Amyloid-Lowering Monoclonal Antibodies for the Treatment of Early Alzheimer's Disease.

Alzheimer's disease (AD) is the leading cause of dementia worldwide. Numerous biomarker studies have clearly demonstrated that AD has a long asymptomatic phase, with the development of pathology occurring at least 2 decades prior to the development of any symptoms. These pathological changes include a stepwise development of amyloid-ß (Aß) plaques, followed by tau neurofibrillary tangles and subsequently extensive neurodegeneration in the brain. In this review, we discuss the first class of drugs intended to be disease modifying to be approved by the US Food and Drug Administration (FDA) for AD-anti-Aß monoclonal antibodies-and the scientific rationale with which they were developed.

Safety and tolerability of lumbar puncture for the evaluation of Alzheimer's disease.

Introduction: Lumbar puncture (LP) to collect and examine cerebrospinal fluid (CSF) is an important option for the evaluation of Alzheimer's disease (AD) biomarkers but it is not routinely performed due to its invasiveness and link to adverse effects (AE). Methods: We include all participants who received at least one LP in the Alzheimer's Disease Neuroimaging Initiative (ADNI) Study. For comparison between groups, two-sample t-tests for continuous, and Pearson's chi-square test for categorical variables were performed. Results: Two hundred twenty-seven LP-related AEs were reported by 172 participants after 1702 LPs (13.3%). The mean age of participants who reported at least one AE was 69.79 (standard deviation (SD) 6.3) versus none 72.44 (7.17) years (p < 0.001) with female predominance (115/172 = 67.4% vs 435/913 = 48%), and had greater entorhinal cortical thickness and hippocampal volume (3.903 (0.782) vs 3.684 (0.775) mm, p = 0.002; 7.38 (1.06) vs 7.05 (1.15) mm3, p < 0.001), respectively. Discussion: We found that younger age, female sex, and greater thickness of the entorhinal cortex were associated with a higher rate of LP-related AE reports.

A mobile battery-powered brain perfusion ultrasound (BPU) device designed for prehospital stroke diagnosis: correlation to perfusion MRI in healthy volunteers.

BACKGROUND: Early prehospital stroke identification is crucial for goal directed hospital admission especially in rural areas. However, clinical prehospital stroke scales are designed to identify any stroke but cannot sufficiently differentiate hemorrhagic from ischemic stroke, including large vessel occlusion (LVO) amenable to mechanical thrombectomy. We report on a novel small, portable and battery driven point-of-care ultrasound system (SONAS®) specifically developed for mobile non-invasive brain perfusion ultrasound (BPU) measurement after bolus injection of an echo-enhancing agent suitable for the use in prehospital stroke diagnosis filling a current, unmet and critical need for LVO identification. METHODS: In a phase I study of healthy volunteers we performed comparative perfusion-weighted magnetic resonance imaging (PWI) and BPU measurements, including safety analysis. RESULTS: Twelve volunteers (n = 7 females, n = 5 males, age ranging between 19 and 55 years) tolerated the measurement extremely well including analysis of blood-brain barrier integrity, and the correlation coefficient between the generated time kinetic curves after contrast agent bolus between PWI and BPU transducers ranged between 0.89 and 0.76. CONCLUSIONS: Mobile BPU using the SONAS® device is feasible and safe with results comparable to PWI. When applied in conjunction with prehospital stroke scales this may lead to a more accurate stroke diagnosis and patients bypassing regular stroke units to comprehensive stroke centers. Further studies are needed in acute stroke patients and in the prehospital phase including assessment of immediate and long-term morbidity and mortality in stroke. TRIAL REGISTRATION: Clinical trials.gov, registered 28.Sep.2017, Identifier: NCT03296852.

Oral Health, Oral Microbiota, and Incidence of Stroke-Associated Pneumonia-A Prospective Observational Study.

Stroke-associated pneumonia is a major cause for poor outcomes in the post-acute phase after stroke. Several studies have suggested potential links between neglected oral health and pneumonia. Therefore, the aim of this prospective observational study was to investigate oral health and microbiota and incidence of pneumonia in patients consecutively admitted to a stroke unit with stroke-like symptoms. This study involved three investigation timepoints. The baseline investigation (within 24 h of admission) involved collection of demographic, neurological, and immunological data; dental examinations; and microbiological sampling (saliva and subgingival plaque). Further investigation timepoints at 48 or 120 h after baseline included collection of immunological data and microbiological sampling. Microbiological samples were analyzed by culture technique and by 16S rRNA amplicon sequencing. From the 99 patients included in this study, 57 were diagnosed with stroke and 42 were so-called stroke mimics. From 57 stroke patients, 8 (14%) developed pneumonia. Stroke-associated pneumonia was significantly associated with higher age, dysphagia, greater stroke severity, embolectomy, nasogastric tubes, and higher baseline C-reactive protein (CRP). There were trends toward higher incidence of pneumonia in patients with more missing teeth and worse oral hygiene. Microbiological analyses showed no relevant differences regarding microbial composition between the groups. However, there was a significant ecological shift over time in the pneumonia patients, probably due to antibiotic treatment. This prospective observational study investigating associations between neglected oral health and incidence of SAP encourages investigations in larger patient cohorts and implementation of oral hygiene programs in stroke units that may help reducing the incidence of stroke-associated pneumonia.

Normal Age- and Sex-Related Values of the Optic Nerve Sheath Diameter and Its Dependency on Position and Positive End-Expiratory Pressure.

Optic nerve sheath diameter (ONSD) sonography is a reliable method for evaluation of intracranial pressure, yet there is a lack of reliable normal values. In the study described here, we established normal ONSD values in three different age groups and both sexes. One hundred eighty-seven volunteers without central nervous system disease were enrolled in this prospective study. ONSD measurements were taken in volunteers in the supine and upright positions and after application of positive end-expiratory pressure (PEEP). Normal ONSD values were 4.9-5.3 mm (patient age range: 20-85), with significant differences between men and women (p < 0.001). ONSD values increased with age (∆ = 0.34 mm, p < 0.001). There were no differences compared with the upright position but application of PEEP led to significantly increased ONSD values (∆ = 0.21 mm, p = 0.008). ONSD values increased with age, correlated well with the width of the third ventricle, were significantly lower in the female cohort and quickly responded to PEEP, especially in women.

Neuromonitoring Using Neurosonography and Pupillometry in A Weaning and Early Neurorehabilitation Unit.

BACKGROUND AND PURPOSE: Long-term surveillance of intracranial pressure (ICP) in neurological/neurosurgical patients during ventilator weaning and early neurorehabilitation currently relies on clinical observation because neuroimaging is rarely readily available. In this prospective study, multimodal neurosonography and pupillometry are evaluated for follow-up monitoring. METHODS: Sonographic neuromonitoring was used to noninvasively examine patients' ICP during weaning and early neurorehabilitation. It allowed assessments of third ventricle width, possible midline shift, middle cerebral artery flow velocities, and bilateral optic nerve sheath diameters. Quantitative pupillometry was used to determine pupil size and reactivity. Other neuroimaging findings, spinal tap ICP measurements, and clinical follow-up data served as controls. RESULTS: Seventeen patients-11 suffering from intracranial hemorrhage, four from encephalopathies, and two from ischemic stroke-were examined for ICP changes by using neurosonography and pupillometry during a mean observation period of 21 days. In total, 354 of 980 analyses (36.1%) yielded pathological results. In 15 of 17 patients (88.2%), pathological values were found during follow-up without a clear clinical correlate. In two patients (11.8%), clinically relevant changes in ICP occurred and were identified using neurosonography. Abnormal pupillometry findings displayed a high predictive value for absent clinical improvement. CONCLUSION: Multimodal neurosonography may be a noninvasive means for long-term ICP assessment, whereas pupillometry may only detect rapid ICP changes during acute neurointensive care. The study also illustrates common pitfalls in neuromonitoring in general, with large numbers of pathological albeit nonsignificant findings. Additional controlled studies should validate the influence of detected subtle changes in ICP on neurological outcome.

Interdisciplinary Decision Making in Hemorrhagic Stroke Based on CT Imaging-Differences Between Neurologists and Neurosurgeons Regarding Estimation of Patients' Symptoms, Glasgow Coma Scale, and National Institutes of Health Stroke Scale.

Background and Purpose: Acute intracerebral hemorrhage (ICH) requires rapid decision making toward neurosurgery or conservative neurological stroke unit treatment. In a previous study, we found overestimation of clinical symptoms when clinicians rely mainly on cerebral computed tomography (cCT) analysis. The current study investigates differences between neurologists and neurosurgeons estimating specific scores and clinical symptoms. Methods: Overall, 14 neurologists and 15 neurosurgeons provided clinical estimates and National Institutes of Health Stroke Scale (NIHSS) as well as Glasgow Coma Scale (GCS) based on cCT images and basic information of 50 patients with hypertensive and lobar ICH. Subgroup analyses were performed for the different professions (neurologists vs. neurosurgeons) and bleeding subtypes (typical location vs. atypical). The differences between the actual GCS and NIHSS scores and the cCT-imaging-based estimated scores were depicted as Bland-Altman plots and negative and positive predictive value (NPV and PPV) for prediction of clinical relevant items. ΔNIHSS points (ΔGCS points) were calculated as the difference between actual and rated NIHSS (GCS) including 95% confidence interval (CI). Results: Mean ΔGCS points for neurosurgeons was 1.16 (95% CI: -2.67-4.98); for neurologists, 0.99 (95% CI: -2.58-4.55), p = 0.308; mean ΔNIHSS points for neurosurgeons was -2.95 (95% CI: -12.71-6.82); for neurologists, -0.33 (95% CI: -9.60-8.94), p < 0.001. NPV and PPV for stroke symptoms were low, with large differences between different symptoms, bleeding subtypes, and professions. Both professions had more problems in proper rating of specific clinic-neurological symptoms than rating scores. Conclusion: Our results stress the need for joint decision making based on detailed neurological examination and neuroimaging findings also in telemedicine.

Value of fluid-attenuated inversion recovery MRI data analyzed by the lesion segmentation toolbox in amyotrophic lateral sclerosis.

BACKGROUND: MRI fluid-attenuated inversion recovery (FLAIR) studies reported hyperintensity in the corticospinal tract and corpus callosum of patients with amyotrophic lateral sclerosis (ALS). PURPOSE: To evaluate the lesion segmentation toolbox (LST) for the objective quantification of FLAIR lesions in ALS patients. STUDY TYPE: Retrospective. POPULATION: Twenty-eight ALS patients (eight females, mean age: 50 range: 24-73, mean ALSFRS-R sum score: 36) were compared with 31 age-matched healthy controls (12 females, mean age: 45, range: 25-67). ALS patients were treated with riluzole and additional G-CSF (granulocyte-colony stimulating factor) on a named patient basis. FIELD STRENGTH/SEQUENCE: 1.5 T, FLAIR, T1 -weighted MRI. ASSESSMENT: The lesion prediction algorithm (LPA) of the LST enabled the extraction of individual binary lesion maps, total lesion volume (TLV), and number (TLN). Location and overlap of FLAIR lesions across patients were investigated by registration to FLAIR average space and an atlas. ALS-specific functional rating scale revised (ALSFRS-R), disease progression, and survival since diagnosis served as clinical correlates. STATISTICAL TESTS: Univariate analysis of variance (ANOVA), repeated-measures ANOVA, t-test, Bravais-Pearson correlation, Chi-square test of independence, Kaplan-Meier analysis, Cox-regression analysis. RESULTS: Both ALS patients and healthy controls exhibited FLAIR alterations. TLN significantly depended on age (F(1,54) = 24.659, P < 0.001) and sex (F(1,54) = 5.720, P = 0.020). ALS patients showed higher TLN than healthy controls depending on sex (F(1, 54) = 5.076, P = 0.028). FLAIR lesions were small and most pronounced in male ALS patients. FLAIR alterations were predominantly detected in the superior and posterior corona radiata, anterior capsula interna, and posterior thalamic radiation. Patients with pyramidal tract (PT) lesions exhibited significantly inferior survival than patients without PT lesions (P = 0.013). Covariate age exhibited strong prognostic value for survival (P = 0.015). DATA CONCLUSION: LST enables the objective quantification of FLAIR alterations and is a potential prognostic biomarker for ALS. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:552-559.

Combinatory Biomarker Use of Cortical Thickness, MUNIX, and ALSFRS-R at Baseline and in Longitudinal Courses of Individual Patients With Amyotrophic Lateral Sclerosis.

Objective: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative process affecting upper and lower motor neurons as well as non-motor systems. In this study, precentral and postcentral cortical thinning detected by structural magnetic resonance imaging (MRI) were combined with clinical (ALS-specific functional rating scale revised, ALSFRS-R) and neurophysiological (motor unit number index, MUNIX) biomarkers in both cross-sectional and longitudinal analyses. Methods: The unicenter sample included 20 limb-onset classical ALS patients compared to 30 age-related healthy controls. ALS patients were treated with standard Riluzole and additional long-term G-CSF (Filgrastim) on a named patient basis after written informed consent. Combinatory biomarker use included cortical thickness of atlas-based dorsal and ventral subdivisions of the precentral and postcentral cortex, ALSFRS-R, and MUNIX for the musculus abductor digiti minimi (ADM) bilaterally. Individual cross-sectional analysis investigated individual cortical thinning in ALS patients compared to age-related healthy controls in the context of state of disease at initial MRI scan. Beyond correlation analysis of biomarkers at cross-sectional group level (n = 20), longitudinal monitoring in a subset of slow progressive ALS patients (n = 4) explored within-subject temporal dynamics of repeatedly assessed biomarkers in time courses over at least 18 months. Results: Cross-sectional analysis demonstrated individually variable states of cortical thinning, which was most pronounced in the ventral section of the precentral cortex. Correlations of ALSFRS-R with cortical thickness and MUNIX were detected. Individual longitudinal biomarker monitoring in four slow progressive ALS patients revealed evident differences in individual disease courses and temporal dynamics of the biomarkers. Conclusion: A combinatory use of structural MRI, neurophysiological and clinical biomarkers allows for an appropriate and detailed assessment of clinical state and course of disease of ALS.

Primary cCT Imaging Based Clinico-Neurological Assessment-Calling for Addition of Telestroke Video Consultation in Patients With Intracerebral Hemorrhage.

Background and Purpose: Intracerebral hemorrhage (ICH) requires rapid decision making to decrease morbidity and mortality although time frame and optimal therapy are still ill defined. Ideally, specialized neurologists, neurosurgeons, and (neuro-) radiologists who know the patient's clinical status and their cerebral computed tomography imaging (cCT) make a joint decision on the clinical management. However, in telestroke networks, a shift toward cCT imaging criteria used for decision making can be observed for practical reasons. Here we investigated the "reverse correlation" from cCT imaging to the actual clinical presentation as evaluated by the Glasgow Coma Scale (GCS) and the National Institutes of Health Stroke Scale (NIHSS). Methods: CCT images and basic information (age, sex, and time of onset) of 50 patients with hypertensive and lobar ICH were presented to 14 experienced neurologists and 15 neurosurgeons. Based on this information, the NIHSS and GCS scores were estimated for each patient. The differences between the actual GCS and NIHSS scores and the cCT-imaging-based estimated scores were plotted in a bland-Altman plot. Results: The average estimated GCS score mainly based on cCT imaging was 12. 4 ± 2.8 (actual value: 13.0 ± 2.5; p = 0.100), the estimated NIHSS score was 13.9 ± 9.1 (actual value: 10.8 ± 7.3; p < 0.001). Thus, in cCT-imaging-based evaluation, the neurological status of patients especially employing the NIHSS was estimated poorer, particularly in patients with lobar ICH. "Reverse clinical" evaluation based on cCT-imaging alone may increase the rate of intubation and secondary transferal and neurosurgical treatment. Telestroke networks should consider both, videoassessment of the actual clinical picture and cCT-imaging findings to make appropriate acute treatment decisions.

Clinical Impact of the Microembolic Signal Burden During Catheter Ablation for Atrial Fibrillation: Just a Lot of Noise?

OBJECTIVES: Microembolic signal detection by transcranial Doppler ultrasonography may be considered a surrogate for cerebral events during invasive cardiac procedures. However, the impact of the microembolic signal count during pulmonary vein isolation on the clinical outcome is not well evaluated. We investigated the effect of the microembolic signal count on the occurrence of new silent cerebral embolism measured by diffusion-weighted imaging (DWI)-magnetic resonance imaging (MRI), changes in neuropsychological testing, and the occurrence of clinical events during long-term follow-up after pulmonary vein isolation. METHODS: Pulmonary vein isolation was performed in 41 patients. The total microembolic signal burden (classified into "solid," "gaseous," and "equivocal") and sustained thromboembolic showers of greater than 30 seconds were recorded. Diffusion-weighted imaging-MRI and neuropsychological testing were performed before and after pulmonary vein isolation to assess for silent cerebral embolism and neuropsychological sequelae. Long-term follow-up was performed by telephone to assess for stroke/transient ischemic attack. RESULTS: A total of 68,729 microembolic signals (14,893 solid, 11,909 gaseous, and 41,927 equivocal) with an average of 1676 signals per patient and 42 thromboembolic showers were recorded. No correlation between the microembolic signal/thromboembolic shower count and the occurrence of new DWI lesions or neuropsychological capability was found. After a mean follow-up ± SD of 49 ± 4 months, 1 patient had an overt transient ischemic event, which was not associated with a high microembolic signal count. CONCLUSIONS: In this multicenter study, we found no impact of the intraprocedural microembolic symbol/thromboembolic shower count on the occurrence of new DWI lesions, neuropsychological capability, or overt neurologic deficits after pulmonary vein isolation. Thus, not only the microembolic signal count but also procedural/individual factors may contribute to commensurable clinical damage, which may challenge this method as a valid biomarker during pulmonary vein isolation.

Longitudinal Diffusion Tensor Imaging-Based Assessment of Tract Alterations: An Application to Amyotrophic Lateral Sclerosis.

Objective: The potential of magnetic resonance imaging (MRI) as a technical biomarker for cerebral microstructural alterations in neurodegenerative diseases is under investigation. In this study, a framework for the longitudinal analysis of diffusion tensor imaging (DTI)-based mapping was applied to the assessment of predefined white matter tracts in amyotrophic lateral sclerosis (ALS), as an example for a rapid progressive neurodegenerative disease. Methods: DTI was performed every 3 months in six patients with ALS (mean (M) = 7.7; range 3 to 15 scans) and in six controls (M = 3; range 2-5 scans) with the identical scanning protocol, resulting in a total of 65 longitudinal DTI datasets. Fractional anisotropy (FA), mean diffusivity (MD), axonal diffusivity (AD), radial diffusivity (RD), and the ratio AD/RD were studied to analyze alterations within the corticospinal tract (CST) which is a prominently affected tract structure in ALS and the tract correlating with Braak's neuropathological stage 1. A correlation analysis was performed between progression rates based on DTI metrics and the revised ALS functional rating scale (ALS-FRS-R). Results: Patients with ALS showed an FA and AD/RD decline along the CST, while DTI metrics of controls did not change in longitudinal DTI scans. The FA and AD/RD decrease progression correlated significantly with ALS-FRS-R decrease progression. Conclusion: On the basis of the longitudinal assessment, DTI-based metrics can be considered as a possible noninvasive follow-up marker for disease progression in neurodegeneration. This finding was demonstrated here for ALS as a fast progressing neurodegenerative disease.

Online Measurement of Microembolic Signal Burden by Transcranial Doppler during Catheter Ablation for Atrial Fibrillation-Results of a Multicenter Trial.

INTRODUCTION: Left atrial pulmonary vein isolation (PVI) is an accepted treatment option for patients with symptomatic atrial fibrillation (AF). This procedure can be complicated by stroke or silent cerebral embolism. Online measurement of microembolic signals (MESs) by transcranial Doppler (TCD) may be useful for characterizing thromboembolic burden during PVI. In this prospective multicenter trial, we investigated the burden, characteristics, and composition of MES during left atrial catheter ablation using a variety of catheter technologies. MATERIALS AND METHODS: PVI was performed in a total of 42 patients using the circular-shaped multielectrode pulmonary vein ablation catheter (PVAC) technology in 23, an irrigated radiofrequency (IRF) in 14, and the cryoballoon (CB) technology in 5 patients. TCD was used to detect the total MES burden and sustained thromboembolic showers (TESs) of >30 s. During TES, the site of ablation within the left atrium was registered. MES composition was classified manually into "solid," "gaseous," or "equivocal" by off-line expert assessment. RESULTS: The total MES burden was higher when using IRF compared to CB (2,336 ± 1,654 vs. 593 ± 231; p = 0.007) and showed a tendency toward a higher burden when using IRF compared to PVAC (2,336 ± 1,654 vs. 1,685 ± 2,255; p = 0.08). TES occurred more often when using PVAC compared to IRF (1.5 ± 2 vs. 0.4 ± 1.3; p = 0.04) and most frequently when ablation was performed close to the left superior pulmonary vein (LSPV). Of the MES, 17.004 (23%) were characterized as definitely solid, 13.204 (18%) as clearly gaseous, and 44.366 (59%) as equivocal. DISCUSSION: We investigated the burden and characteristics of MES during left atrial catheter ablation for AF. All ablation techniques applied in this study generated a relevant number of MES. There was a significant difference in total MES burden using IRF compared to CB and a tendency toward a higher burden using IRF compared to PVAC. The highest TES burden was found in the PVAC group, particularly during ablation close to the LSPV. The composition of thromboembolic particles was balanced. The impact of MES, TES, and composition of thromboembolic particles on neurological outcome needs to be evaluated further. (Clinical Trial Registration: Deutsches Register Klinischer Studien, https://drks-neu.uniklinik-freiburg.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00003465. DRKS00003465.).

Silent cerebral events as a result of left atrial catheter ablation do not cause neuropsychological sequelae--a MRI-controlled multicenter study.

PURPOSE: Recently, diffusion-weighted magnetic resonance imaging (DW-MRI) revealed silent cerebral events (SCEs) as an acute complication of pulmonary vein isolation (PVI). We investigated whether SCEs following PVI are associated with neuropsychological deficits observed during patients' follow-up examinations. METHODS: After PVI, 52 patients were eligible for follow-up. PVI was performed using a variety of ablation technologies (duty-cycled phased radiofrequency (RF) multipolar ablation with the Pulmonary Vein Ablation Catheter® (PVAC) in 24 patients, cooled-tip RF ablation in 23 patients, and cryoballoon ablation in five patients). Fluid-attenuated inversion recovery (FLAIR)- and DW-MRI studies were performed 1 day before PVI and 1 day and 1 month afterward to detect pre-existing cerebral lesions or post-ablation SCEs. At the same times, eight neuropsychological tests were administered. We evaluated changes in patients' neuropsychological capabilities and compared changes in patients with SCEs to those without SCEs. RESULTS: FLAIR-MRI revealed pre-existing cerebral lesions in 42 patients (81 %), and DW-MRI demonstrated new SCEs in 25 patients (48 %) (17 treated with phased RF (PVAC) (71 %), six treated with irrigated RF (26 %), and two treated with cryoablation (40 %)). Neuropsychological test results showed no significant impairment (in median z scores) 1 day and 1 month after the ablation procedure. There was no difference in neuropsychological capabilities between patients with SCEs and those without SCEs except in one subtest (part of the verbal working memory test). CONCLUSIONS: The incidence of pre-existing cerebral lesions and post-ablation SCEs was high. The frequency of SCEs depends on the ablation technology used. Neither PVI nor post-ablation SCEs have any effect on neuropsychological capabilities.

Intracranial hemorrhage: frequency, location, and risk factors identified in a TeleStroke network.

Intracranial hemorrhages are associated with high rates of disability and mortality. Telemedicine in general provides clinical healthcare at a distance by using videotelephony and teleradiology and is used particularly in acute stroke care medicine (TeleStroke). TeleStroke considerably improves quality of stroke care (for instance, by increasing thrombolysis) and may be valuable for the management of intracranial hemorrhages in rural hospitals and hospitals lacking neurosurgical departments, given that surgical/interventional therapy is only recommended for a subgroup of patients. The aim of this study was to analyze the frequency, anatomical locations of intracranial hemorrhage, risk factors, and the proportion of patients transferred to specialized hospitals. We evaluated teleconsultations conducted between 2008 and 2010 in a large cohort of patients consecutively enrolled in the Telemedical Project for Integrated Stroke Care (TEMPiS) network. In cases in which intracranial hemorrhage was detected, all images were re-examined and analyzed with a focus on frequency, location, risk factors, and further management. Overall, 6187 patients presented with stroke-like symptoms. Intracranial hemorrhages were identified in 631 patients (10.2%). Of these, intracerebral hemorrhages were found in 423 cases (67.0%), including 174 (41.1%) in atypical locations and 227 (53.7%) in typical sites among other locations. After 14 days of hospitalization in community facilities, the mortality rate in patients with intracranial hemorrhages was 15.1% (95/631). Two hundred and twenty-three patients (35.3%) were transferred to neurological/neurosurgical hospitals for diagnostic workup or additional treatment. Community hospitals are confronted with patients with intracranial hemorrhage, whose management requires specific neurosurgical and hematological expertise with respect to hemorrhage subtype and clinical presentation. TeleStroke networks help select patients who need advanced neurological and/or neurosurgical care. The relatively low proportion of interhospital transfers shown in this study reflects a differentiated decision process on the basis of both guidelines and standard operating procedures.

Safety and feasibility of long term administration of recombinant human granulocyte-colony stimulating factor in patients with amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neuronal disease resulting in a loss of the upper and lower motor neurons and subsequent death within three to four years after diagnosis. Mouse models and preliminary human exposure data suggest that the treatment with granulocyte-colony stimulating factor (G-CSF) has neuro-protective effects and may delay ALS progression. As data on long-term administration of G-CSF in patients with normal bone marrow (BM) function are scarce, we initiated a compassionate use program including 6 ALS patients with monthly G-CSF treatment cycles. Here we demonstrate that G-CSF injection was safe and feasible throughout our observation period up to three years. Significant decrease of mobilization efficiency occurred in one patient and a loss of immature erythroid progenitors was observed in all six patients. These data imply that follow-up studies analyzing BM function during long-term G-CSF stimulation are required.

Cerebral ischemia-reperfusion injury in rats--a 3 T MRI study on biphasic blood-brain barrier opening and the dynamics of edema formation.

Serial magnetic resonance imaging (MRI) was performed to investigate the temporal and spatial relationship between the biphasic nature of blood-brain barrier (BBB) opening and, in parallel, edema formation after ischemia-reperfusion (I/R) injury in rats. T(2)-weighted imaging combined with T(2)-relaxometry, mainly for edema assessment, was performed at 1 h after ischemia, after reperfusion, and at 4, 24 and 48 h after reperfusion. T(1)-weighted imaging was performed before and after gadolinium contrast at the last three time points to assess BBB integrity. The biphasic course of BBB opening with a significant reduction in BBB permeability at 24 h after reperfusion, associated with a progressive expansion of leaky BBB volume, was accompanied by a peak ipsilateral edema formation. In addition, at 4 h after reperfusion, edema formation could also be detected at the contralateral striatum as determined by the elevated T(2)-values that persisted to varying degrees, indicative of widespread effects of I/R injury. The observations of this study may indicate a dynamic temporal shift in the mechanisms responsible for biphasic BBB permeability changes, with complex relations to edema formation. Stroke therapy aimed at vasogenic edema and drug delivery for neuroprotection may also be guided according to the functional status of the BBB, and these findings have to be confirmed in human stroke.