Stefanie Leistner

Intravenous tPA for Ischemic Stroke Team Performance Over Time, Safety, and Efficacy in a Single-Center, 2-Year Experience

Background and Purpose Safety and efficacy concerns toward thrombolysis for ischemic stroke prevail among many neurologists because of the risks of hemorrhage and the small proportion of suitable patients. We therefore prospectively assessed feasibility, safety, efficacy, and team performance in a single center to prove whether thrombolytic treatment is practical in daily clinical routine. Methods Patients were prospectively recruited over a 2-year period. Major inclusion and exclusion criteria from large, randomized controlled trials were combined. Prespecified outcome parameters were the modified Rankin scale (MRS) and the Barthel Index (BI) at 3 months and symptomatic hemorrhagic complications. In addition, certain time intervals during the diagnostic process preceding thrombolysis were prospectively recorded. Results Within 2 years a total of 75 patients underwent intravenous thrombolysis, corresponding to 9.4% of all admitted patients with stroke and 14.9% of patients with ischemic stroke. Mean±SD age was 68±13 (range 34 to 90) years; median baseline National Institutes of Health Stroke Scale score was 13±6 (range 2 to 34). Thrombolysis was started at an average time of 144 minutes after symptom onset, and 13 patients (17.3%) were treated beyond 3 hours. Two cerebral hemorrhages (2.7%) occurred. Outcome according to the MRS was good (MRS 0 to 1) in 40%, moderate (MRS 2 to 3) in 32%, and poor (MRS 4 to 5) in 13%; the corresponding results, as measured by the BI, were 61% (BI 95 to 100, good), 16% (BI 55 to 90, moderate), and 8% (BI 0 to 50, poor). The mortality rate was 15%. Over 2 years the median door-to-CT time decreased from 30 to 22 minutes (27%), and the door-to-needle time was shortened from 96 to 73 minutes (14%). The mean number of patients treated per month increased from 2 to 4. Conclusions Thrombolytic therapy can be performed safely and efficaciously in daily clinical routine. More than a minority of acute stroke patients might be eligible for intravenous thrombolysis. The performance of a stroke team can be improved over time, subsequently increasing the proportion of eligible patients and thereby the efficiency of the method.

Prophylactic antipyretic treatment with acetaminophen in acute ischemic stroke: a pilot study.

Fever is associated with poor outcome in acute stroke. Forty-two consecutive, normothermic patients with acute ischemic stroke were, within 24 hours from symptom onset, randomized to either receive 4 g acetaminophen daily (n = 20) or matched placebo (n = 22). Fever of greater than 37.5 °C occurred in 36.4% of patients in the placebo group, compared with 5.0% in the acetaminophen group (Fisher’s exact test, p = 0.014). Prophylactic antipyretic treatment with acetaminophen may be effective in the prevention of fever after acute ischemic stroke.

Scattered Brain Infarct Pattern on Diffusion-Weighted Magnetic Resonance Imaging in Patients with Acute Ischemic Stroke

Background and Purpose: Infarct patterns on brain imaging contribute to the etiologic classification of ischemic stroke. However, the association of specific subtypes of infarcts and etiologic mechanisms is often weak, and acute lesions are frequently missed on initial computed tomography (CT). Diffusion-weighted imaging (DWI) is superior in visualizing acute ischemic lesions as compared to CT and conventional magnetic resonance imaging (MRI). In our prospective study, we addressed the question whether a distinct pattern of infarction on DWI is associated with infarct etiology and clinical outcome. Methods: Sixty-two patients with clinical signs of acute ischemic stroke and negative acute CT upon admission underwent DWI within 10 days after the ictus. Neurological status was documented using the NIH stroke scale. A scattered lesion pattern was defined by at least 2 separate hyperintense DWI lesions within the territory of one of the major cerebral arteries. Ischemic lesions were defined as acute if the region was demarcated strongly hyperintense in all DW images, and if the apparent diffusion coefficient was below normal. Results: In 32 patients, DWI revealed a scattered lesion pattern, while in 30 patients a single acute lesion was detected. In patients with scattered lesions, potential arterial or cardiac embolic sources were detected in 26 patients (81.3%), as compared to 5 patients (16.6%) in the group with single lesions (χ2 test, p < 0.0001). The neurological status of patients with scattered lesions improved significantly more than among patients with single lesions (Mann-Whitney test, p < 0.0003). Conclusion: A scattered lesion pattern on DWI in patients with acute brain infarction and negative initial CT scan is associated with an embolic etiology and may indicate a favorable clinical outcome.

Delayed Occlusion after Internal Carotid Artery Dissection under Heparin

Internal carotid artery dissection (ICAD) is a frequent etiology of stroke in the young. Immediate anticoagulation with unfractionated heparin is the most frequent treatment. A theoretical side effect of unfractionated heparin is an increase in the intramural hematoma resulting in hemodynamic cerebral infarction. We studied 20 patients with ICAD. All patients were immediately treated with unfractionated heparin. Activated partial thromboplastin time (aPTT) ratios were measured twice daily. We prospectively monitored the course of ICAD with repeated ultrasound in hospital. Unexpectedly, delayed ICA occlusion was noted in 5 patients under treatment. One of these developed a watershed infarct. We then analyzed the aPTT ratios over the first 6 days after diagnosis. Patients with delayed occlusion had significantly higher aPTT ratios (2.6 ± 0.4 vs. 2.0 ± 0.5, p < 0.05). Within the limits of a partially retrospective design, our study seems to support the notion that unfractionated heparin can increase the intramural hematoma. Our findings further justify a randomized clinical trial to resolve the anticoagulant/antiplatelet debate.

Neurovascular coupling analyzed non-invasively in the human brain

Most functional brain imaging methods detect neuronal activations indirectly through the accompanying neurovascular response. Here, we demonstrate that a novel methodological approach, the combination of DC-magnetoencephalography (DC-MEG) and near-infrared spectroscopy (NIRS), allows non-invasive assessment of the dynamics of neurovascular coupling in the human brain: detecting directly slow neuronal processes (with time constants of 30 s), DC-MEG revealed, even in unaveraged recordings, sustained neuronal activations at pericentral hand cortices contralateral to repetitive finger movements; these were accompanied by the ensuing local vascular response showing similar dynamical features as quantified by simultaneously recorded NIRS. This non-invasive approach opens a new avenue for the understanding of neurovascular coupling during physiological tasks as well as in diseases involving slow neuronal depolarization shifts and alterations of blood flow, such as stroke or migraine.

Non-invasive single-trial monitoring of human movement-related brain activation based on DC-magnetoencephalography.

Neuroimaging techniques, such as fMRI, PET and near-infrared spectroscopy, monitor task-related neuronal activations in the brain indirectly through the associated neurovascular/metabolic responses. To assess the primary neuronal activations directly, magnetoencephalography was combined here with a mechanical modulation of the head-to-sensor position and signal separation via independent component analysis. In all of five subjects this approach allowed to monitor the time evolution of DC fields (< 0.1 Hz) over the left hemisphere related to complex finger movements of the right hand alternating with rest periods (30 s each). Throughout the recording period of 30 min, stable task-related DC fields were recordable in a single-trial mode, i.e. without any averaging. DC-MEG opens up the possibility of analysing non-invasively cortical DC-activity also in stroke, migraine or epilepsy patients.

DC-magnetoencephalography and time-resolved near-infrared spectroscopy combined to study neuronal and vascular brain responses

The temporal relation between vascular and neuronal responses of the brain to external stimuli is not precisely known. For a better understanding of the neuro-vascular coupling changes in cerebral blood volume and oxygenation have to be measured simultaneously with neuronal currents. With this motivation modulation dc-magnetoencephalography was combined with multi-channel time-resolved near-infrared spectroscopy to simultaneously monitor neuronal and vascular parameters on a scale of seconds. Here, the technique is described, how magnetic and optical signals can be measured simultaneously. In a simple motor activation paradigm (alternating 30 s of finger movement with 30 s of rest for 40 min) both signals were recorded non-invasively over the motor cortex of eight subjects. The off-line averaged signals from both modalities showed distinct stimulation related changes. By plotting changes in oxy- or deoxyhaemoglobin as a function of magnetic field a characteristic trajectory was created, which was similar to a hysteresis loop. A parametric analysis allowed quantitative results regarding the timing of coupling: the vascular signal increased significantly slower than the neuronal signal.

Secondary prevention after minor stroke and TIA - usual care and development of a support program.

Background Effective methods of secondary prevention after stroke or TIA are available but adherence to recommended evidence-based treatments is often poor. The study aimed to determine the quality of secondary prevention in usual care and to develop a stepwise modeled support program. Methods Two consecutive cohorts of patients with acute minor stroke or TIA undergoing usual outpatient care versus a secondary prevention program were compared. Risk factor control and medication adherence were assessed in 6-month follow-ups (6M-FU). Usual care consisted of detailed information concerning vascular risk factor targets given at discharge and regular outpatient care by primary care physicians. The stepwise modeled support program additionally employed up to four outpatient appointments. A combination of educational and behavioral strategies was employed. Results 168 patients in the observational cohort who stated their openness to participate in a prevention program (mean age 64.7 y, admission blood pressure (BP): 155/84 mmHg) and 173 patients participating in the support program (mean age 67.6 y, BP: 161/84 mmHg) were assessed at 6 months. Proportions of patients with BP according to guidelines were 50% in usual-care and 77% in the support program (p<0.01). LDL<100 mg/dl was measured in 62 versus 71% (p = 0.12). Proportions of patients who stopped smoking were 50 versus 79% (p<0.01). 72 versus 89% of patients with atrial fibrillation were on oral anticoagulation (p = 0.09). Conclusions Risk factor control remains unsatisfactory in usual care. Targets of secondary prevention were met more often within the supported cohort. Effects on (cerebro-)vascular recurrence rates are going to be assessed in a multicenter randomized trial.

Judgment of FLAIR signal change in DWI-FLAIR mismatch determination is a challenge to clinicians.

Preliminary data suggest that the diffusion-weighted imaging (DWI)–fluid-attenuated inversion recovery (FLAIR) mismatch (where a new hyperintense lesion is not seen on FLAIR but is apparent on DWI) can be used for allocation to the most likely time window for intravenous thrombolysis therapy in stroke patients [1–5, 9]. However, the criteria for determination of DWI–FLAIR mismatch are difficult to standardize, and a challenge to clinicians. In the case described herein intravenous thrombolysis was withheld from a patient with an unknown time of onset due to a subtle increase of signal intensity on FLAIR, only recognizable with knowledge of the DWI lesion. The 63-year-old patient woke up with a left sensomotoric hemiparesis, moderate dysarthria, multimodal neglect, and anosognosia [National Institutes of Health Stroke Scale (NIHSS) 6]. Magnetic resonance imaging (MRI) examination performed 2.5 h after first found abnormal time (FAT) and 8.5 h after last normal time (LNT) revealed a DWI lesion in the right middle cerebral artery (MCA) territory with a corresponding M3 occlusion. Using visual analysis of signal intensity changes on FLAIR and DWI, within the area of the DWI lesion a subtle FLAIR hyperintensity was noted (Fig. 1). Neither acute intracranial hemorrhage nor microbleeds were visible on T2*, but white matter disease was visible (Wahlund score 17). It was unclear whether the subtle hyperintensity on the FLAIR lesion should be classified as DWI–FLAIR match or mismatch. After some discussion, according to Aoki et al. [1], we deemed this as a pattern of DWI–FLAIR match. We therefore did not give tissue plasminogen activator (tPA). Based on the diagnosis of atrial fibrillation, infarct etiology was classified as cardioembolic. The patient received aspirin only. Unfortunately, 9 h after first found abnormal time (FAT) the patient developed reduced consciousness, left brachiofacial sensorimotor hemiplegia, severe dysarthria, and dysphagia (NIHSS 16). Computed tomography (CT) showed symptomatic intracranial hemorrhage (sICH) in the posterior territory of the right MCA with 5 mm midline shift (Fig. 2a–c). Follow-up MRI with MR angiography showed recanalization of the right middle cerebral artery branch (M3) and a progressive midline shift (Fig. 2d–e). Three weeks after the acute stroke event the patient was still severely affected with fluctuating vigilance, severe dysphagia, and hemipareses (NIHSS 15). Up to 25% of stroke patients awake with their symptoms with unknown onset. DWI–FLAIR mismatch thrombolysis may provide clinicians a practical tool for an intervention. Recently, Aoki and colleagues described intravenous thrombolysis based on DWI–FLAIR mismatch in stroke with unknown onset time [1]. They observed no symptomatic intracerebral hemorrhage (sICH) after DWI– FLAIR mismatch-based thrombolysis in 10 patients with median interval between LNT and intravenous thrombolysis of 5.6 h. However, absence of sICH did not prove increased safety in a population of 10 patients. Our case is a good example that the definition and clinical application of DWI–FLAIR mismatch is still an arbitrary call, especially the judgment of FLAIR hyperintensities within the DWI lesion. Focal FLAIR hyperintensities within the acute DWI lesion are predictors of sICH [2]. Patients with large signal changes on DWI are more likely to develop early FLAIR positivities [3, 4, 6]. It is A. Ziegler (&) M. Ebinger J. B. Fiebach H. J. Audebert S. Leistner Department of Neurology, Charite, Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany e-mail: annerose.ziegler@charite.de

Differential Infraslow (<0.1 Hz) Cortical Activations in the Affected and Unaffected Hemispheres From Patients With Subacute Stroke Demonstrated by Noninvasive DC-Magnetoencephalography

BACKGROUND AND PURPOSE Sustained mass depolarization of neurons, termed cortical spreading depolarization, is one electrophysiological correlate of the ischemic injury of neurons. Cortical spreading depolarizations spread in the gray matter at a rate of approximately 3 mm/min and are associated with large infraslow extracellular potential changes (<0.05 Hz). Moreover, smaller infraslow potential changes accompany functional activation and might help to assess neuronal repair after stroke. The objective of the present pilot study was to investigate whether it is feasible to apply noninvasive near-DC-magnetoencephalography to detect and monitor infraslow field changes in patients with acute stroke. METHODS A simple motor condition was used to induce physiological cortical infraslow field changes. Five patients in a subacute state after ischemic stroke performed self-paced simple finger movements (30-second periods of finger movements, always separated by 30-second periods of rest, for a total of 15 minutes). Near-DC-magnetoencephalography signals were recorded over the contralateral primary motor cortex for the affected and unaffected hemisphere, respectively. RESULTS In all patients, the time courses of the contralateral cortical field amplitudes in the infraslow frequency range followed closely the motor task cycles revealing statistically significant differences between finger movement and rest periods. In 4 of 5 patients, infraslow field amplitudes were significantly stronger over the unaffected hemisphere compared with the affected hemisphere. CONCLUSIONS This study demonstrates that cortical infraslow activity can be recorded noninvasively in patients in the subacute state after ischemic stroke. It is suggested that near-DC-magnetoencephalography is a promising tool to also detect cortical spreading depolarization noninvasively.