Causes of brain dysfunction in acute coma: a cohort study of 1027 patients in the emergency department

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

implementation of an in-house management routine

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

The accuracy of initial diagnoses in coma: an observational study in 835 patients with non-traumatic disorder of consciousness

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 kappa = .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

Impaired Representation of Geometric Relationships in Humans with Damage to the Hippocampal Formation

The pivotal role of the hippocampus for spatial memory is well-established. However, while neurophysiological and imaging studies suggest a specialization of the hippocampus for viewpoint-independent or allocentric memory, results from human lesion studies have been less conclusive. It is currently unclear whether disproportionate impairment in allocentric memory tasks reflects impairment of cognitive functions that are not sufficiently supported by regions outside the medial temporal lobe or whether the deficits observed in some studies are due to experimental factors. Here, we have investigated whether hippocampal contributions to spatial memory depend on the spatial references that are available in a certain behavioral context. Patients with medial temporal lobe lesions affecting systematically the right hippocampal formation performed a series of three oculomotor tasks that required memory of a spatial cue either in retinal coordinates or relative to a single environmental reference across a delay of 5000 ms. Stimulus displays varied the availability of spatial references and contained no complex visuo-spatial associations. Patients showed a selective impairment in a condition that critically depended on memory of the geometric relationship between spatial cue and environmental reference. We infer that regions of the medial temporal lobe, most likely the hippocampal formation, contribute to behavior in conditions that exceed the potential of viewpoint-dependent or egocentric representations. Apparently, this already applies to short-term memory of simple geometric relationships and does not necessarily depend on task difficulty or integration of landmarks into more complex representations. Deficient memory of basic geometric relationships may represent a core deficit that contributes to impaired performance in allocentric spatial memory tasks

The role of the medial temporal lobe for associative short-term memory in humans

Der mediale Temporallappen (MTL) und seine Bedeutung für das Gedächtnis sind seit Jahrzehnten Gegenstand der wissenschaftlichen Diskussion. Bislang besteht kein Konsens über das Zusammenspiel seiner einzelnen neuroanatomischen Untereinheiten bei der Verarbeitung und Repräsentation von Gedächtnisinhalten. Die Funktion des Hippokampus steht dabei aufgrund seiner zentralen Lage und besonderen Konnektivität vorrangig im Fokus des Interesses. Trotz umfangreicher Untersuchungen an Menschen und Tiermodellen fehlt gegenwärtig eine umfassende Theorie seiner Funktion, da der Hippokampus mit mehreren zum Teil gegensätzlich erscheinenden Domänen des Gedächtnisses in Verbindung gebracht wird. Problematisch ist in diesem Zusammenhang das Fehlen eines einheitlichen humanen Läsionsmodells in der bisherigen Literatur, was die eindeutige Interpretation von Läsionsstudien oftmals erschwert. Die vorliegende Arbeit präsentiert Daten aus neuropsychologischen Untersuchungen an Patienten mit umschriebenen chirurgischen Läsionen des MTL. Es wird gezeigt, dass der Hippokampus entgegen der traditionellen Lehrmeinung auch an Kurzzeitgedächtnisprozessen beteiligt ist und dass dabei eine Spezialisierung auf räumlich-assoziative Gedächtnisinhalte vorliegt. Nicht-räumliche Assoziationen scheinen hingegen unabhängig vom Hippokampus repräsentiert zu werden. Darüber hinaus werden anhand einer vergleichenden Läsionsstudie Belege für Kompensationsmechanismen erbracht, welche von der Ätiologie der MTL-Läsion abhängig sind und deren Effizienz das Ausmaß funktioneller Defizite nach Läsionen des MTL mitbestimmt. Rückschlüsse auf Struktur-Funktions-Beziehungen in Läsionsstudien müssen solche Kompensationsprozesse berücksichtigen.For decades, the medial temporal lobe (MTL) and its role in memory have been the subject of intense scientific discussion. In this context, the hippocampus has been of particular interest due to its central position within the MTL. To date, there is no consensus on how the hippocampus and adjacent regions of the MTL interact during processing and representation of memory content. Experimental work in humans and animal models suggests involvement of the hippocampus in multiple memory domains, some of which appear to be conflicting. As a consequence, there is currently no comprehensive theory of hippocampal function. The discussion is complicated by the lack of an integrative experimental model of human hippocampal dysfunction which is why an unambiguous interpretation of human lesion studies is difficult. This thesis presents data from behavioural studies on patients with circumscribed surgical lesions of the MTL performing delayed-match-to-sample tasks with different stimulus material. In contrast to the traditional view, it shows that the hippocampus is also involved in short term memory, at least with stimulus material that contains spatial associations. On the other hand, the representation of non-spatial associations seems to be largely independent of the hippocampus. Furthermore, evidence of compensational mechanisms following hippocampal damage in the early stages of brain maturation is presented. It is proposed that the efficiency of these mechanisms co-determines the magnitude and pattern of functional deficits following damage to the MTL. Conclusions drawn from lesion studies about structure-function-relationships must take into account these compensational mechanisms

Requirements for stress gradient-based fatigue assessment of notched structures according to theory of critical distance

Notches, local stress raisers within structural components, are one of the most important locations for fatigue crack initiation. It is well known that fatigue is governed by the effective stresses in the vicinity of notches. Within this study, differences in prediction accuracy between different types of theory of critical distance methods, that is, point and line methods, are systematically investigated in conjunction with a sensitivity study regarding mesh refinement, assumed strength hypothesis and material behaviour. For this purpose, a finite element analysis parameter study on notched structures is performed and recommendations for the application of stress gradient methods are presented. Difference in effective stress of up to 30%, and hence a significant difference in fatigue life (e.g., 185% for a slope of S-N curve of k = 4), is found for typical notch shapes, for example, in welded joints.The work was performed within the research project ESM-50 ‘Fatigue of welded structures at sub-zero temperatures’, funded by the German Research Association of the Working Group of the Iron- and Metal-processing Industry e.V. as part of the Donors' Association for the Promotion of Sciences and Humanities in Germany under project number AVIF-No. A301

Example and group results.

<p>LEFT: Example results of a control subject and a patient (H.N.) in the EGO task (top row), ALLO-EGO task (middle row) and ALLO task (bottom row). Data are shown separately for the three memory cue positions, collapsed over all quadrants of the visual field (red, 8°/30°-position; green 12°/20°-position; blue, 12°/40° position). Filled black circles denote saccade end points. Ellipses are centered on a subjects' average saccade end point for a given memory cue position. Ellipse extent represents the horizontal and vertical standard deviation of saccade end points. Note decreased accuracy of the patients' saccade end points in the ALLO task. RIGHT: Group results. Mean systematic and variable saccade amplitude error in controls (light grey bars) and patients (dark grey bars) in the EGO task (top row), ALLO-EGO task (middle row) and ALLO task (bottom row). Dots represent individual performance. In patients, white dots represent performance of patients D.B. and S.D. (i.e. patients with involvement of parahippocampal cortex) and grey dots performance of patients H.N., A.M. and S.W. (i.e. patients without involvement of parahippocampal cortex). Asterisks indicate significant differences between groups (* p<0.01, ** p<0.001).</p