Dobri Baldaranov

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. T2-weighted imaging combined with T2-relaxometry, mainly for edema assessment, was performed at 1 h after ischemia, after reperfusion, and at 4, 24 and 48 h after reperfusion. T1-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 T2-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.

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.

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.

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.

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.)

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

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.

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 patients 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.

Influence of Positive End-Expiratory Pressure Ventilation on CerebralPerfusion and Cardiac Hemodynamics

Objective: Positive end-expiratory pressure (PEEP) ventilation is used to prevent alveolar collapse and improve oxygenation. PEEP ventilation hinders venous backflow to the right atrium as well as venous outflow from the brain including the spinal cord. This may have an effect on cardiac output (CO) and could result in an elevation in intracranial pressure (ICP) — an important cause of secondary brain injury. The aim of this study was to investigate the effect of moderate changes in PEEP values on hemodynamics and cerebral perfusion in neurological patients experiencing respiratory failure. Methods: The study focused on 7 patients in a neurological intensive care unit who suffered from respiratory failure. Cerebral blood flow velocity was measured using transcranial color-coded duplex sonography (TCCS) while moderate changes in PEEP levels (10 cm, 7 cm or 5 cm H2O) were made to investigate cerebral arterial blood flow velocity, third ventricular diameter, and midline shift. Simultaneously, cardiac output was measured using a minimally invasive hemodynamic monitoring system (Vigileo® or PiCCO®). Results: Rising PEEPs resulted in a non-significant trend toward increased brain volume, as shown by a mild linear regression of changes in third ventricular diameter. However, no significant changes in cerebral blood flow parameters or hemodynamics values such as blood pressure, heart frequency or cardiac output, were noticed. Conclusion: Low to moderate changes in PEEP appear to increase brain volume slightly, but cerebral autoregulatory compensatory mechanisms are sufficient to stabilize cerebral perfusion pressure and intravasal volume status. The effects of these changes in PEEP may be challenging in patients with impaired cerebral autoregulation (for example, in patients after subarachnoid hemorrhage or severe brain trauma) as well as in patients requiring a high level of PEEP ventilation (that is, patients with acute respiratory distress syndrome). In such patients TCCS and cardiac hemodynamics monitoring are warranted.

Assessing motor units with an improved MUNIX

In contrast to the original MUNIX method, with I-MUNIX a continuous SIP was recorded during increasing muscle contraction (Figure 1A). These recordings were subject to later analysis with the modified I-MUNIX-algorithms. The modifications included baseline correction, filter settings, rectification, SIP interval. For abductor digiti minimi (ADM) muscles 160 different parameter settings were applied, and 96 for trapezius (TRA) muscles. Thus, a total of 6080 I-MUNIX values were analyzed for ADM, and 2976 for TRA. To compensate artifacts in SIPs, a new parameter was introduced, maxArtarea, restricting the program to SIP intervals that did not differ from baseline above the maxArtarea value. For comparison, the results of I-MUNIX and the original MUNIX were each correlated to the results of the ‘gold-standard’ motor unit number estimation (MUNE) methods, respectively (Figure 2). For inter-rater agreement analysis, each muscle was studied by three independent persons (a clinical neurophysiologist, a specifically trained student, and a technician). The analyses of these data sets were run by another three independent raters, who were only briefly introduced into the I-MUNIX analysis. ASSESSING MOTOR UNITS WITH IMPROVED MUNIX