Peak Edema Extension Distance: An Edema Measure Independent from Hematoma Volume Associated with Functional Outcome in Intracerebral Hemorrhage.

BACKGROUND: Our objective was to test the association between hematoma volume and long-term (> 72 h) edema extension distance (EED) evolution and the association between peak EED and early EED increase with functional outcome at 3 months in patients with intracerebral hemorrhage (ICH). METHODS: This retrospective cohort study included patients with spontaneous supratentorial ICH between January 2006 and January 2014. EED, an edema measure defined as the distance between the hematoma border and the outer edema border, was calculated by using absolute hematoma and edema volumes. We used multivariable logistic regression accounting for age, ICH volume, and location and receiver operating characteristic analysis for assessing measures associated with functional outcome and EED evolution. Functional outcome after 3 months was assessed by using the modified Rankin Scale (0-3 = favorable, 4-6 = unfavorable). To identify properties associated with peak EED multivariable linear and logistic regression analyses were conducted. RESULTS: A total of 292 patients were included. Median age was 70 years (interquartile range [IQR] 62-78), median ICH volume on admission 17.7 mL (IQR 7.9-40.2), median peak perihemorrhagic edema (PHE) volume was 37.5 mL (IQR 19.1-60.6), median peak EED was 0.67 cm (IQR 0.51-0.84) with an early EED increase up to 72 h (EED72-0) of 0.06 cm (- 0.02 to 0.15). Peak EED was found to be independent of ICH volume (R2 = 0.001, p = 0.6). In multivariable analyses, peak EED (odds ratio 0.224, 95% confidence interval [CI] [0.071-0.705]) and peak PHE volume (odds ratio 0.984 [95% CI 0.973-0.994]) were inversely associated with favorable functional outcome at 3 months. Receiver operating characteristic analysis identified a peak PHE volume of 26.8 mL (area under the curve 0.695 [95% CI 0.632-0.759]; p ≤ 0.001) and a peak EED of 0.58 cm (area under the curve 0.608 [95% CI 0.540-0.676]; p = 0.002) as best predictive values for outcome discrimination. CONCLUSIONS: Compared with absolute peak PHE volume, peak EED represents a promising edema measure in patients with ICH that is largely hematoma volume-independent and nevertheless associated with functional outcome.

Amantadine treatment is associated with improved consciousness in patients with non-traumatic brain injury.

OBJECTIVE: This study determined the effect of amantadine treatment on consciousness in patients with non-traumatic brain injury. METHODS: We pooled individual patient data of five single-centre observational studies to determine the effect of amantadine treatment among patients with ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, community-acquired bacterial meningitis and status epilepticus, admitted between January 2012 and December 2015 and ventilated ≥7 days. Patient selection and multivariable regression modelling were used to adjust for differences in intergroup comparison and for parameters associated with consciousness. Improvement of consciousness 5 days after treatment initiation was defined as primary outcome. Secondary outcomes included Glasgow Coma Scale (GCS) at day 5 and GCS at day 10, rate of ICU delirium, epileptic seizures and all-cause mortality at 90 days. RESULTS: Overall, 84 of 294 (28.6%) eligible patients received amantadine. Amantadine treatment was associated with improvement of consciousness at day 5 (amantadine: 86.9% vs control: 54.0%; absolute difference: 32.9 (20.0-44.2); adjusted OR (aOR): 5.71 (2.50-13.05), p<0.001). Secondary outcomes showed differences in GCS 5 days (9 (8-11) vs 6 (3-9), p<0.001) and GCS 10 days (10(8-11) vs 9(6-11),p=0.003) after treatment initiation. There were no significant differences regarding all-cause mortality (aOR: 0.89 (0.44-1.82), p=0.758) and ICU delirium (aOR: 1.39 (0.58-3.31), p=0.462). Rate of epileptic seizures after initiation of amantadine treatment was numerically higher in the amantadine group (amantadine: 10.7% vs control: 3.0%; absolute difference: 7.7 (0.3-16.4); aOR: 3.68 (0.86-15.71), p=0.079). CONCLUSIONS: Amantadine treatment is associated with improved consciousness among patients with different types of non-traumatic brain injury in this observational cohort analysis. Epileptic seizures should be considered as potential side effects and randomised controlled trials are needed to confirm these findings.

Neutrophil-to-lymphocyte ratio is associated with increased cerebral blood flow velocity in acute bacterial meningitis.

In community-acquired bacterial meningitis (CABM) intracranial vascular alterations are devastating complications which are triggered by neuroinflammation and result in worse clinical outcome. The Neutrophil-to-Lymphocyte ratio (NLR) represents a reliable parameter of the inflammatory response. In this study we analyzed the association between NLR and elevated cerebral blood flow velocity (CBFv) in CABM-patients. This study included all (CABM)-patients admitted to a German tertiary center between 2006 and 2016. Patients' demographics, in-hospital measures, neuroradiological data and clinical outcome were retrieved from institutional databases. CBFv was assessed by transcranial doppler (TCD). Patients', radiological and laboratory characteristics were compared between patients with/without elevated CBFv. Multivariate-analysis investigated parameters independently associated with elevated CBFv. Receiver operating characteristic(ROC-)curve analysis was undertaken to identify the best cut-off for NLR to discriminate between increased CBFv. 108 patients with CABM were identified. 27.8% (30/108) showed elevated CBFv. Patients with elevated CBFv and normal CBFv, respectively had a worse clinical status on admission (Glasgow Coma Scale: 12 [9-14] vs. 14 [11-15]; p = 0.005) and required more often intensive care (30/30 [100.0%] vs. 63/78 [80.8%]; p = 0.01).The causative pathogen was S. pneumoniae in 70%. Patients with elevated CBFv developed more often cerebrovascular complications with delayed cerebral ischemia (DCI) within hospital stay (p = 0.031). A significantly higher admission-NLR was observed in patients with elevated CBFv (median [IQR]: elevated CBFv:24.0 [20.4-30.2] vs. normal CBFv:13.5 [8.4-19.5]; p < 0.001). Multivariate analysis, revealed NLR to be significantly associated with increased CBFv (Odds ratio [95%CI] 1.042 [1.003-1.084]; p = 0.036). ROC-analysis identified a NLR of 20.9 as best cut-off value to discriminate between elevated CBFv (AUC = 0.713, p < 0.0001, Youden's Index = 0.441;elevated CBFv: NLR ≥ 20.9 19/30[63.5%] vs. normal CBFv: NLR > 20.9 15/78[19.2%]; p < 0.001). Intracranial vascular complications are common among CABM-patients and are a risk factor for unfavorable outcome at discharge. Elevated NLR is independently associated with high CBFv and may be useful in predicting patients' prognosis.

Automated Pupillometry Identifies Absence of Intracranial Pressure Elevation in Intracerebral Hemorrhage Patients.

INTRODUCTION: Although automated pupillometry is increasingly used in critical care settings, predictive value of automatically assessed pupillary parameters during different intracranial pressure (ICP) levels and possible clinical implications are unestablished. METHODS: This retrospective cohort study at the neurocritical care unit of the University of Erlangen-Nuremberg (2016-2018) included 23 nontraumatic supratentorial (intracerebral hemorrhage) ICH patients without signs of abnormal pupillary function by manual assessment, i.e., absent light reflex. We assessed ICP levels by an external ventricular drain simultaneously with parameters of pupillary reactivity [i.e., maximum and minimum apertures, light reflex latency (Lat), constriction and redilation velocities (CV, DV), and percentage change of apertures (per-change)] using a portable pupillometer (NeurOptics®). Computed tomography (CT) scans were analyzed to determine lesion location, size, intraventricular hemorrhage, hydrocephalus, midline shift, and compression or absence of the basal cisterns. We performed receiver operating characteristics analysis to investigate associations of ICP levels with pupillary parameters and to determine best cutoff values for prediction of ICP elevation. After dichotomization of assessments according to ICP values (normal: < 20 mmHg, elevated: ≥ 20 mmHg), prognostic performance of the determined cutoff parameters of pupillary function versus of CT-imaging findings was analyzed by calculating sensitivity, specificity, positive and negative predictive values (logistic regression, corresponding ORs with 95% CIs). RESULTS: In 23 patients (11 women, median age 59.0 (51.0-69.0) years), 1,934 assessments were available for analysis. A total of 74 ICP elevations ≥ 20 mmHg occurred in seven patients. Best discriminative thresholds for ICP elevation were: CV < 0.8 mm/s (AUC 0.740), per-change < 10% (AUC 0.743), DV < 0.2 mm/s (AUC 0.703), and Lat > 0.3 s (AUC 0.616). Positive predictive value of all four parameters to indicate ICP elevation ranged between 7.2 and 8.3% only and was similarly low for CT abnormalities (9.1%). We found high negative predictive values of pupillary parameters [CV: 99.2% (95% CI 98.3-99.6), per-change: 98.7% (95% CI 97.8-99.2), DV: 98.0% (95% CI 97.0-98.7), Lat: 97.0% (95% CI 96.0-97.7)], and CT abnormalities [99.7% (95% CI 99.2-99.9)], providing evidence that both techniques adequately identified ICH patients without ICP elevation. CONCLUSIONS: Our data suggest an association between noninvasively detected changes in pupillary reactivity and ICP levels in sedated ICH patients. Although automated pupillometry and neuroimaging seem not sufficient to noninvasively indicate ICP elevation, both techniques, however, adequately identified ICH patients without ICP elevation. This finding may facilitate routine management by saving invasive ICP monitoring or repeated CT controls in patients with specific automated pupillometry readings.

Management of Stroke in Patients with Left Ventricular Assist Devices.

INTRODUCTION: The number of patients with left ventricular assist devices (LVAD) is rapidly growing in industrialized countries. While cerebrovascular events comprise a significant complication, data on stroke etiology, clinical management and functional outcome are scarce. METHODS: Consecutive LVAD patients with ischemic or hemorrhagic stroke receiving treatment at an university stroke center between 2010 and 2018 were included into an institutional registry. Clinical characteristics, causes, management and functional outcome of stroke occurring within this cohort are reported. Acceptable functional outcome was defined as mRS 0-3. RESULTS: N = 30 acute strokes occurred in 20 patients (77% ischemic, 23% hemorrhagic, mean age 57 ± 13 years, 10% female, 8 patients (40%) had more than one event). 87% of all events happened with non-pulsatile devices, on average 9 (IQR 3-22) months after the implantation. All patients used oral anticoagulation with a Vitamin-K antagonist in combination with anti-platelets. The international normalized ratio (INR)-values were outside the therapeutic range in 39% of ischemic strokes and in 57% of hemorrhagic strokes. Ischemic strokes were predominantly of cardioembolic origin (92%) and of mild to moderate clinical severity (median NIHSS 6 (IQR 4-10). None qualified to receive intravenous thrombolysis or intra-arterial endovascular therapy. 61% of IS-patients showed an acceptable functional outcome after three months. 4/7 patients with hemorrhagic stroke received immediate reversal of anticoagulation without any thrombotic complications. CONCLUSION: The majority of LVAD patients with ischemic stroke had an acceptable functional outcome after three months. Future clinical research is warranted to improve therapeutic strategies for acute care and stroke prevention.

Increased Neutrophil-to-Lymphocyte Ratio is Associated with Unfavorable Functional Outcome in Acute Ischemic Stroke.

BACKGROUND: Inflammatory response is the hallmark of secondary brain injury in stroke patients. Neutrophil-to-lymphocyte ratio (NLR) emerged as a marker for functional outcome in several diseases. OBJECTIVES: To investigate the association between NLR on admission and during hospital stay and functional outcome in acute ischemic stroke (AIS). METHODS: This observational study included all consecutive AIS patients admitted at a German stroke center covering 2011-2013. Patient characteristics and clinical data were retrieved from institutional databases. Multivariate analysis was conducted to investigate parameters associated with functional outcome. Receiver operating characteristic (ROC) analysis was performed to identify the best cutoff for NLR to discriminate between favorable and unfavorable functional outcome. To account for imbalances in baseline characteristics, propensity score matching was carried out to assess the influence of NLR on functional outcome. RESULTS: A total of 807 patients with AIS were included for analysis. Patients with worse functional outcome at 3 months were older and had worse clinical status on admission, higher rates of infectious complications, and an increased NLR. ROC analysis identified a NLR of 3.3 as best cutoff value to discriminate between favorable and unfavorable functional outcomes (area under the curve 0.693, p < 0.001, Youden's index = 0.318; p < 0.001; sensitivity 68.5%, specificity 63.9%). Propensity-matched analysis still demonstrated a higher rate of unfavorable functional outcome at 3 months in patients with NLR ≥ 3.3 [modified Rankin scale 3-6 at 3 months: NLR ≥ 3.3 51.5% vs. NLR < 3.3 36.4%; p = 0.002]. CONCLUSIONS: In AIS patients we identified NLR as an important predictor for unfavorable functional outcome.

Influence of the Extent of Intraventricular Hemorrhage on Functional Outcome and Mortality in Intracerebral Hemorrhage.

BACKGROUND AND OBJECTIVE: Intraventricular hemorrhage (IVH) is a verified independent prognostic parameter in patients with intracerebral hemorrhage (ICH). However, the impact of the extent of IVH on clinical outcomes is unestablished. METHODS: We analyzed 1,112 consecutive primary ICH patients of the UKER-ICH cohort (NCT03183167) and hypothesized that there is no difference in outcome between patients without IVH and patients with minor IVH not leading to obstructive hydrocephalus. Propensity score matching and multivariable analyses were performed to account for imbalances in baseline characteristics. Primary outcome was defined as functional outcome 3 months after ICH -assessed using the modified Rankin Scale (mRS) dichotomized into favorable (mRS = 0-3) and unfavorable outcome (mRS = 4-6). Secondary outcomes included mortality at 3  months and a Graeb score-based threshold analysis for association of the extent of IVH with unfavorable clinical outcome. RESULTS: Among the 461 out of 1,112 (41.5%) ICH patients with IVH, 191 out of 461 (41.4%) showed IVH without obstructive hydrocephalus and no requirement of external ventricular drain (EVD) placement. After adjusting for baseline imbalances we found no difference in functional outcome at 3 months between patients without IVH (No-IVH) and patients with IVH not requiring EVD (IVH-w/o-EVD): mRS 0-3: No-IVH 64/161 (39.8%) vs. IVH-w/o-EVD 53/170 (31.2%); p = 0.103. However, there was a trend toward a higher mortality in IVH-w/o-EVD patients (mRS 6: No IVH 40/161 [24.8%] vs. IVH-w/o-EVD 57/170 [33.5%]; p = 0.083). Multivariable analysis revealed that a Graeb score >2 was independently associated with unfavorable outcome (mRS 4-6: OR 3.16 [1.54-6.48]; p = 0.002), and higher mortality (mRS 6: OR 2.57 [1.40-4.74]; p = 0.002) in IVH patients. CONCLUSIONS: Small amounts of intraventricular blood (Graeb score ≤2) not leading to obstructive hydrocephalus are not associated with unfavorable outcome or death after ICH. Thus, IVH per se should not be considered a binary variable in outcome prediction for ICH patients.

Neutrophil-to-lymphocyte ratio as an independent predictor for unfavorable functional outcome in aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Stroke-associated immunosuppression and inflammation are increasingly recognized as factors triggering infections and thus potentially influencing outcome after stroke. Several studies have demonstrated that elevated neutrophil-to-lymphocyte ratio (NLR) is a significant predictor of adverse outcomes for patients with ischemic stroke or intracerebral hemorrhage. Thus far, in patients with subarachnoid hemorrhage the association between NLR and outcome is insufficiently established. The authors sought to investigate the association between NLR on admission and functional outcome in aneurysmal subarachnoid hemorrhage (aSAH). METHODS: This observational study included all consecutive aSAH patients admitted to a German tertiary center over a 5-year period (2008-2012). Data regarding patient demographics and clinical, laboratory, and in-hospital measures, as well as neuroradiological data, were retrieved from institutional databases. Functional outcome was assessed at 3 and 12 months using the modified Rankin Scale (mRS) score and categorized into favorable (mRS score 0-2) and unfavorable (mRS score 3-6). Patients' radiological and laboratory characteristics were compared between aSAH patients with favorable and those with unfavorable outcome at 3 months. In addition, multivariate analysis was conducted to investigate parameters independently associated with favorable outcome. Receiver operating characteristic (ROC) curve analysis was undertaken to identify the best cutoff for NLR to discriminate between favorable and unfavorable outcome in these patients. To account for imbalances in baseline characteristics, propensity score matching was carried out to assess the influence of NLR on outcome measures. RESULTS: Overall, 319 patients with aSAH were included. Patients with unfavorable outcome at 3 months were older, had worse clinical status on admission (Glasgow Coma Scale score and Hunt and Hess grade), greater amount of subarachnoidal and intraventricular hemorrhage (modified Fisher Scale grade and Graeb score), and higher rates of infectious complications (pneumonia and sepsis). A significantly higher NLR on admission was observed in patients with unfavorable outcome according to mRS score (median [IQR] NLR 5.8 [3.0-10.0] for mRS score 0-2 vs NLR 8.3 [4.5-12.6] for mRS score 3-6; p < 0.001). After adjustments, NLR on admission remained a significant predictor for unfavorable outcome in SAH patients (OR [95% CI] 1.014 [1.001-1.027]; p = 0.028). In ROC analysis, an NLR of 7.05 was identified as the best cutoff value to discriminate between favorable and unfavorable outcome (area under the curve = 0.614, p < 0.001, Youden's index = 0.211; mRS score 3-6: 94/153 [61.4%] for NLR ≥ 7.05 vs 67/166 [40.4%] for NLR < 7.05; p < 0.001). Subanalysis of patients with NLR levels ≥ 7.05 vs < 7.05, performed using 2 propensity score-matched cohorts (n = 133 patients in each group), revealed an increased proportion of patients with unfavorable functional outcome at 3 months in patients with NLR ≥ 7.05 (mRS score 3-6 at 3 months: NLR ≥ 7.05 82/133 [61.7%] vs NLR < 7.05 62/133 [46.6%]; p = 0.014), yet without differences in mortality at 3 months (NLR ≥ 7.05 37/133 [27.8%] vs NLR < 7.05 27/133 [20.3%]; p = 0.131). CONCLUSIONS: Among aSAH patients, NLR represents an independent parameter associated with unfavorable functional outcome. Whether the impact of NLR on functional outcome is related to preexisting comorbidities or represents independent causal relationships in the context of stroke-associated immunosuppression should be investigated in future studies.

Impact of timing of continuous intravenous anesthetic drug treatment on outcome in refractory status epilepticus.

BACKGROUND: Patients in refractory status epilepticus (RSE) may require treatment with continuous intravenous anesthetic drugs (cIVADs) for seizure control. The use of cIVADs, however, was recently associated with poor outcome in status epilepticus (SE), raising the question of whether cIVAD therapy should be delayed for attempts to halt seizures with repeated non-anesthetic antiepileptic drugs. In this study, we aimed to determine the impact of differences in therapeutic approaches on RSE outcome using timing of cIVAD therapy as a surrogate for treatment aggressiveness. METHODS: This was a retrospective cohort study over 14 years (n = 77) comparing patients with RSE treated with cIVADs within and after 48 h after RSE onset, and functional status at last follow-up was the primary outcome (good = return to premorbid baseline or modified Rankin Scale score of less than 3). Secondary outcomes included discharge functional status, in-hospital mortality, RSE termination, induction of burst suppression, use of thiopental, duration of RSE after initiation of cIVADs, duration of mechanical ventilation, and occurrence of super-refractory SE. Analysis was performed on the total cohort and on subgroups defined by RSE severity according to the Status Epilepticus Severity Score (STESS) and by the variables contained therein. RESULTS: Fifty-three (68.8%) patients received cIVADs within the first 48 h. Early cIVAD treatment was independently associated with good outcome (adjusted risk ratio [aRR] 3.175, 95% confidence interval [CI] 1.273-7.918; P = 0.013) as well as lower chance of both induction of burst suppression (aRR 0.661, 95% CI 0.507-0.861; P = 0.002) and use of thiopental (aRR 0.446, 95% CI 0.205-0.874; P = 0.043). RSE duration after cIVAD initiation was shorter in the early cIVAD cohort (hazard ratio 1.796, 95% CI 1.047-3.081; P = 0.033). Timing of cIVAD use did not impact the remaining secondary outcomes. Subgroup analysis revealed early cIVAD impact on the primary outcome to be driven by patients with STESS of less than 3. CONCLUSIONS: Patients with RSE treated with cIVADs may benefit from early initiation of such therapy.

Initiating anticoagulant therapy after ICH is associated with patient characteristics and treatment recommendations.

BACKGROUND: The proportion of patients with intracerebral hemorrhage (ICH) and concomitant indication for oral anticoagulant (OAC) therapy is increasing. Although recent studies documented a favorable risk-benefit profile of OAC initiation, deciding whether, when, and which OAC should be started remains controversial. We investigated (1) OAC recommendations, its implementation, and adherence and (2) factors associated with OAC initiation after ICH. METHODS: This prospective observational study analyzed consecutive ICH patients (n = 246) treated at the neurological and neurosurgical department of the University-Hospital Erlangen, Germany over a 21-month inclusion period (05/2013-01/2015). We analyzed the influence of patient characteristics, in-hospital measures, and functional status on treatment recommendations and on OAC initiation during 12-month follow-up. RESULTS: In-hospital mortality of 24.8% (n = 61/246) left 185 patients discharged alive of which 34.1% (n = 63/185) had OAC indication. In these patients, OAC initiation was clearly recommended in only 49.2% (n = 31/63) and associated with favorable [modified Rankin Scale (mRS) = 0-3] functional discharge status [OR 7.18, CI (1.05-49.13), p = 0.04], less frequent heart failure [OR 0.19, CI (0.05-0.71), p = 0.01], and younger age [OR 0.95, CI (0.90-1.00), p = 0.05]. OAC was more often started if clearly recommended [n = 19/31 (61.3%) versus (no recommendation) n = 4/26 (15.4%), p < 0.001; (clearly not recommended, n = 6)] and associated with younger age [67 (58-74) versus 79 (73-83), p < 0.001], favorable functional outcome [n = 10/23 (43.5%) versus n = 5/40 (12.5%), p = 0.01], decreased mortality [n = 6/23 (26.1%) versus n = 19/40 (47.5%), p = 0.06], and functional improvement [n = 13/17 (76.5%) versus n = 7/21 (33.3%), p = 0.01]. We observed no differences in rates of intracranial complications [thromboembolism, n = 3/23 (13.0%) versus n = 4/40 (10.0%), p = 1.00; hemorrhage, n = 1/23 (4.3%) versus n = 3/40 (7.5%), p = 1.00]. CONCLUSIONS: Clear treatment recommendations by attending stroke physicians significantly influence OAC initiation after ICH. OAC were more frequently recommended and started in younger patients with better functional recovery independent from intracranial complications. This might represent an important determinant of observed beneficial associations, hinting towards an indication bias which might affect observational analyses.

Peak perihemorrhagic edema correlates with functional outcome in intracerebral hemorrhage.

OBJECTIVE: To evaluate the association of perihemorrhagic edema (PHE) evolution and peak edema extent with day 90 functional outcome in patients with intracerebral hemorrhage (ICH) and identify pathophysiologic factors influencing edema evolution. METHODS: This retrospective cohort study included patients with spontaneous supratentorial ICH between January 2006 and January 2014. ICH and PHE volumes were studied using a validated semiautomatic volumetric algorithm. Multivariable logistic regression and propensity score matching (PSM) accounting for age, ICH volume, and location were used for assessing measures associated with functional outcome and PHE evolution. Clinical outcome on day 90 was assessed using the modified Rankin Scale (0-3 = favorable, 4-6 = poor). RESULTS: A total of 292 patients were included. Median age was 70 years (interquartile range [IQR] 62-78), median ICH volume on admission 17.7 mL (IQR 7.9-40.2). Besides established factors for functional outcome, i.e., ICH volume and location, age, intraventricular hemorrhage, and NIH Stroke Scale score on admission, multivariable logistic regression revealed peak PHE volume (odds ratio [OR] 0.984 [95% confidence interval (CI) 0.973-0.994]) as an independent predictor of day 90 outcome. Peak PHE volume was independently associated with initial PHE increase up to day 3 (OR 1.060 [95% CI 1.018-1.103]) and neutrophil to lymphocyte ratio on day 6 (OR 1.236 [95% CI 1.034-1.477; PSM cohort, n = 124]). Initial PHE increase (PSM cohort, n = 224) was independently related to hematoma expansion (OR 3.647 [95% CI 1.533-8.679]) and fever burden on days 2-3 (OR 1.456 [95% CI 1.103-1.920]). CONCLUSION: Our findings suggest that peak PHE volume represents an independent predictor of functional outcome after ICH. Inflammatory processes and hematoma expansion seem to be involved in PHE evolution and may represent important treatment targets.

Influence of Prior Nicotine and Alcohol Use on Functional Outcome in Patients after Intracerebral Hemorrhage.

BACKGROUND: The influence of prior nicotine or alcohol use (legal drug use [LDU]) on outcome measures after intracerebral hemorrhage (ICH) is insufficiently established. We investigated drug-specific associations with (1) neuroradiologic and clinical parameters and (2) functional long-term outcome after ICH. METHODS: This observational cohort study analyzed consecutive spontaneous patients with ICH (n = 554) from our prospective institutional registry over a 5-year study period (January 2010 to December 2014). We compared no-LDU patients with LDU patients, and patients using only nicotine, only alcohol, or both. To account for baseline imbalances, we reanalyzed cohorts after propensity score matching. RESULTS: Prevalence of prior LDU was 197 of 554 (35.6%), comprising 94 of 554 (17.0%) with only nicotine use, 33 of 554 (6.0%) with only alcohol use, and 70 of 554 (12.6%) with alcohol and nicotine use. LDU patients were younger (65 [56-73] versus 75 [67-82], P <.01), less often female (n = 61 of 197 [31.0%] versus n = 188 of 357 [52.7%], P <.01), had more often prior myocardial infarction (n = 29 of 197 [14.7%] versus n = 24 of 357 [6.7%], P <.01), and in-hospital complications (sepsis or systemic inflammatory response syndrome: n = 95 of 197 [48.2%] versus n = 98 of 357 [27.5%], P <.01; pneumonia: n = 89 of 197 [45.2%] versus n = 110 of 357 [30.8%], P <.01). Except for an increased risk of pneumonia (odds ratio 2.22, confidence interval [1.04-4.75], P = .04) in patients using both nicotine and alcohol, we detected no significant differences upon reanalysis after propensity score matching of neuroradiologic or clinical parameters, complications, or long-term outcome between patients with and without LDU (mortality: n = 48 of 150 [32.0%] versus n = 45 of 150 [30.0%], P = .71; favorable outcome [modified Rankin Scale 0-3]: n = 56 of 150 [37.3%] versus n = 53 of 150 [35.3%], P = .72). CONCLUSIONS: Prior nicotine use, alcohol use, and their combination were associated with significant differences in baseline characteristics. However, adjusting for unevenly balanced baseline parameters revealed no differences in functional long-term outcome after ICH.

Factors associated with occurrence and outcome of super-refractory status epilepticus.

PURPOSE: Super-refractory status epilepticus (SRSE) represents a challenging medical condition with high morbidity and mortality. In this study, we aimed to establish variables related to SRSE development and outcome. METHODS: We retrospectively screened our databases for refractory SE (RSE) and SRSE episodes between January 2001 and January 2015. Baseline demographics, SE characteristics, and variables reflecting the clinical course were compared in order to identify factors independently associated with SRSE occurrence. Within the SRSE cohort, predictors of in-hospital mortality as well as good functional outcome in survivors to discharge were established through univariate and multivariable analyses. RESULTS: A total of 131 episodes were included, among those 46 (35.1%) meeting the criteria of SRSE. Comparison of RSE and SRSE episodes revealed a lower premorbid mRS score (odds ratio (OR) per mRS point, 0.769; p=0.039) and non-convulsive SE (NCSE) in coma (OR, 4.216; p=0.008) as independent predictors of SRSE. SRSE in-hospital mortality was associated with age (OR, 1.091 per increasing year; p=0.020) and worse premorbid functional status (OR, 1.938 per mRS point; p=0.044). Good functional outcome in survivors was independently related to shorter SRSE duration (OR, 0.714 per day; p=0.038). CONCLUSION: Better premorbid functional status and NCSE in coma as worst seizure type indicate a role of acute underlying etiologies in the development of SRSE. In-hospital mortality in SRSE is determined by nonmodifiable factors, while functional outcome in survivors depends on seizure duration underscoring the need of achieving rapid seizure termination.

Presence of Concomitant Systemic Cancer is Not Associated with Worse Functional Long-Term Outcome in Patients with Intracerebral Hemorrhage.

BACKGROUND: Data on clinical characteristics and outcome of patients with intracerebral hemorrhage (ICH) and concomitant systemic cancer disease are very limited. METHODS: Nine hundred and seventy three consecutive primary ICH patients were analyzed using our prospective institutional registry over a period of 9 years (2006-2014). We compared clinical and radiological parameters as well as outcome - scored using the modified Rankin Scale (mRS) and analyzed in a dichotomized fashion as favorable outcome (mRS = 0-3) and unfavorable outcome (mRS = 4-6) - of ICH patients with and without cancer. Relevant imbalances in baseline clinical and radiological characteristics were adjusted using propensity score (PS) matching. RESULTS: Prevalence of systemic cancer among patients with ICH was 8.5% (83/973). ICH patients with cancer were older (77 [70-82] vs. 72 [63-80] years; p = 0.002), had more often prior renal dysfunction (19/83 [22.9%] vs.107/890 [12.0%]; p = 0.005), and smaller hemorrhage volumes (10.1 [4.8-24.3] vs. 15.3 [5.4-42.9] mL; p = 0.017). After PS-matching there were no significant differences neither in mortality nor in functional outcome both at 3 months (mortality: 33/81 [40.7%] vs. 55/158 [34.8%]; p = 0.368; mRS = 0-3: 28/81 [34.6%] vs. 52/158 [32.9%]; p = 0.797) and 12 months (mortality: 39/78 [50.0%] vs. 70/150 [46.7%]; p = 0.633; mRS = 0-3: 25/78 [32.1%] vs. 53/150 [35.3%]; p = 0.620) among patients with and without concomitant systemic cancer. ICH volume tended to be highest in patients with hematooncologic malignancy and smallest in urothelial cancer. CONCLUSIONS: Patients with ICH and concomitant systemic cancer on average are older; however, they show smaller ICH volumes compared to patients without cancer. Yet, mortality and functional outcome is not different in ICH patients with and without cancer. Thus, the clinical history or the de novo diagnosis of concomitant malignancies in ICH patients should not lead to unjustified treatment restrictions.

Neutrophil-to-Lymphocyte Ratio Is an Independent Predictor for In-Hospital Mortality in Spontaneous Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Stroke-associated immunosuppression and inflammation are increasingly recognized as factors that trigger infections and thus, potentially influence the outcome after stroke. Several studies demonstrated that elevated neutrophil-to-lymphocyte ratio (NLR) is a significant predictor of adverse outcomes in patients with ischemic stroke. However, little is known about the impact of NLR on short-term mortality in intracerebral hemorrhage (ICH). METHODS: This observational study included 855 consecutive ICH-patients. Patient demographics, clinical, laboratory, and in-hospital measures as well as neuroradiological data were retrieved from institutional databases. Functional 3-months-outcome was assessed and categorized as favorable (modified Rankin Scale [mRS] 0-3) and unfavorable (mRS 4-6). We (i) studied the natural course of NLR in ICH, (ii) analyzed parameters associated with NLR on admission (NLROA), and (iii) evaluated the clinical impact of NLR on mortality and functional outcome. RESULTS: The median NLROA of the entire cohort was 4.66 and it remained stable during the entire hospital stay. Patients with NLR ≥4.66 showed significant associations with poorer neurological status (National Institute of Health Stroke Scale [NIHSS] 18 [9-32] vs. 10 [4-21]; p < 0.001), larger hematoma volume on admission (17.6 [6.9-47.7] vs. 10.6 [3.8-31.7] mL; p = 0.001), and more frequently unfavorable outcome (mRS 4-6 at 3 months: 317/427 [74.2%] vs. 275/428 [64.3%]; p = 0.002). Patients with an NLR under the 25th percentile (NLR <2.606) - compared to patients with NLR >2.606 - presented with a better clinical status (NIHSS 12 [5-21] vs. 15 [6-28]; p = 0.005), lower hematoma volumes on admission (10.6 [3.6-30.1] vs. 15.1 [5.7-42.3] mL; p = 0.004) and showed a better functional outcome (3 months mRS 0-3: 82/214 [38.3%] vs. 185/641 [28.9%]; p = 0.009). Patients associated with high NLR (≥8.508 = above 75th-percentile) showed the worst neurological status on admission (NIHSS 21 [12-32] vs. 12 [5-23]; p < 0.001), larger hematoma volumes (21.0 [8.6-48.8] vs. 12.2 [4.1-34.9] mL; p < 0.001), and higher proportions of unfavorable functional outcome at 3 months (mRS 4-6: 173/214 vs. 418/641; p < 0.001). Further, NLR was linked to more frequently occurring infectious complications (pneumonia 107/214 vs. 240/641; p = 0.001, sepsis: 78/214 vs. 116/641; p < 0.001), and increased c-reactive-protein levels on admission (p < 0.001; R2 = 0.064). Adjusting for the above-mentioned baseline confounders, multivariable logistic analyses revealed independent associations of NLROA with in-hospital mortality (OR 0.967, 95% CI 0.939-0.997; p = 0.029). CONCLUSIONS: NLR represents an independent parameter associated with increased mortality in ICH patients. Stroke physicians should focus intensely on patients with increased NLR, as these patients appear to represent a population at risk for infectious complications and increased short-mortality. Whether these patients with elevated NLR may benefit from a close monitoring and specially designed therapies should be investigated in future studies.

Ischaemic stroke and Clostridium septicum sepsis and meningitis in a patient with occult colon carcinoma - a case report and review of the literature.

BACKGROUND: Clostridium septicum is a rare cause of meningitis and brain abscess in children and adults. Gas production by the pathogen can lead to pneumocephalus and the overall mortality rate of Clostridium septicum CNS infection is as high as 74%. The most common entry site of the pathogen is the gastrointestinal tract. CASE PRESENTATION: We describe a 74-year-old man who presented with a left-sided cerebral infarction in the middle cerebral artery territory. In addition the patient showed signs of Systemic Inflammatory Response Syndrome and Disseminated Intravascular Coagulation. Examination of blood cultures and cerebrospinal fluid led to the diagnosis of sepsis and meningitis caused by Clostridium septicum. Despite appropriate antibiotic therapy the condition of the patient deteriorated rapidly and he died on day 2 after admission. Autopsy revealed a previously unknown adenocarcinoma of the colon ascendens as entry site of the pathogen. CONCLUSION: Clostridium septicum should be considered as potential pathogen in patients with sepsis and meningitis. Gram stain morphology in conjunction with severe sepsis can rapidly point into the direction of this pathogen. CNS infections manifest either as meningoencephalitis/cerebritis or as brain abscess. Entry site of the pathogen is almost uniquely the gastrointestinal tract. In adults more than 50% suffer from colorectal carcinoma, therefore survivors of Clostridium septicum infections should be examined for underlying occult colorectal malignancy.

Lymphocytopenia Is an Independent Predictor of Unfavorable Functional Outcome in Spontaneous Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Stroke-associated immunosuppression is an increasingly recognized factor triggering infections and thus potentially influencing outcome after stroke. Specifically, lymphocytopenia after intracerebral hemorrhage (ICH) has only been addressed in small-sized retrospective studies of mixed intracranial bleedings. This cohort study investigated the natural course of lymphocytopenia, parameters associated with lymphocytopenia on admission (LOA) and during stay, and evaluated the clinical impact of lymphocytopenia in solely ICH patients. METHODS: This observational study included 855 consecutive patients with ICH. Patient demographics, clinical and neuroradiological data as well as laboratory and in-hospital measures were retrieved from institutional prospective databases. Functional 3-month outcome was assessed by mailed questionnaires. Lymphocytopenia was defined as <1.0 (10(9)/L) and was correlated with patient's characteristics and outcome. RESULTS: Prevalence of LOA was 27.3%. Patients with LOA showed significant associations with poorer neurological status (18 [10-32] versus 13 [5-24]; P<0.001), larger hematoma volume (18.5 [6.2-46.2] versus 12.8 [4.4-37.8]; P=0.006), and unfavorable outcome (74.7% versus 63.3%; P=0.0018). Natural course of lymphocyte count during hospital stay revealed a lymphocyte nadir of 1.1 (0.80-1.53 [10(9)/L]) at day 5. Focusing on patients with day-5-lymphocytopenia, compared with patients with LOA, revealed increased rates of infections (63 [71.6] versus 113 [48.5]; P<0.001) and poorer functional outcome at 3 months (76 [86.4] versus 175 [75.1); P=0.029). Adjusting for baseline confounders, multivariable logistic and receiver operating characteristics analyses documented independent associations of day-5-lymphocytopenia with unfavorable outcome (day-5-lymphocytopenia: odds ratio, 2.017 [95% confidence interval, 1.029-3.955], P=0.041; LOA: odds ratio, 1.391 [0.795-2.432], P=0.248; receiver operating characteristics: day-5-lymphocytopenia: area under the curve=0.673, P<0.0001, Youden's index=0.290; LOA: area under the curve=0.513, P=0.676, Youden's index=0.084), whereas receiver operating characteristics analyses revealed no association of age or hematoma volume with day-5-lymphocytopenia (age: area under the curve=0.540, P=0.198, Youden's index=0.106; volume: area under the curve=0.550, P=0.0898, Youden's index=0.1224). CONCLUSIONS: Lymphocytopenia is frequently present in patients with ICH and may represent an independent parameter associated with unfavorable functional outcome. Developing lymphocytopenia affected outcome even stronger than LOA, a finding that may open up new therapeutic avenues in specific subsets of patients with ICH.

Characterization of the betaherpesviral pUL69 protein family reveals binding of the cellular mRNA export factor UAP56 as a prerequisite for stimulation of nuclear mRNA export and for efficient viral replication.

UL69 of human cytomegalovirus (HCMV) encodes a pleiotropic transactivator protein and has a counterpart in every member of the Herpesviridae family thus far sequenced. However, little is known about the conservation of the functions of the nuclear phosphoprotein pUL69 in the homologous proteins of other betaherpesviruses. Therefore, eukaryotic expression vectors were constructed for pC69 of chimpanzee cytomegalovirus, pRh69 of rhesus cytomegalovirus, pM69 of murine cytomegalovirus, pU42 of human herpesvirus 6, and pU42 of elephant endotheliotropic herpesvirus. Indirect immunofluorescence experiments showed that all pUL69 homologs expressed by these vectors were localized to the cell nucleus. Coimmunoprecipitation experiments identified homodimerization as a conserved feature of all homologs, whereas heterodimerization with pUL69 was restricted to its closer relatives. Further analyses demonstrated that pC69 and pRh69 were the only two homologs that functioned, like pUL69, as viral-mRNA export factors. As we had reported recently that nucleocytoplasmic shuttling and interaction with the cellular DExD/H-box helicases UAP56 and URH49 were prerequisites for the nuclear-mRNA export activity of pUL69, the homologs were characterized with regard to these properties. Heterokaryon assays demonstrated nucleocytoplasmic shuttling for all homologs, and coimmunoprecipitation and mRNA export assays revealed that the interaction of UAP56 and/or URH49 with pC69 or pRh69 was required for mRNA export activity. Moreover, characterization of HCMV recombinants harboring mutations within the N-terminal sequence of pUL69 revealed a strong replication defect of viruses expressing pUL69 variants that were deficient in UAP56 binding. In summary, homodimerization and nucleocytoplasmic shuttling activity were identified as conserved features of betaherpesviral pUL69 homologs. UAP56 binding was shown to represent a unique characteristic of members of the genus Cytomegalovirus that is required for efficient replication of HCMV.