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Severe traumatic brain injury (TBI) produces shearing forces on long-range axons and brain vessels, causing axonal and vascular injury. To examine whether microbleeds and axonal injury colocalize after TBI, we performed whole-brain susceptibility-weighted imaging (SWI) and diffusion tensor imaging (DTI) in 14 patients during the subacute phase after severe TBI. SWI was used to determine the number and volumes of microbleeds in five brain regions: the frontotemporal lobe; parieto-occipital lobe; midsagittal region (cingular cortex, parasagittal white matter, and corpus callosum); deep nuclei (basal ganglia and thalamus); and brainstem. Averaged fractional anisotropy (FA) and mean diffusivity (MD) were measured to assess microstructural changes in the normal appearing white matter attributed to axonal injury in the same five regions. Regional expressions of microbleeds and microstructure were used in a partial least-squares model to predict the impairment of consciousness in the subacute stage after TBI as measured with the Coma Recovery Scale-Revised (CRS-R). Only in the midsagittal region, the expression of microbleeds was correlated with regional changes in microstructure as revealed by DTI. Microbleeds and microstructural DTI-based metrics of deep, but not superficial, brain regions were able to predict individual CRS-R. Our results suggest that microbleeds are not strictly related to axonal pathology in other than the midsagittal region. While each measure alone was predictive, the combination of both metrics scaled best with individual CRS-R. Structural alterations in deep brain structures are relevant in terms of determining the severity of impaired consciousness in the acute stage after TBI.

Background Loss of consciousness has been shown to reduce cerebral metabolic rates of glucose (CMRglc) measured by brain [18F]FDG-PET. Measurements of regional metabolic patterns by normalization to global cerebral metabolism or cerebellum may underestimate widespread reductions. New method The aim of this study was to compare quantification methods of whole brain glucose metabolism, including whole brain [18F]FDG uptake normalized to uptake in cerebellum, normalized to injected activity, normalized to plasma tracer concentration, and two methods for estimating CMRglc. Six patients suffering from severe traumatic brain injury (TBI) and ten healthy controls (HC) underwent a 10 min static [18F]FDG-PET scan and venous blood sampling. Results Except from normalizing to cerebellum, all quantification methods found significant lower level of whole brain glucose metabolism of 25–33% in TBI patients compared to HC. In accordance these measurements correlated to level of consciousness. Comparison with existing methods Our study demonstrates that the analysis method of the [18F]FDG PET data has a substantial impact on the estimated whole brain cerebral glucose metabolism in patients with severe TBI. Importantly, the SUVR method which is often used in a clinical setting was not able to distinguish patients with severe TBI from HC at the whole-brain level. Conclusion We recommend supplementing a static [18F]FDG scan with a single venous blood sample in future studies of patients with severe TBI or reduced level of consciousness. This can be used for simple semi-quantitative uptake values by normalizing brain activity uptake to plasma tracer concentration, or quantitative estimates of CMRglc.

Background: We estimated the annually incidence and mortality of acquired brain injury (ABI) in people aged 15-30years during 1994-2013.Methods: All Danes with a first-ever hospital diagnosis of ABI, including traumatic brain injury (TBI), encephalopathy, CNS-infection or brain tumour, were identified in the Danish National Patient Register. Incidence rates (IRs) and estimated annual percentage changes (EAPC) were estimated by Poisson regression. Mortality was estimated by the Kaplan-Meier estimator and adjusted hazard ratios (aHR) were computed using Cox regression with 1994-1998.Results: A total of 10,542 individuals were hospitalized with a first-time diagnosis of ABI. The IR for ABI decreased from 63.36 to 33.91/100,000person-years from 1994 to 2013 [EAPC: -2.78% (95% CI: -3.26 to -2.28)] mainly driven by a decreasing IR of TBI [EAPC: -6.53% (95% CI: -9.57 to -3.39)] during 2007-2013. IRs of brain tumour and CNS infections also decreased significantly. The mortality after ABI tended to be higher during 1999-2013 compared to 1994-1998. For brain tumour, the 1-year mortality decreased significantly [2009-2013 aHR: 0.41 (95% CI: 0.23-0.72)].Conclusion: Incidence of hospitalisations for ABI and in particular TBI has decreased significantly. Overall, the mortality after ABI has not improved, but the mortality after brain tumour has decreased significantly.

Objective: (1) To determine patterns of return to work (RTW) after traumatic brain injury and other causes of acquired brain injury (ABI) among young adults aged 19-30 years and (2) to compare the stability of long-term labor-market attachment (LMA) to the background population. Method: Nationwide registry-based inception cohort study of 10 years weekly data of employment status. Patients (n=8,496) aged 19-30 years with first-ever diagnosis of TBI, stroke, subarachnoid hemorrhage, encephalopathy, brain tumor or CNS infections during 1999-2015. For comparison, a general population cohort (n=206,025) individually matched on age, sex and municipality was identified. The main outcome was RTW, which was defined as time to LMA, i.e. a week without public assistance benefits except education grants/leave. Stable labor-market attachment (sLMA) was defined as LMA for at least 75% over 52 weeks. The cumulative incidence proportions of RTW and stable RTW in the ABI cohort were estimated with the Aalen-Johansen estimator with death as a competing event. Results: Twelve weeks after diagnosis 46.9% of ABI cohort had returned to stable RTW, which increased to 57.4% one year after, and 69.7% ten years after. However, compared to controls fewer had sLMA one year (OR: 0.25 [95% CI 0.24-0.27]) and ten years after diagnosis (OR: 0.35 [95% CI: 0.33-0.38]). Despite significant variations, sLMA was lower compared to the control cohort for all subtypes of ABI and no significant improvements were seen after 2-5 years. Conclusion: Despite relatively fast RTW only a minor proportion of young patients with ABI achieves sLMA. Key words: Brain Injury, return to work, employment, prognosis, TBI, yung adults

IntroductionTraumatic brain injury (TBI) is considered one of the most pervasive causes of disability in people under the age of 45. TBI often results in disorders of consciousness, and clinical assessment of the state of consciousness in these patients is challenging due to the lack of behavioural responsiveness. Functional neuroimaging offers a means to assess these patients without the need for behavioural signs, indicating that brain connectivity plays a major role in consciousness emergence and maintenance. However, little is known regarding how changes in connectivity during recovery from TBI accompany changes in the level of consciousness. Here, we aim to combine cutting-edge neuroimaging techniques to follow changes in brain connectivity in patients recovering from severe TBI.Methods and analysisA multimodal, longitudinal assessment of 30 patients in the subacute stage after severe TBI will be made comprising an MRI session combined with electroencephalography (EEG), a positron emission tomography session and a transcranial magnetic stimulation (TMS) combined with EEG (TMS/EEG) session. A group of 20 healthy participants will be included for comparison. Four sessions for patients and two sessions for healthy participants will be planned. Data analysis techniques will focus on whole-brain, both data-driven and hypothesis-driven, connectivity measures that will be specific to the imaging modality.Ethics and disseminationThe project has received ethical approval by the local ethics committee of the Capital Region of Denmark and by the Danish Data Protection. Results will be published as original research articles in peer-reviewed journals and disseminated in international conferences. None of the measurements will have any direct clinical impact on the patients included in the study but may benefit future patients through a better understanding of the mechanisms underlying the recovery process after TBI.Trial registration number:NCT02424656; Pre-results.

BACKGROUND: Post traumatic hydrocephalus (PTH) is a frequent complication during rehabilitation following severe TBI. However, the diagnosis of PTH is not straightforward and despite shunting recovery may be delayed. OBJECTIVE: To study the influence of PTH on recovery and outcome during rehabilitation. METHODS: We studied 417 patients with severe TBI admitted consecutively to a single hospital-based neurorehabilitation department serving Eastern Denmark between 2000 and 2010. Demographics (age and gender) and clinical characteristics (length of acute treatment, post traumatic amnesia (PTA), level of consciousness, injury severity (ISS), and admission FIM TM ), and PTH were related to recovery (discharge FIM TM ), outcome (GOS), and length of rehabilitation stay. RESULTS: Patients with PTH were older, brain injury more severe, and acute treatment was longer. At discharge they had more disability, longer rehabilitation stays, and unfavorable outcome. However, after adjusted multiple regression analyses PTH was not associated with disability at discharge or outcome. Instead, PTH was associated with longer stay for rehabilitation. CONCLUTIONS: Shunting for PTH does not affect recovery and outcome per se, but prolongs lengths of stay by almost 3 weeks. Therefore, patients treated for PTH are as likely to benefit from rehabilitation as patients without, but require longer rehabilitation stays.

Objective To investigate timing and clinical predictors that might predict hydrocephalus emerging during rehabilitation until 1 year following severe traumatic brain injury (TBI). Background Posttraumatic hydrocephalus (PTH) may lead to clinical deterioration and poor outcome if untreated. However, PTH can be successfully treated if detected. Nevertheless, PTH is easily overlooked during rehabilitation, particularly in severe cases. Method We prospectively followed all patients (n = 444) in Eastern Denmark (population 2.5 mill) sustaining severe TBI, who required lengthy rehabilitation between 2000 and 2010. All patients with PTH were tracked retrospectively. Demographics, surgery, injury severity, consciousness level, and disability were compared for patients with versus without PTH. Independent predictors of PTH during rehabilitation were identified through multiple logistic regression models. Results PTH occurred in 14.2% and 3/4 emerged during rehabilitation. Patients with PTH were older, had more severe brain injuries, were more frequently in vegetative state, and needed longer rehabilitation stays. After adjusted analyses, however, only older age and low level of consciousness were independently associated with PTH. Conclusion Most cases of PTH emerge during rehabilitation. Therefore, attention towards this complication should be present also beyond the acute stage after TBI, particularly among older patients and patients with severe disordered consciousness.

Background Studies have reported increasing incidence of ischemic stroke in adults younger than 50 to 55 years. Information on temporal trends of other stroke subtypes and transient ischemic attack ( TIA ) is sparse. The aim of this study was to investigate temporal trends of the incidence of hospitalizations for TIA and stroke including sex‐ and subtype‐specific trends in young adults aged 15 to 30 years. Methods and Results From the Danish National Patient Register, we identified all cases of first‐ever stroke and TIA (age 15–30 years) in Denmark, who were hospitalized during the study period of 1994 to 2012. Incidence rates and estimated annual percentage changes ( EAPCs ) were estimated by using Poisson regression. During the study period, 4156 cases of first‐ever hospitalization for stroke/ TIA were identified. The age‐standardized incidence rates of hospitalizations for stroke increased significantly ( EAPC 1.83% [95% CI 1.11–2.55%]) from 11.97/100 000 person‐years ( PY ) in 1994 to 16.77/100 000 PY in 2012. TIA hospitalizations increased from 1.93/100 000 PY in 1994 to 5.81/100 000 PY in 2012 and after 2006 more markedly in men than in women ( EAPC 16.61% [95% CI 10.45–23.12%]). The incidence of hospitalizations for ischemic stroke was markedly lower among men, but increased significantly from 2006 ( EAPC 14.60% [95% CI 6.22–23.63%]). The incidences of hospitalizations for intracerebral hemorrhage and subarachnoid hemorrhage remained stable during the study period. Conclusions The incidence rates of first‐time hospitalizations for ischemic stroke and TIA in young Danish adults have increased substantially since the mid 1990s. The increase was particularly prominent in the most recent years.

Background and Purpose— Evidence of a causal relation between serum cholesterol and stroke is inconsistent. We investigated the relation between total serum cholesterol and both stroke severity and poststroke mortality to test the hypothesis that hypercholesterolemia is primarily associated with minor stroke. Methods— In the study, 652 unselected patients with ischemic stroke arrived at the hospital within 24 hours of stroke onset. A measure of total serum cholesterol was obtained in 513 (79%) within the 24-hour time window. Stroke severity was measured with the Scandinavian Stroke Scale (0=worst, 58=best); a full cardiovascular risk profile was established for all. Death within 10 years after stroke onset was obtained from the Danish Registry of Persons. Results— Mean±SD age of the 513 patients was 75±10 years, 54% were women, and the mean±SD Scandinavian Stroke Scale score was 39±17. Serum cholesterol was inversely and almost linearly related to stroke severity: an increase of 1 mmol/L in total serum cholesterol resulted in an increase in the Scandinavian Stroke Scale score of 1.32 (95% CI, 0.28 to 2.36, P =0.013), meaning that higher cholesterol levels are associated with less severe strokes. A survival analysis revealed an inverse linear relation between serum cholesterol and mortality, meaning that an increase of 1 mmol/L in cholesterol results in a hazard ratio of 0.89 (95% CI, 0.82 to 0.97, P =0.01). Conclusions— The results of our study support the hypothesis that a higher cholesterol level favors development of minor strokes. Because of selection, therefore, major strokes are more often seen in patients with lower cholesterol levels. Poststroke mortality, therefore, is inversely related to cholesterol.

Poststroke epilepsy (PSE) is a feared complication after stroke and is reported in 3% to 5% of stroke survivors. In this study we sought to identify incidence and predictors of PSE in an unselected stroke population with a follow-up period of 7 years. The study was community-based and comprises a cohort of 1197 consecutively and prospectively admitted patients with stroke. Patients were followed up for 7 years. We defined PSE as recurrent epileptic seizures with onset after stroke and requiring antiepileptic prophylaxis. PSE was related to clinical factors (age, sex, onset stroke severity, lesion size on computed tomography scans, stroke subtype, localization, stroke risk factor profile, and early seizures) in univariate analyses. Independent predictors of PSE were identified through multiple logistic regression analyses. Overall, 38 patients (3.2%) developed PSE. Univariately, PSE was associated with younger age, intracerebral hemorrhage, and larger lesions. PSE was less frequently associated with atrial fibrillation and ischemic heart disease. In the final multiple regression model for the dependent variable PSE, independent predictors were younger age (odds ratio [OR] 1.7/10 years; 95% confidence interval [CI] 1.3-2.1), onset stroke severity (OR 1.3-/10-point decrease; 95% CI 1.0-1.6), lesion size (OR 1.2-/10-mm enlargement; 95% CI 1.0-1.3), intracerebral hemorrhage (OR 3.3; 95% CI 1.3-8.6), and early seizures (OR 4.5; 95% CI 1.3-16.0). We conclude that PSE occurs in about 3% of all patients with stroke within 7 years after stroke. Age, intracerebral hemorrhage, lesion size, increasing stroke severity, and early seizures are independent predictors of PSE.

Although diverging, most studies show that sex has no significant influence on stroke survival.In a Copenhagen, Denmark, community all patients with stroke during March 1992 to November 1993 were registered on hospital admission. Stroke severity was measured using the Scandinavian Stroke Scale (0-58); computed tomography determined stroke type. A risk factor profile was obtained for all including ischemic heart disease, hypertension, diabetes mellitus, atrial fibrillation, previous stroke, smoking, and alcohol consumption. Date of death was obtained within a 10-year follow-up period. Predictors of death were identified using a Cox proportional hazards model.Of 999 patients, 559 (56%) were women and 440 (44%) were men. Women were older (77.0 v 70.9 years; P.001) and had more severe strokes (Scandinavian Stroke Scale: 36.1 v 40.5; P.001). Age-adjusted risk factors showed no difference between sexes for ischemic heart disease, hypertension, atrial fibrillation, diabetes mellitus, and previous stroke. Men more often were smokers and alcohol consumers. Unadjusted survival in men and women did not differ: 70.3% versus 66.7% (1-year), 40.0% versus 38.9% (5-year), and 17.4% versus 18.7% (10-year), respectively. Adjusting for age, stroke severity, stroke type, and risk factors, women had a higher probability of survival at 1 year (hazard ratio 1.47, 95% confidence interval 1.10-2.00); 5 years (hazard ratio 1.47, 95% confidence interval 1.23-1.76); and 10 years (hazard ratio 1.49, 95% confidence interval 1.28-1.76). Before 9 months poststroke, no difference in survival was seen. Severity of stroke had the same effect on sex.Stroke is equally severe in men and women. Short-term survival is the same. Having survived stroke, women, however, live longer.

BACKGROUND AND PURPOSE The very old are expected to become a growing part of the stroke population in the industrialised part of the world. The aims of this study were to evaluate clinical characteristics of patients aged 85 years or more at stroke onset and to investigate very old age as an independent predictor of short- and long-term outcome. METHODS In the community-based Copenhagen Stroke Study we recorded admission clinical characteristics in 1197 consecutive stroke patients. Patients were stratified according to age groups on admission. Follow-up was performed at a mean of 7 years after stroke onset. By way of multiple logistic regression and survival analyses very old age was independently related to short- and long-term mortality and nursing home placement independent of other clinical characteristics. RESULTS 16% of patients were 85 years or older at the time of stroke onset. More of the very old were women (75% versus 50%, P

Background and Purpose — Body temperature is considered crucial in the management of acute stroke patients. Recently hypothermia applied as a therapy for stroke has been demonstrated to be feasible and safe in acute stroke patients. In the present study, we investigated the predictive role of admission body temperature to the long-term mortality in stroke patients. Methods — We studied 390 patients with acute stroke admitted within 6 hours from stroke onset. Admission clinical characteristics (age, sex, admission stroke severity, admission blood glucose, cardiovascular risk factor profile, and stroke subtype) were recorded for patients with hypothermia (body temperature ≤37°C) versus patients with hyperthermia (body temperature >37°C). Univariately the mortality rates for all patients were studied by Kaplan-Meier statistics. To find independent predictors of long-term mortality for all patients, Cox proportional-hazards models were built. We included all clinical characteristics and body temperature as a continuous variable. Results — Patients with hyperthermia had more severe strokes and more frequently diabetes, whereas no difference was found for the other clinical characteristics. For all patients mortality rate at 60 months after stroke was higher for patients with hyperthermia (73 per 100 cases versus 59 per 10 cases, P =0.001). When body temperature was studied in a multivariate Cox proportional-hazards model, a 1°C increase of admission body temperature independently predicted a 30% relative increase (95% CI, 4% to 57%) in long-term mortality risk. For 3-month survivors we found no association between body temperature and long-term survival when studied in a multivariate Cox proportional hazard model (hazards ratio, 1.11 per 1°C; 95% CI, 0.82 to 1.52). Conclusion — Low body temperature on admission is considered to be an independent predictor of good short-term outcome. The present study suggests that admission body temperature seems to be a major determinant even for long-term mortality after stroke. Hypothermic therapy in the early stage in which body temperature is kept low for a longer period after ictus could be a long-lasting neuroprotective measure.

Pedersen PM, Jorgensen HS, Kammersgaard LP, Nakayama H, Raaschou HO, Olsen TS: Manual and oral apraxia in acute stroke, frequency and influence on functional outcome: the Copenhagen Stroke Study. Am J Phys Med Rehabil 2001;80:685‐ 692. Objectives: To determine the frequency of manual and oral apraxia in acute stroke and to examine the influence of these symptoms on functional outcome. Design: Seven hundred seventy six unselected, acute stroke patients who were admitted within seven days of stroke onset with unimpaired consciousness were included. If possible, the patients were assessed for manual and oral apraxia on acute admission. Neurologic stroke severity including aphasia was assessed with the Scandinavian Stroke Scale, and activities of daily living function was assessed with the Barthel Index. All patients completed their rehabilitation in the same large stroke unit. Results: Six hundred eighteen patients could cooperate with the apraxia assessments. Manual apraxia was found in 7% of subjects (10% in left and 4% in right hemispheric stroke; 2 9.0; P 0.003). Oral apraxia was found in 6% (9% in left and 4% in right hemispheric stroke; 2 5.4; P 0.02). Both manual and oral apraxia were related to increasing stroke severity, and manual, but not oral, apraxia was associated with increasing age. There was no gender difference in frequency of apraxia. Patients with either type of apraxia had temporal lobe involvement more often than patients without. When analyzed with multiple linear and logistic regression analyses, neither manual nor oral apraxia had any independent influence on functional outcome. Conclusion: Apraxia is significantly less frequent in unselected patients with acute stroke than has previously been assumed and has no independent negative influence on functional outcome.

In the Copenhagen Stroke Study, we evaluated the combined impact on stroke outcome of potentially treatable factors such as acute body temperature, blood glucose, and stroke in progression. The patients were stratified into two groups: (1) patients with ‘good’ prognostic parameters (body temperature on admission ≤37.0°C and plasma glucose on admission ≤6.5 mmol/l and who did not develop stroke in progression) and (2) patients with correspondingly ‘poor’ prognostic parameters. A poor outcome was observed in 4% of the patients with good prognostic parameters versus in 49% of the patients with poor prognostic parameters (p < 0.01). In the multivariate analysis which also included stroke severity, blood glucose contributed significantly to poor outcome with an odds ratio (OR) of 1.2/1.0 mmol/l increase, body temperature with an OR of 2.2/1°C increase, and stroke in progression with an OR of 2.9. However, the combined effect of all three factors was more than additive with an OR of 10.0 (95% CI 1.5–56; p < 0.01). We have shown that in human stroke a strong and more than additive association exists between potentially reversible parameters and outcome. Intervention trials can prove whether these marked relations are causal.

Background and Purpose —Hypothermia reduces neuronal damage in animal stroke models. Whether hypothermia is neuroprotective in patients with acute stroke remains to be clarified. In this case-control study, we evaluated the feasibility and safety of inducing modest hypothermia by a surface cooling method in awake patients with acute stroke. Methods —We prospectively included 17 patients (cases) with stroke admitted within 12 hours from stoke onset (mean 3.25 hours). They were given hypothermic treatment for 6 hours by the “forced air” method, a surface cooling method that uses a cooling blanket with a flow of cool air (10°C). Pethidine was given to treat compensatory shivering. Cases were compared with 56 patients (controls) from the Copenhagen Stroke Study matched for age, gender, initial stroke severity, body temperature on admission, and time from stroke onset to admission. Blood cytology, biochemistry, ECGs, and body temperature were monitored during hypothermic treatment. Multiple regression analyses on outcome were performed to examine the safety of hypothermic therapy. Results —Body temperature decreased from t 0 =36.8°C to t 6 =35.5°C ( P 0 =36.8°C versus t 10 =36.5°C; P =0.01). Mortality at 6 months after stroke was 12% in cases versus 23% in controls ( P =0.50). Final neurological impairment (Scandinavian Stroke Scale score at 6 months) was mean 42.4 points in cases versus 47.9 in controls ( P =0.21). Hypothermic therapy was not a predictor of poor outcome in the multivariate analyses. Conclusions —Modest hypothermia can be achieved in awake patients with acute stroke by surface cooling with the “forced air” method, in combination with pethidine to treat shivering. It was not associated with a poor outcome. We suggest a large, randomized clinical trial to test the possible beneficial effect of induced modest hypothermia in unselected patients with stroke.

Background and Purpose —The beneficial effects of treatment and rehabilitation of patients with acute stroke in a dedicated stroke unit (SU) are well established. We wanted to examine if these effects are limited to certain groups of patients or if they apply to all patients independent of age, sex, comorbidity, and initial stroke severity. Methods —This was a community-based study of outcome in 1241 consecutive stroke patients from 2 communities in Copenhagen: In one (Frederiksberg), treatment and rehabilitation were given in general neurological and medical wards (GW), and in the other (Bispebjerg) in one single large SU. Outcome measures were initial, 1-year, and 5-year mortality rates, a poor outcome (initial death or discharge to a nursing home), and length of hospital stay (LOHS). Multivariate regression analyses were used to examine the independent effect of SU treatment on the various subgroups. Results —The relative risks of initial death, poor outcome, and 1-year and 5-year mortality rates were reduced by 40% on average in patients treated in the SU compared with the GW. A beneficial effect of SU treatment was observed regardless of the patient’s age, sex, comorbidity, and initial stroke severity. Those who benefited most appeared to be the patients with the most severe strokes (poor outcome: OR 0.17; 95% CI 0.05 to 0.58). Those who benefited least were patients with mild or moderate strokes (poor outcome: OR 0.66; 95% CI 0.41 to 0.98) and patients Conclusions —A beneficial effect of treatment in a SU is achieved in completely unselected patients independent of their age, sex, comorbidity, and stroke severity. Those who had the most severe strokes appeared to benefit most. All patients with acute stroke should therefore have access to treatment and rehabilitation in a dedicated SU.

This article describes basic characteristics and primary outcomes of unselected patients with stroke. These patients were part of the Copenhagen Stroke Study, a prospective, consecutive, and community-based study of 1197 acute stroke patients. The setting and care was multidisciplinary and all treatment was performed within the dedicated stroke unit. Neurologic impairment was measured at admission, weekly throughout the hospital stay, and again at the 6-month follow up. Basic activities of daily living, as measured by the Barthel Index, were assessed within the first week of admission, weekly throughout the hospital stay, and again after 6 months. Upon completion of the in-hospital rehabilitation, which averaged 37 days, two-thirds of surviving patients were discharged to their homes, with another 15% being discharged to a nursing home. Only 4% of the patients with very severe strokes reached independent function, as compared with 13% of patients with severe stroke, 37% of patients with moderate stroke, and 68% of patients with mild stroke.

Leukocytosis is a common finding in the acute phase of stroke. A detrimental effect of leukocytosis on stroke outcome has been suggested, and trials aiming at reducing the leukocyte response in acute stroke are currently being conducted. However, the influence of leukocytosis on stroke outcome has not been clarified. Methods: In 763 unselected patients with stroke admitted within 24 hours from onset, we prospectively studied the relation between leukocyte count and outcome considering relevant confounders and predictors such as initial stroke severity, risk factor profile, body temperature, and infection. Results: Univariate, leukocyte count on admission was significantly related to initial stroke severity (assessed by the Scandinavian Stroke Scale), lesion size on computed tomography, mortality, and outcome in survivors. However, multivariate regression analysis revealed that only the relation between leukocytosis and initial stroke severity was independent of other factors, whereas the relations found univariately between leukocytosis and lesion size, mortality, and outcome in survivors disappeared when initial stroke severity was included in the multivariate model. Conclusion: Leukocytosis on admission was related to initial stroke severity but not to outcome. Leukocyte count on admission seems merely to reflect initial stroke severity and is most likely a stress response with no independent influence on outcome. Our study may suggest that attempts aimed merely at lowering leukocyte count in peripheral circulating blood in the acute phase of stroke cannot be expected to improve outcome.

The eight papers included in this doctoral thesis were made during my position as a clinical research assistant at the Department of Neurology, Bispebjerg Hospital. All papers are based on the Copenhagen Stroke Study, which comprises a cohort of 1197 patients with acute stroke admitted to a single stroke unit and recruited from a well-defined area in Copenhagen, Denmark. This thesis focuses on the survival after stroke in relation to several baseline clinical characteristics and risk factors for cardiovascular disease. The thesis comes in three sections with regard to whether factors or clinical characteristics are permanent, potentially modifiable, or possible to change. The relative importance of the factors and clinical characteristics are discussed in relation to short-, intermediate-, and long-term survival after stroke. The results from the Copenhagen Stroke Study are compared to the results from other community-based or population-based studies. The two most prominent factors that determine both short- and long-term survival after stroke are age and stroke severity at onset. Advancing age and increasing severity are perceptively negatively correlated to survival. In some cases emerging therapies such as thrombolytic therapy and hypothermia may alleviate the burden of stroke severity, but this is not the case for the majority of stroke patients. The necessity to measure stroke severity with a validated stroke scale when comparing stroke patients in randomized clinical trials or population-based surveys is emphasized. For factors such as sex, and most cardiovascular risk factors further studies are necessary to clarify the relation to survival because studies disagree. Conclusions from studies of the relation between survival and alcohol intake are still debatable, mostly because of diverging definitions of the intensity of exposure. Smoking is uniformly associated with a poorer survival after stroke. Stroke unit treatment improves both short- and longterm survival regardless of stroke type, severity, age, and cardiovascular risk factor profile.

Background and Purpose— Stroke patients with hemorrhagic (HS) and ischemic strokes were compared with regard to stroke severity, mortality, and cardiovascular risk factors. Methods— A registry started in 2001, with the aim of registering all hospitalized stroke patients in Denmark, now holds information for 39 484 patients. The patients underwent an evaluation including stroke severity (Scandinavian Stroke Scale), CT, and cardiovascular risk factors. They were followed-up from admission until death or censoring in 2007. Independent predictors of death were identified by means of a survival model based on 25 123 individuals with a complete data set. Results— Of the patients 3993 (10.1%) had HS. Stroke severity was almost linearly related to the probability of having HS (2% in patients with the mildest stroke and 30% in those with the most severe strokes). Factors favoring ischemic strokes vs HS were diabetes, atrial fibrillation, previous myocardial infarction, previous stroke, and intermittent arterial claudication. Smoking and alcohol consumption favored HS, whereas age, sex, and hypertension did not herald stroke type. Compared with ischemic strokes, HS was associated with an overall higher mortality risk (HR, 1.564; 95% CI, 1.441–1.696). The increased risk was, however, time-dependent; initially, risk was 4-fold, after 1 week it was 2.5-fold, and after 3 weeks it was 1.5-fold. After 3 months stroke type did not correlate to mortality. Conclusion— Strokes are generally more severe in patients with HS. Within the first 3 months after stroke, HS is associated with a considerable increase of mortality, which is specifically associated with the hemorrhagic nature of the lesion.

Response: We appreciate Dr Sheikh’s thoughtful comments on our work.1 The key issue is whether or not total serum cholesterol (TSC) taken within 24 hours after a stroke reflects usual cholesterol levels. There are pros and cons. This is discussed in the article. It is important to note, however, that a correlation between stroke severity and an alteration in the lipid profile in the first few days after the stroke has …

Lene Odgaard,1 Ingrid Poulsen,2 Lars Peter Kammersgaard,2 Søren Paaske Johnsen,3 Jørgen Feldbæk Nielsen,1 1Hammel Neurorehabilitation Center and University Research Clinic, Aarhus University, Aarhus, Denmark; 2Department of Neurorehabilitation, TBI and Research Unit on Brain injury rehabilitation (RUBRIC), Glostrup Hospital, Copenhagen University, Copenhagen, Denmark; 3Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark Purpose: To identify all hospitalized patients surviving severe traumatic brain injury (TBI) in Denmark and to compare these patients to TBI patients admitted to highly specialized rehabilitation (HS-rehabilitation). Patients and methods: Patients surviving severe TBI were identified from The Danish National Patient Registry and The Danish Head Trauma Database. Overall incidence rates of surviving severe TBI and incidence rates of admission to HS-rehabilitation after severe TBI were estimated and compared. Patient-related predictors of no admission to HS-rehabilitation among patients surviving severe TBI were identified using multivariable logistic regression. Results: The average incidence rate of surviving severe TBI was 2.3 per 100,000 person years. Incidence rates of HS-rehabilitation were generally stable around 2.0 per 100,000 person years. Overall, 84% of all patients surviving severe TBI were admitted to HS-rehabilitation. Female sex, older age, and non-working status pre-injury were independent predictors of no HS-rehabilitation among patients surviving severe TBI. Conclusion: The incidence rate of hospitalized patients surviving severe TBI was stable in Denmark and the majority of the patients were admitted to HS-rehabilitation. However, potential inequity in access to HS-rehabilitation may still be present despite a health care system based on equal access for all citizens. Keywords: database, health care disparities, registries, validity&nbsp

Background: The treatment of cardiovascular risk factors has improved over the recent years and may have improved survival. The aim of this study was to investigate the up-to-date prognostic significance of cardiovascular risk factors for 5-year survival in a large unselected ischemic stroke population. Methods: We studied 905 ischemic stroke patients from the community-based Copenhagen Stroke Study. Patients had a CT scan and stroke severity was measured by the Scandinavian Stroke Scale on admission. A comprehensive evaluation was performed by a standardized medical examination and questionnaire for cardiovascular risk factors, age, and sex. Follow-up was performed 5 years after stroke, and data on mortality were obtained for all, except 6, who had left the country. Five-year mortality was calculated by the Kaplan-Meier procedure and the influence of multiple predictors was analyzed by Cox proportional hazards analyses adjusted for age, gender, stroke severity, and risk factor profile. Results: In Kaplan-Meier analyses atrial fibrillation (AF), ischemic heart disease, diabetes, and previous stroke were associated with increased mortality, while smoking and alcohol intake were associated with decreased mortality. No association was found for hypertension or intermittent claudication. In the final Cox proportional hazard model predictors of 5-year mortality were AF (hazard ratio, HR 1.4; 95% CI 1.1–1.7), diabetes (HR 1.3; 95% CI 1.0–1.6), smoking (HR 1.2; 95% CI 1.0–1.4), and previous stroke (HR 1.4; 95% CI 1.1–1.7), after adjustment for age, gender, and stroke severity. Conclusions: AF, diabetes, smoking, and previous stroke significantly affect long-term survival. Although smoking and daily alcohol consumption appeared to be associated with improved survival in the univariate analyses, adjustment for other factors and especially age revealed the lethal effect of smoking, while the positive effect of alcohol disappeared. More focus on secondary preventive measures, such as anticoagulation for AF, smoking cessation, and proper treatment of diabetes may significantly improve long-term survival.

Despite their proven efficacy in stroke prevention, warfarin and antiplatelets remain underused. We determined the frequency of ischemic strokes attributable to underuse of warfarin and antiplatelets for stroke prevention in a Danish community. We included all patients with ischemic stroke in a Copenhagen community with 302,000 inhabitants admitted to the hospital between September 1999 and May 2000 (n = 426). Patients who did not receive warfarin or antiplatelet medication even though they were at known risk for cardiovascular disease before the incident stroke were identified; they had known atrial fibrillation, prior myocardial infarction, angina, or prior stroke transient ischemic attack (TIA). Sufficient information on cardiovascular risk factors before stroke was available in 404 patients. A total of 54 patients had atrial fibrillation known before the stroke. Of these, 16 had not received warfarin or antiplatelets on admission, 27 had not received warfarin but had received antiplatelets, and 11 had received warfarin. Assuming that warfarin and antiplatelets reduces the risk of stroke by 66% and 25%, respectively, it was calculated that between 6 and 12 of these strokes with atrial fibrillation could have been prevented if warfarin or antiplatelets had been given before stroke. A total of 147 patients had known stroke/TIA and/or myocardial infarction/angina before stroke (41 patients had not received antiplatelets on admission). If antiplatelet therapy had been given before stroke, 10 of these strokes could have been prevented. Our findings indicate that underuse of warfarin and antiplatelets is still of considerable magnitude and attributable to 4% to 5% (16 to 22 out of 404) of the ischemic strokes in a Danish urban community.

Summary Experimental evidence and clinical experience show that hypothermia protects the brain from damage during ischaemia. There is a growing hope that the prevention of fever in stroke will improve outcome and that hypothermia may be a therapeutic option for the treatment of stroke. Body temperature is directly related to stroke severity and outcome, and fever after stroke is associated with substantial increases in morbidity and mortality. Normalisation of temperature in acute stroke by antipyretics is generally recommended, although there is no direct evidence to support this treatment. Despite its obvious therapeutic potential, hypothermia as a form of neuroprotection for stroke has been investigated in only a few very small studies. Therapeutic hypothermia is feasible in acute stroke but owing to serious side-effects— such as hypotension, cardiac arrhythmia, and pneumonia—it is still thought of as experimental, and evidence of efficacy from clinical trials is needed.

Early admission after stroke and TIA is important in modern stroke treatment. We studied the time delay to admission and explored predictive factors of early/late admission.The study was prospective and community-based comprising all patients with stroke or TIA admitted to a Copenhagen hospital from 1 September 1999 to 30 April 2000. The catchment area is well defined with 283,000 inhabitants. All had a neurological examination and a structured interview within three days with registration of age, gender, premorbid Rankin, Scandinavian stroke scale score, time of onset, knowledge of the cause of symptoms, cohabitation, alone at onset, whether admitted by a general practitioner (GP) or by ambulance after calling emergency, and relevant stroke risk factors. Univariate and multivariate statistics were used.Altogether 494 patients with stroke and 63 with TIA were entered; 49% were admitted by a GP, 38% by ambulance after calling emergency, 13% via other routes. Time from onset to hospital admission could be assessed reliably in 374 patients (67%) and was a median of 2.6 hours; 37% arrived within 0-3 hours, 55% within 0-6 hours. Patients calling an ambulance over emergency arrived at a median of 1.0 hour after the stroke; those calling the GP a median of 6.0 hours after the stroke. In a multivariate analysis only admission by ambulance after calling emergency (OR 5.7), TIA (OR 5.6), or the patient's knowledge of the cause of the symptoms (OR 2.2) were predictors of early admission.Patients with stroke or TIA in a Danish metropolitan area arrive at hospital a median of 2.6 hours after the stroke. Admission by ambulance after calling emergency was associated with the shortest onset to admission time.

At present it is possible to dissolve cerebral blood clots with thrombolysis. This is a standard treatment in the USA and Canada for early onset ischaemic strokes within three hours of the stroke. Acceptance of thrombolysis is based on a single clinical trial. However, three other clinical trials have cast doubt on the benefit of the treatment and it has not yet been approved in Denmark and other countries. We sought to investigate the possible impact of thrombolysis in an unselected Danish stroke population.This prospective study examined 502 unselected patients with acute stroke admitted over a period of eight months. The most important exclusion criteria from the North American trial with thrombolysis for acute ischaemic stroke were applied on the Danish cohort. The number of patients who might benefit from thrombolytic therapy was estimated from the North American trial, which reported a 32% relative increase in patients who would fully recover.Thirty-nine (8%) would be eligible for thrombolytic therapy. Thirteen patients (3%) would die, irrespective of treatment, and 11 patients (2%) would fully recover spontaneously. Three patients (0.6%) would benefit from thrombolytic therapy. In the ideal situation--all patients admitted in due time--11 patients (2.2%) would have benefited.Our study shows that few stroke patients would benefit from thrombolysis. The result is very well in line with the clinical experiences reported from the USA. Introduction of thrombolysis in Denmark to benefit the few would require extensive reorganisation of stroke care.

Infection is a frequent complication in the early course of acute stroke and may adversely affect stroke outcome. In the present study, we investigate early infection developing in patients within 3 days of admission to the hospital and its independent relation to recovery and stroke outcome. In addition, we identify predictors for early infections, infection subtypes, and their relation to initial stroke severity.In the community-based Copenhagen Stroke Study, 1,156 unselected patients were examined for early infection. Stroke severity was assessed with the Scandinavian Stroke Scale (SSS) on admission and at discharge. Multiple logistic and linear regression analyses were used to determine independent relations to early infection. Relevant stroke risk factors, admission stroke severity, and body temperature were included in the analysis.Of the subjects studied, 19.4% developed early infection. In women, 68% of the early infections were urinary tract infections, and in men, 49% of the early infections were pneumonias. Independent predictors of early infection were advanced age (OR per 10 years, 1.24; 95% CI, 1.02-1.64), female gender (OR, 2.0; 95% CI, 1.3-3.0), and decreased SSS score on admission (OR per 10 points, 0.69; 95% CI, 0.62-0.78). The presence of early infection prolonged hospital stay by a mean of 9.3 days (P.0001) but not death during hospital stay (P = .78), stroke severity at discharge (P = .32), or rate of discharge to nursing home (P = .17).Advanced age, female gender, and increased stroke severity independently predict development of early infection. The present study indicates that early infection does not influence outcome in acute stroke patients per se, but it delays patient discharge from the hospital.

Background and Purpose —Even patients with the most severe strokes sometimes experience a remarkably good recovery. We evaluated possible predictors of a good outcome to search for new therapeutic strategies. Methods —We included the 223 patients (19%) with the most severe strokes (Scandinavian Stroke Scale score Results —Decreasing age (odds ratio [OR], 0.50 per 10-year decrease; 95% CI, 0.25 to 0.99; P =0.04), a spouse (OR, 3.1; 95% CI, 1.1 to 8.8; P =0.03), decreasing body temperature on admission (OR, 1.8 per 1°C decrease; 95% CI, 1.1 to 3.1; P =0.01), and neurological recovery after 1 week (OR, 3.2 per 10-point increase in Scandinavian Stroke Scale score; 95% CI, 1.1 to 7.8; P =0.01) were all independent predictors of good functional outcome. Conclusions —Patients with the most severe strokes who achieve a good functional outcome are generally characterized by younger age, the presence of a spouse at home, and early neurological recovery. Body temperature was a strong predictor of good functional outcome and the only potentially modifiable factor. We suggest that a randomized controlled trial be undertaken to evaluate whether active reduction of body temperature can improve the generally poor prognosis of patients with the most severe strokes.

Alteplase (recombinant tissue plasminogen activator) can be used to dissolve blood clots and achieve reperfusion in some stroke patients. Three randomised controlled trials have studied its clinical effect.1–3 A US trial studied patients who were treated within three hours of onset of stroke and reported a 32% (95% confidence interval 1% to 70%) relative increase in the proportion of patients with full recovery but no effect on overall mortality.1 This led to approval of alteplase for stroke patients in the United States. A European trial of patients treated within six hours of stroke onset was negative,2 and a second trial, published recently, reported no significant positive effect.3 An application for European approval of alteplase treatment within three hours of stroke onset is being considered. Alteplase often leads to bleeding and should be given only by …

Background and Purpose —We have previously reported a marked reduction in mortality up to 1 year after treatment and rehabilitation on a stroke unit versus on general neurological and medical wards in unselected stroke patients. In the present study we wanted to test the hypothesis that this mortality-reducing effect is not temporary but is long lasting. Methods —We performed a community-based comparison of outcome in 1241 stroke patients from 2 adjacent communities in Copenhagen: in one (Frederiksberg), treatment and rehabilitation were provided on general neurological and medical wards, and in the other (Bispebjerg), treatment and rehabilitation were provided on a single large stroke unit. Results —The 2 stroke populations were comparable regarding age, sex, initial stroke severity, lesion diameter on CT, and stroke subtype (hemorrhage/infarct), but patients treated on the stroke unit had a higher frequency of comorbidity and lower incomes. One-year mortality was 39% (general wards) versus 32% (stroke unit) ( P =0.01). This difference was still present 5 years after stroke (71% versus 64%; P =0.02). In a multiple logistic regression model of 5-year mortality, treatment on a stroke unit reduced the relative risk of death by 40% (odds ratio, 0.60; 95% CI, 0.42 to 0.85; P Conclusions —The mortality-reducing effect of treatment and rehabilitation on a dedicated stroke unit is long lasting rather than temporary. Stroke unit treatment reduced the relative risk of death within 5 years after stroke by 40% in an unselected, community-based stroke population. These results emphasize the need for organization of treatment and rehabilitation of unselected stroke patients on dedicated stroke units.