3 and 3.5, 3.5 and 4, and 4 and 4.5 h post Gd-DTPA(2-) application. Our preliminary data therefore suggest that the time window suitable for a dGEMRIC (delayed gadolinium-enhanced MRI of cartilage)-like T(1) mapping of the menisci is relatively short, and lies between 2.5 and 4.5 h after Gd-DTPA(2-) injection.

Tracking the implicit self using event-related potentials

Negative biases in implicit self-evaluation are thought to be detrimental to subjective well-being and have been linked to various psychological disorders, including depression. An understanding of the neural processes underlying implicit self-evaluation in healthy subjects could provide a basis for the investigation of negative biases in depressed patients, the development of differential psychotherapeutic interventions, and the estimation of relapse risk in remitted patients. We thus studied the brain processes linked to implicit self-evaluation in 25 healthy subjects using event-related potential (ERP) recording during a self-relevant Implicit Association Test (sIAT). Consistent with a positive implicit self-evaluation in healthy subjects, they responded significantly faster to the congruent (self-positive mapping) than to the incongruent sIAT condition (self-negative mapping). Our main finding was a topographical ERP difference in a time window between 600 and 700 ms, whereas no significant differences between congruent and incongruent conditions were observed in earlier time windows. This suggests that biases in implicit self-evaluation are reflected only indirectly, in the additional recruitment of control processes needed to override the positive implicit self-evaluation of healthy subjects in the incongruent sIAT condition. Brain activations linked to these control processes can thus serve as an indirect measure for estimating biases in implicit self-evaluation. The sIAT paradigm, combined with ERP, could therefore permit the tracking of the neural processes underlying implicit self-evaluation in depressed patients during psychotherapy.

Immediate and delayed transplantation of mesenchymal stem cells improve muscle force after skeletal muscle injury in rats

Mesenchymal stem cell (MSC) therapy is a promising approach for regaining muscle function after trauma. Prior to clinical application, the ideal time of transplantation has to be determined. We investigated the effects of immediate and delayed transplantation. Sprague-Dawley rats received a crush trauma to the left soleus muscle. Treatment groups were transplanted locally with 2 × 10(6) autologous MSCs, either immediately or 7 days after trauma. Saline was used as sham therapy. Contraction force tests and histological analyses were performed 4 weeks after injury. GFP-labelled MSCs were followed after transplantation. The traumatized soleus muscles of the sham group displayed a reduction of twitch forces to 36 ± 17% and of tetanic forces to 29 ± 11% of the non-injured right control side, respectively. Delayed MSC transplantation resulted in a significant improvement of contraction maxima in both stimulation modes (twitch, p = 0.011; tetany, p = 0.014). Immediate transplantation showed a significant increase in twitch forces to 59 ± 17% (p = 0.043). There was no significant difference in contraction forces between muscles treated by immediate and delayed cell transplantation. We were able to identify MSCs in the interstitium of the injured muscles up to 4 weeks after transplantation. Despite the fundamental differences of the local environment, which MSCs encounter after transplantation, similar results could be obtained with respect to functional muscle regeneration. We believe that transplanted MSCs residing in the interstitial compartment evolve their regenerative capabilities through paracrine pathways. Our data suggest a large time window of the therapeutical measures.