Komatöse Patienten stellen eine substanzielle Herausforderung für Kliniker in Notaufnahmen und im Rettungsdienst dar. Diese Patienten zeichnen sich durch schwerwiegende Erkrankungen aus, die regelmäßig zu erheblichen Abweichungen der Vitalparameter führen. Die differenzialdiagnostischen Überlegungen, die bei der Akutversorgung komatöser Patienten angestellt werden, sind durch eine bemerkenswerte Komplexität gekennzeichnet.

Abstract Background Management of patients with coma of unknown etiology (CUE) is a major challenge in most emergency departments (EDs). CUE is associated with a high mortality and a wide variety of pathologies that require differential therapies. A suspected diagnosis issued by pre-hospital emergency care providers often drives the first approach to these patients. We aim to determine the accuracy and value of the initial diagnostic hypothesis in patients with CUE. Methods Consecutive ED patients presenting with CUE were prospectively enrolled. We obtained the suspected diagnoses or working hypotheses from standardized reports given by prehospital emergency care providers, both paramedics and emergency physicians. Suspected and final diagnoses were classified into I) acute primary brain lesions, II) primary brain pathologies without acute lesions and III) pathologies that affected the brain secondarily. We compared suspected and final diagnosis with percent agreement and Cohen’s Kappa including sub-group analyses for paramedics and physicians. Furthermore, we tested the value of suspected and final diagnoses as predictors for mortality with binary logistic regression models. Results Overall, suspected and final diagnoses matched in 62% of 835 enrolled patients. Cohen’s Kappa showed a value of κ = .415 (95% CI .361–.469, p < .005). There was no relevant difference in diagnostic accuracy between paramedics and physicians. Suspected diagnoses did not significantly interact with in-hospital mortality (e.g., suspected class I: OR .982, 95% CI .518–1.836) while final diagnoses interacted strongly (e.g., final class I: OR 5.425, 95% CI 3.409–8.633). Conclusion In cases of CUE, the suspected diagnosis is unreliable, regardless of different pre-hospital care providers’ qualifications. It is not an appropriate decision-making tool as it neither sufficiently predicts the final diagnosis nor detects the especially critical comatose patient. To avoid the risk of mistriage and unnecessarily delayed therapy, we advocate for a standardized diagnostic work-up for all CUE patients that should be triggered by the emergency symptom alone and not by any suspected diagnosis.

BACKGROUND:Coma of unknown etiology (CUE) is a major challenge in emergency medicine. CUE is caused by a wide variety of pathologies that require immediate and targeted treatment. However, there is little empirical data guiding rational and efficient management of CUE. We present a detailed investigation on the causes of CUE in patients presenting to the ED of a university hospital.METHODS:One thousand twenty-seven consecutive ED patients with CUE were enrolled. Applying a retrospective observational study design, we analyzed all clinical, laboratory and imaging findings resulting from a standardized emergency work-up of each patient. Following a predefined protocol, we identified main and accessory coma-explaining pathologies and related these with (i.a.) GCS and in-hospital mortality.RESULTS:On admission, 854 of the 1027 patients presented with persistent CUE. Their main diagnoses were classified into acute primary brain lesions (39%), primary brain pathologies without acute lesions (25%) and pathologies that affected the brain secondarily (36%). In-hospital mortality associated with persistent CUE amounted to 25%. 33% of patients with persistent CUE presented with more than one coma-explaining pathology. In 173 of the 1027 patients, CUE had already resolved on admission. However, these patients showed a spectrum of main diagnoses similar to persistent CUE and a significant in-hospital mortality of 5%.CONCLUSION:The data from our cohort show that the spectrum of conditions underlying CUE is broad and may include a surprisingly high number of coincidences of multiple coma-explaining pathologies. This finding has not been reported so far. Thus, significant pathologies may be masked by initial findings and only appear at the end of the diagnostic work-up. Furthermore, even transient CUE showed a significant mortality, thus rendering GCS cutoffs for selection of high- and low-risk patients questionable. Taken together, our data advocate for a standardized diagnostic work-up that should be triggered by the emergency symptom CUE and not by any suspected diagnosis. This standardized routine should always be completed - even when initial coma-explaining diagnoses may seem evident.

Coma of unknown origin is an emergency caused by a variety of possibly life-threatening pathologies. Although lethality is high, there are currently no generally accepted management guidelines.

Objectives To assess the sensitivity of stimulated echo acquisition mode diffusion weighted imaging (STEAM-DWI) to ischemic stroke in comparison to echo-planar imaging diffusion weighted imaging (EPI-DWI) in the infratentorial compartment. Methods Fifty-seven patients presenting with clinical features of infratentorial stroke underwent STEAM-DWI, high-resolution EPI-DWI (HR-DWI, 2.5 mm slice thickness) and low-resolution EPI-DWI (LR-DWI, 5 mm slice thickness). Four readers assessed the presence of ischemic lesions and artifacts. Agreement between sequences and interobserver agreement on the presence of ischemia were calculated. The sensitivities of the DWI sequences were calculated in 45 patients with a confirmed diagnosis of infratentorial stroke. Results Median time from symptom onset to imaging was 24 hours. STEAM-DWI agreed with LR-DWI in 89.5% of cases (kappa = 0.72, p<0.0001) and with HR-DWI in 89.5% of cases (kappa = 0.68, p<0.0001). STEAM-DWI showed fewer intraparenchymal artifacts (1/57) than HR-DWI (44/57) and LR-DWI (41/57). Ischemia was visible in 87% of cases for LR-DWI, 93% of cases for HR-DWI, and 89% of cases for STEAM-DWI. Interobserver agreement was good for STEAM-DWI (kappa = 0.62, p<0.0001). Conclusions Compared to the best currently available MR sequence for detecting ischemia (HR-DWI), STEAM-DWI shows fewer artifacts and a similar sensitivity to infratentorial stroke.

Etanercept is an inhibitor of the pro-inflammatory and immunoregulatory cytokine tumor necrosis factor-α (TNFα). It has been proved highly effective in the treatment of rheumatoid arthritis, psoriasis and ankylosing spondylitis, although several potentially severe side effects have been reported, including infections and allergic reactions. Recently, attention has been drawn to an increased risk of demyelinating diseases in patients treated with TNFα inhibitors [1]. Here, we present a case of a patient who developed an acute demyelinating spinal cord lesion while being treated with etanercept. We report on a 55-year-old woman with psoriatic arthritis without history of neurological symptoms. She was on treatment with etanercept (50 mg weekly) for 6 months and did not take any other disease-modifying anti-rheumatic drugs when she presented with successively developing dysesthesia in the gluteal and genital region and in the lower extremities. Examination showed gait ataxia, reduced joint position and vibratory sense at distal lower extremities and urinary dysfunction. There were no clinical signs of infection and routine blood tests and CSF analysis were unremarkable. MRI revealed a singular 8 mm hyperintense lesion in the dorsal thoracic spine and no further lesions in the brain or spinal cord were detected (Fig. 1). Etanercept was discontinued and treatment with IV methylprednisolone (1000 mg/day for 5 days) initiated, resulting in rapid alleviation of symptoms. Skeletal scintigraphy showed no signs of active arthritis and the patient therefore was not re-started on a disease-modifying anti-rheumatic drug. At follow-up 8 months later, remission persisted and the patient had no neurological deficits. There were no clinical signs of psoriatic arthritis, although psoriatic skin changes recurred. Figure 1: (a) Sagittal T2-weighted MRI shows a single posterior hyperintense demyelinating lesion of the cord at T5-6. (b) Sagittal CE T1 shows contrast enhancement of the lesion indicative of blood-spinal cord barrier disruption. (c): On axial CE T1 the lesion ... Our case highlights myelitis as a rare side-effect of etanercept that should prompt discontinuation of the drug and consideration of immunotherapy. It is well known that TNFα inhibitors can increase the number of exacerbations and gadolinium-enhancing lesions in patients with multiple sclerosis (MS) and they are accordingly contraindicated in patients with a history of a demyelinating disorder [2, 3]. More recently, peripheral and central demyelinating diseases have been reported in patients naive of demyelinating events that were treated with TNFα inhibitors [1, 4]. Observed disorders ranged from Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy (CIDP) to retrobulbar neuritis, demyelinating (MS-like) encephalitis and transverse myelitis. Symptoms partially or fully resolved in the majority of patients after discontinuation of TNFα inhibitors and glucocorticoid treatment [1, 4]. Arguments in favour of a true association between TNFα inhibition and occurrence of demyelination in our case include the temporal association between etanercept treatment and manifestation of symptoms and improvement of symptoms upon etanercept discontinuation. A causal link is moreover supported by the report of similar disorders after exposure to TNFα inhibitors and positive re-challenge phenomena described in several cases [4, 5]. Without rechallenge, our patient remained without neurological deficits after follow-up of 8 months. Previous studies furthermore suggest that inhibition of TNFα induces complex alterations of immune homeostasis that are not restricted to suppression of pro-inflammatory actions (effective in the treatment of rheumatic diseases) but may also include promotion of autoimmune mechanisms [4]. The latter is in line with observations of stimulation of autoantibody production induced by treatment with TNFα inhibitors [6]. In summary, these observations strongly suggest a causal role of TNFα inhibition in the pathogenesis of myelitis in our patient, although there is no definite proof without a positive re-challenge phenomenon. Taken together, our report demonstrates a rare but important side effect of etanercept treatment. Clinicians thus need to consider demyelinating diseases as differential diagnosis in patients with TNFα inhibitor treatment that present with new neurological deficits. In these patients, a discontinuation of etanercept treatment and IV glucocorticoid treatment is warranted.

Background: In animal models of stroke, the time course of blood-brain barrier (BBB) disruptions has been elaborately studied. In human patients, leakage of gadolinium into cerebrospinal fluid (CSF) space, visualized on MRI fluid attenuated inversion recovery (FLAIR) images, is considered a sign of BBB disruptions. It was termed ‘hyperintense acute reperfusion marker' (HARM) and was associated with hemorrhages. However, the time course of the leakage is unknown and difficult to study in human patients. Also, the association of HARM with signal intensities and enhancement in the parenchyma on FLAIR images has not been thoroughly researched. Methods: We analyzed imaging data of acute ischemic stroke patients who underwent repetitive MRI examinations within the first 36 h after the time of symptom onset. HARM was evaluated on FLAIR images. Regions of interest (ROI) of the hyperintensities on diffusion-weighted imaging (DWI) were determined for each time point and mirrored to the contralateral side. The ROI were furthermore corrected for CSF-filled space, using apparent diffusion coefficient (ADC) images. The corrected ROI were used to determine mean signal intensities of the lesions relative to the contralateral side on FLAIR, ADC and B₀ images for each time point. Results: The 18 included patients (5 females; median age: 69 years; median NIHSS score: 5) received 3-5 MRI examinations on the first day and 1-2 examinations on day 2 after stroke. Eight of the patients (44.4%) showed HARM on at least 1 examination. In 6 of these patients, HARM was already seen at the second examination, at the earliest 3.5 h after symptom onset. The HARM-positive patients had higher relative signal intensities (rSI) on FLAIR images in the parenchyma corresponding to the DWI-positive tissue compared with the HARM-negative patients. This difference between groups was statistically significant for the 2nd and 3rd examination (medians of 4.31 and 6.37 h from symptom onset, p < 0.001 and p = 0.005, respectively). No significant difference in rSI between groups was seen for ADC or B₀ images. Conclusion: HARM does not only represent a contrast medium leakage from the pial system into the CSF space. It is accompanied by a markedly increased rSI in the early ischemic lesion on FLAIR images, which is likely due to parenchymal enhancement. The lack of differences on B₀ images excludes a pure T2 effect.

Background: Randomized controlled clinical trials are the gold standard for scientific evaluation of clinical diagnostic and treatment concepts. Frequently, recruitment of participants is slower than expected, especially in acute conditions with a short time frame for inclusion. Simple prediction models have been proposed to extrapolate recruitment rates. We hypothesized a significant overestimation of recruitment when ignoring interdependence of selection criteria, leading to an insufficient representation of reality by available models. We proposed that slight modifications to inclusion criteria might augment recruitment without causing selection bias. Methods: We analyzed recruitment in an acute intervention trial of acute ischemic stroke initiated by our facility. Frequencies of selection criteria were recorded and analyzed individually as well as cumulatively. We then amended the trial protocol by moderate modifications to the selection criteria. The main outcome criterion was the rate of recruited over screened patients, with the goal of increasing recruitment fourfold without adding unacceptable selection bias. A previously presented prediction model was applied to our trial and compared with actual recruitment. Data were compared between screening periods at recruitment prior to and after the implementation of the amendments. Results: The impact of typical as well as novel inclusion criteria such as age limits, imaging-based definition of pathology, time between onset and presentation as well as inability to consent were quantified. Age restriction, definition of index event and late arrival after ictus were identified as the most challenging modifiable selection criteria. Amending those criteria increased recruitment by a factor of 4.1. Inability to consent was a significant exclusion criterion gaining impact with the target population. The selection criteria had a cumulative rather than separate recruitment-limiting impact. A previously presented model did not predict recruitment sufficiently. Conclusion: We describe frequencies of selection criteria in a typical cohort of patients suffering from acute cerebrovascular events, and their cumulative impact. These data may help to better understand recruitment limitations and allow designing future trials more effectively. Ability to consent especially is a major contributor to trial exclusion, strongly interfering with the targeted trial population of ischemic stroke. Tentative prescreening phases before site or trial initiation should be considered. No predictive statistical models of recruitment have been established so far. (C) 2013 S. Karger AG, Basel

The burden of cerebrovascular disease (CVD) is huge and therapeutic options are limited. Physical activity is effective in preventing coronary heart and peripheral artery disease both experimentally and clinically. It is likely that the protective effects of exercise can be extended to both CVD and cognitive impairment. The pleiotropic protective and preventive mechanisms induced by physical activity include increased perfusion as well as mechanisms of collateral recruitment and neovascularization mediated by arterio- and angiogenesis. Physical activity increases the bioavailability of nitric oxide, bone marrow-derived CD34+ cells and growth factors, all of which promote neovascularization. Additionally, shear stress is discussed as a potential mechanism for vessel growth. Moreover, physical activity plays a role in endothelial function and cerebral autoregulation in small- and large-artery CVD. The vascular niche hypothesis highlights the complex interactions of neuro- and angiogenesis for regenerative and repair mechanisms in the human brain. Experimental and clinical studies demonstrate the positive impact of prior physical activity on stroke lesion size and on outcome after stroke. Clinical trials are necessary to further address the impact of physical activity on primary and secondary stroke prevention, outcome and cognitive function.

Objectives: Vessel size imaging is a novel technique to evaluate pathological changes of the microvessel density quantity Q and the mean vessel size index (VSI). As a follow-up study, we assessed these parameters for microscopic description of ischemic penumbra and their potentials in predicting lesion growth. Methods: Seventy-five patients with a perfusion-diffusion mismatch were examined within 24 h from symptom onset. We defined three regions of interest: the initial infarct (INF), the ischemic penumbra (IPE), and the healthy region (HEA) symmetric to the IPE. For 23 patients with a 6th-day follow-up, IPE regions were divided into areas of infarct growth and areas of oligemia. Result: The median values of Q and VSI were: for INF 0.29 s-1/3 and 15.8 µm, for IPE 0.33 s-1/3 and 20.6 µm and for HEA 0.36 s-1/3 and 17.4 µm. The Q in the IPE was significantly smaller than in HEA, and VSI was significantly larger. The Q with a threshold of 0.32 s-1/3 predicted the final infarction with a sensitivity of 69% and a specificity of 64%. Conclusions: The reduced Q and increased VSI in the IPE confirmed our previous pilot results. Although Q showed a trend to identify the severity of ischemia in an overall voxel population, its potential in predicting infarct growth needs to be further tested in a larger cohort including a clear status of reperfusion and recanalization.

Background and Purpose— Impaired kidney function is thought to be associated with small vessel disease, outcome, and mortality in the general stroke population. Data are limited regarding young patients. The aim of this study was to investigate the association of kidney function and white matter hyperintensities (WMHs) in young patients with first ischemic stroke. Methods— We analyzed 2500 young (18–55 years) patients with first-ever ischemic stroke from the prospective observational Stroke in Young Fabry Patients (SIFAP1) study with available MRI data on WMH. Of these, 2009 had available data concerning estimated glomerular filtration rate (eGFR). Kidney function was expressed as eGFR by the Modification of Diet in Renal Disease method. Deep WMHs on MRI were classified by the Fazekas score. Multivariate analysis was performed using a regression model with random effects. Results— Mean eGFR was 96.7 mL/min in those with WMH Grade 0 to 1 (none to mild), 90.7 mL/min in WMH Grade 2 (moderate), and 89 mL/min in WMH Grade 3 (severe). Univariate analysis revealed WMH to be associated with age (P<0.001), hypertension (P<0.001), cardiovascular disease (P=0.015), overweight (body mass index >25 kg/m2; P=0.013), current smoking (P=0.044), and eGFR (P=0.009). In multivariate analysis, age, hypertension, and eGFR remained associated with WMH severity. Conclusions— In young patients with acute ischemic stroke, lower eGFR values in the normal range are associated with the presence of moderate to severe WMH. Clinical Trial Registration— URL: http://clinicaltrials.gov. Unique Identifier: NCT00414583.

The aim of this study was to test the feasibility of vessel size imaging with precise evaluation of apparent diffusion coefficient and cerebral blood volume and to apply this novel technique in acute stroke patients within a pilot group to observe the microvascular responses in acute ischemic tissue. Microvessel density-related quantity Q and mean vessel size index (VSI) were assessed in 9 healthy volunteers and 13 acute stroke patients with vessel occlusion within 6 hours after symptom onset. Our results in healthy volunteers matched with general anatomical observations. Given the limitation of a small patient cohort, the median VSI in the ischemic area was higher than that in the mirrored region in the contralateral hemisphere (P<0.05). Decreased Q was observed in the ischemic region in 2 patients, whereas no obvious changes of Q were found in the remaining 11 patients. In a patient without recanalization, the VSI hyperintensity in the subcortical area matched well with the final infarct. These data reveal that different observations of microvascular response in the acute ischemic tissue seem to emerge and vessel size imaging may provide useful information for the definition of ischemic penumbra and have an impact on future therapeutic approaches.

Background: The MRI-based mismatch concept has been used to estimate the risk of infarction in ischemic stroke. Based on multiple studies on magnetic resonance perfusion imaging, it seems unlikely that any perfusion parameter threshold will provide a reliable prediction of radiological or clinical outcome for all patients. The goal of our study was to find a minimally biased yet maximally useful perfusion postprocessing protocol which would offer the treating physician a useful estimate of tissue fate. Methods: One hundred and forty-five acute ischemic stroke patients, admitted within 24 h after stroke to the Charité – University Medicine Hospital in Berlin between March 2008 and November 2009, were included in this study. Using three different software packages (Perfscape/Neuroscape, PMA and Stroketool), maps of mean transit time, cerebral blood flow (CBF) and Tmax were created. Three different thresholds were applied on each parameter map and subsequent volumes of hypoperfused tissue were calculated. Results: Overall, the maps and thresholds giving the least amount of overestimation of the final infarct volume were Tmax 8 s in Perfscape/Neuroscape, CBF 20 ml/100 g/min in PMA and CBF 15% (of the highest value on the scale for a given patient) in Stroketool. In patients with persistent vessel occlusion, a CBF map with a restrictive threshold showed volumes of tissue at definite risk of infarction in up to 100% of patients. The additional use of a CBF map with a high threshold enabled identification of patients without penumbras. Conclusions: No combination of software, map and threshold was able to give a reliable estimate of tissue fate for either all patients or any subgroup of patients. However, in patients with vessel occlusion, combination of a CBF map with a low and a high threshold can enable calculation of the minimum volume of brain tissue that will inevitably be lost if the occlusion persists.

BACKGROUND:We recently demonstrated an immediate immunodepressive state after acute ischemic stroke in humans.METHODS:In the present study, we prospectively analyzed immune responses in patients with middle cerebral artery stroke (n=20), acute myocardial infarction (n=20) and healthy controls (n=20, also matched for age and gender).RESULTS:Compared to controls, a rapid depression of monocytic HLA-DR expression and a defective lymphocytic IFN-γ production was obvious after ischemic stroke or myocardial infarction, while total counts of leukocytes and monocytes were significantly higher after myocardial infarction. A T cell-mediated lymphopenia was accentuated in patients with severe stroke, obviously predisposing these patients for nosocomial infections.CONCLUSIONS:Our data reveal an immediate and to some extent differential suppression of cell-mediated immune responses after ischemic stroke or myocardial infarction respectively.

OBJECTIVES:The hyperintense acute reperfusion marker (HARM) has been described as a predictor for haemorrhagic transformation (HT) in acute ischaemic stroke. We hypothesised that this phenomenon is not present in the elderly.METHODS:It was possible to assess 47/84 consecutive patients aged 80 and over with diagnosed ischaemic stroke or transient ischaemic attack (TIA). MRI was performed within 24 h of onset of symptoms with follow-up MRI within a further 48 h.RESULTS:Of 47 included patients, 19 showed HARM; it was only seen on follow-up examination. Ten of the 47 patients underwent thrombolysis with recombinant tissue plasminogen activator (rt-PA); 4 of them showed HARM, and 1 of those showed HT. HARM was found in three out of eight patients with haemorrhagic transformation on baseline and/or follow-up MRI. We did not observe an association between HARM and early HT either in the whole group or in the patients who received thrombolysis.CONCLUSION:HARM was not associated with HT in the elderly after ischaemic stroke, independent of treatment. While it may indicate dysfunction of the blood-brain barrier (BBB), it does not necessarily amount to HT.

Background The mismatch between diffusion weighted imaging (DWI) lesion and perfusion imaging (PI) deficit volumes has been used as a surrogate of ischemic penumbra. This pathophysiology-orientated patient selection criterion for acute stroke treatment may have the potential to replace a fixed time window. Two recent trials - DEFUSE and EPITHET - investigated the mismatch concept in a multicenter prospective approach. Both studies randomized highly selected patients (n = 74/n = 100) and therefore confirmation in a large consecutive cohort is desirable. We here present a single-center approach with a 3T MR tomograph next door to the stroke unit, serving as a bridge from the ER to the stroke unit to screen all TIA and stroke patients. Our primary hypothesis is that the prognostic value of the mismatch concept is depending on the vessel status. Primary endpoint of the study is infarct growth determined by imaging, secondary endpoints are neurological deficit on day 5-7 and functional outcome after 3 months. Methods and design 1000Plus is a prospective, single centre observational study with 1200 patients to be recruited. All patients admitted to the ER with the clinical diagnosis of an acute cerebrovascular event within 24 hours after symptom onset are screened. Examinations are performed on day 1, 2 and 5-7 with neurological examination including National Institute of Health Stroke Scale (NIHSS) scoring and stroke MRI including T2*, DWI, TOF-MRA, FLAIR and PI. PI is conducted as dynamic susceptibility-enhanced contrast imaging with a fixed dosage of 5 ml 1 M Gadobutrol. For post-processing of PI, mean transit time (MTT) parametric images are determined by deconvolution of the arterial input function (AIF) which is automatically identified. Lesion volumes and mismatch are measured and calculated by using the perfusion mismatch analyzer (PMA) software from ASIST-Japan. Primary endpoint is the change of infarct size between baseline examination and day 5-7 follow up. Discussions The aim of this study is to describe the incidence of mismatch and the predictive value of PI for final lesion size and functional outcome depending on delay of imaging and vascular recanalization. It is crucial to standardize PI for future randomized clinical trials as for individual therapeutic decisions and we expect to contribute to this challenging task. Trial Registration clinicaltrials.gov NCT00715533

Background: We have recently shown that ischemic stroke causes a stress-mediator-induced long-lasting immunodepressive state in mice. Methods: Using head magnetic resonance imaging and standardized immunoassays, we prospectively investigated whether poststroke immunodepression is also seen in humans. Results: Compared to healthy volunteers (n = 30), a rapid depression of lymphocyte counts and a functional deactivation of monocytes and T helper type 1 cells was observed in acute stroke patients (SP; n = 40). Immunodepression was more pronounced in patients with severe clinical deficit or large infarction. On admission the combination of monocytic tumor necrosis factor α release ex vivo and the National Institute of Health Stroke Scale score were the best predictors for nosocomial infection, preferentially affecting older SP. Conclusion: Our data provide evidence for an immediate suppression of cell-mediated immune responses after ischemic stroke in humans.