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Background Identifying the cause of non-traumatic coma in the emergency department is challenging. The clinical neurological examination is the most readily available tool to detect focal neurological deficits as indicators for cerebral causes of coma. Previously proposed clinical pathways have granted the interpretation of clinical findings a pivotal role in the diagnostic work-up. We aimed to identify the actual diagnostic reliability of the neurological examination with regard to identifying acute brain damage. Methods Eight hundred and fifty-three patients with coma of unknown etiology (CUE) were examined neurologically in the emergency department following a predefined routine. Coma-explaining pathologies were identified retrospectively and grouped into primary brain pathology with proof of acute brain damage and other causes without proof of acute structural pathology. Sensitivity, specificity and percentage of correct predictions of different examination protocols were calculated using contingency tables and binary logistic regression models. Results The full neurological examination was 74% sensitive and 60% specific to detect acute structural brain damage underlying CUE. Sensitivity and specificity were higher in non-sedated patients (87/61%) compared to sedated patients (64%/59%). A shortened four-item examination protocol focusing on pupils, gaze and pyramidal tract signs was only slightly less sensitive (67%) and more specific (65%). Conclusions Due to limited diagnostic reliability of the physical examination, the absence of focal neurological signs in acutely comatose patients should not defer from a complete work-up including brain imaging. In an emergency, a concise neurological examination should thus serve as one part of a multimodal diagnostic approach to CUE.

Koma unklarer Genese („coma of unknown origin“, CUO) ist ein haufiges unspezifisches Notfallleitsymptom mit hoher Mortalitat. Die Diagnostik steht unter Zeitdruck bei einem gleichzeitig breiten Spektrum moglicher zugrunde liegender Erkrankungen mit ca. 50 % primaren ZNS-Pathologien und ca. 50 % extrazerebralen, fast ausschlieslich internistischen Ursachen. Trotz der mit dem Leitsymptom assoziierten hohen Mortalitat gibt es keine verbindlichen Leitlinien fur das Akutmanagement erwachsener CUO-Patienten. Wir schlagen einen interdisziplinaren Voralarm fur CUO-Patienten vor, wie wir ihn an unserem Klinikum der Maximalversorgung etabliert haben. Der Alarm wird anhand einfacher, aber fur die praklinische Identifikation von CUO ausreichender Triagekriterien bereits vor Eintreffen des Patienten ausgelost. Die fachliche Fuhrung liegt bei der Neurologie. Die Behandlungsroutine beinhaltet eine strukturierte Interaktion mit Pflege, innerer Medizin, Anasthesie, Radiologie (CT, CTA) und Labor (inkl. Liquor, Toxikologie) mit fakultativer Hinzuziehung von Neurochirurgie und Traumatologie. Die von uns erhobenen Daten sprechen fur ein standardisiertes leitsymptombasiertes diagnostisches Management, das die Neurologie und innere Medizin an den Anfang des diagnostischen Vorgehens stellt. Bildgebende Diagnostik sollte nicht nur abhangig von der klinisch-syndromalen Zuordnung erfolgen, weil Sensitivitat, Spezifitat und Interrater-Variabilitat Letzterer nicht ausreichen und mehrfache Pathologien, die auch einzeln CUO erklaren konnten, haufig sind. Klinische Untersuchung, Bildgebung und Laboruntersuchungen sollten als Bausteine eines integrativen diagnostischen Ansatzes gesehen werden, in dem die atiologische Zuordnung erst nach kompletter diagnostischer Aufarbeitung erfolgen sollte.

Background 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. Methods We implemented a new interdisciplinary standard operating procedure (SOP) for patients presenting with non-traumatic coma of unknown origin. It includes a new in- house triage process, a new alert call, a new composition of the clinical response team and a new management algorithm (altogether termed “coma alarm”). It is triggered by two simple criteria to be checked with out-of-hospital emergency response teams before the patient arrives. A neurologist in collaboration with an internal specialist leads the in-hospital team. Collaboration with anaesthesiology, trauma surgery and neurosurgery is organised along structured pathways that include standardised laboratory tests and imaging. Patients were prospectively enrolled. We calculated response times as well as sensitivity and false positive rates, thus proportions of over- and undertriaged patients, as quality measures for the implementation in the SOP. Results During 24 months after implementation, we identified 325 eligible patients. Sensitivity was 60 % initially (months 1–4), then fluctuated between 84 and 94 % (months 5–24). Overtriage never exceeded 15 % and undertriage could be kept low at a maximum of 11 % after a learning period. We achieved a median door-to-CT time of 20 minutes. 85 % of patients needed subsequent ICU treatment, 40 % of which required specialised neuro- ICUs. Discussion Our results indicate that our new simple in-house triage criteria may be sufficient to identify eligible patients before arrival. We aimed at ensuring the fastest possible proceedings given high portions of underlying time-sensitive neurological and medical pathologies while using all available resources as purposefully as possible. Conclusions Our SOP may provide an appropriate tool for efficient management of patients with non- traumatic coma. Our results justify the assignment of the initial diagnostic workup to neurologists and internal specialists in collaboration with anaesthesiologists.

Background: Vascular hyperintensities of brain-supplying arteries on stroke FLAIR MRI are common and represent slow flow or stasis. FLAIR vascular hyperintensities (FVH) are discussed as an independent marker for cerebral hypoperfusion, but the impact on infarct size and clinical outcome in acute stroke patients is controversial. This study evaluates the association of FVH with infarct morphology, clinical stroke severity and infarct growth in patients with symptomatic internal carotid artery (ICA) or middle cerebral artery (MCA) occlusion. Methods: MR images of 84 patients [median age 73 years (IQR 65–80), 56.0% male, median NIHSS 7 (IQR 3–13)] with acute stroke due to symptomatic ICA or MCA occlusion or stenosis were reviewed. Vessel occlusions were identified by MRA time of flight and graded with the TIMI score. Diffusion and perfusion deficit volumes on admission and FLAIR lesion volumes on discharge were assessed. The presence and number of FVH were evaluated according to MCA-ASPECT areas, and associations with MR volumes, morphology of infarction, recanalization status, presence of white matter disease and hemorrhagical transformation as well as with stroke severity (NIHSS), stroke etiology and thrombolysis rate were analyzed. Results: FVH were detectable in 75 (89.3%) patients. The median number of FVH was 4 (IQR 2–7). Patients with FVH >4 presented with more severe strokes due to NIHSS (p = 0.021), had larger initial DWI lesions (p = 0.008), perfusion deficits (p = 0.001) and mismatch volumes/ratios (p = 0.005). The final infarct volume was larger (p = 0.005), and hemorrhagic transformation was more frequent (p = 0.029) in these patients. Conclusions: The presence of FVH indicates larger ischemic areas in brain parenchyma predominantly caused by proximal anterior circulation vessel occlusion. A high count of FVH might be a further surrogate marker for initial ischemic mismatch and stroke severity.

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 6hours 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.

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: 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.

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 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.

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. 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. 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. 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.