Efficacy and safety of combined intraventricular fibrinolysis with lumbar drainage for prevention of permanent shunt dependency after intracerebral hemorrhage with severe ventricular involvement: A randomized trial and individual patient data meta-analysis.

OBJECTIVE: Intraventricular hemorrhage (IVH) is a negative prognostic factor in intracerebral hemorrhage (ICH) and is associated with permanent shunt dependency in a substantial proportion of patients post-ICH. IVH treatment by intraventricular fibrinolysis (IVF) was recently linked to reduced mortality rates in the CLEAR III study and IVF represents a safe and effective strategy to hasten clot resolution that may reduce shunt rates. Additionally, promising results from observational studies reported reductions in shunt dependency for a combined treatment approach of IVF plus lumbar drains (LDs). The present randomized, controlled trial investigated efficacy and safety of a combined strategy-IVF plus LD versus IVF alone-on shunt dependency in patients with ICH and severe IVH. METHODS: This randomized, open-label, parallel-group study included patients aged 18 to 85 years, prehospital modified Rankin Scale ≤3, ICH volume < 60ml, Glasgow Coma Scale of <9, and severe IVH with tamponade of the third and fourth ventricles requiring placement of external ventricular drainage (EVD). Over a 3-year recruitment period, patients were allocated to either standard treatment (control group receiving IVF consisting of 1mg of recombinant human tissue plasminogen activator every 8 hours until clot clearance of third and fourth ventricles) or a combined treatment approach of IVF and-upon clot clearance of third and fourth ventricles-subsequent placement of an LD for drainage of cerebrospinal fluid (CSF; intervention group). The primary endpoint consisted of permanent shunt placement indicated after a total of three unsuccessful EVD clamping attempts or need for CSF drainage longer than 14 days in both groups. Secondary endpoints included IVF- and LD-related safety, such as bleeding or infections, and functional outcome at 90 and 180 days. Conducted endpoint analyses used individual patient data meta-analyses. The study was registered at clinicaltrials.gov (NCT01041950). RESULTS: The trial was stopped upon predefined interim analysis after 30 patients because of significant efficacy of tested intervention. The primary endpoint was analyzed without dropouts and was reached in 43% (7 of 16) of the control group versus 0% (0 of 14) of the intervention group (p = 0.007). Meta-analyses were based on overall 97 patients, 45 patients receiving IVF plus LD versus 42 with IVF only. Meta-analyses on shunt dependency showed an absolute risk reduction of 24% for the intervention (LD, 2.2% [1 of 45] vs no-LD, 26.2% [11 of 42]; odds ratio [OR] = 0.062; confidence interval [CI], 0.011-0.361; p = 0.002). Secondary endpoints did not show significant differences for CSF infections (OR = 0.869;CI, 0.445-1.695; p = 0.680) and functional outcome at 90 days (OR = 0.478; CI, 0.190-1.201; p = 0.116), yet bleeding complications were significantly reduced in favor of the intervention (OR = 0.401; CI, 0.302-0.532; p < 0.001). INTERPRETATION: The present trial and individual patient data meta-analyses provide evidence that, in patients with severe IVH, as compared to IVF alone, a combined approach of IVF plus LD treatment is feasible and safe and significantly reduces rates of permanent shunt dependency for aresorptive hydrocephalus post-ICH. ANN NEUROL 2017;81:93-103.

Specific Lobar Affection Reveals a Rostrocaudal Gradient in Functional Outcome in Spontaneous Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Several studies have reported a better functional outcome in lobar intracerebral hemorrhage (ICH) compared with deep location. However, among lobar ICH, a correlation of hemorrhage site-involving the specific lobes-with functional outcome has not been established. METHODS: Conservatively treated patients with supratentorial ICH, admitted to our hospital over a 5-year period (2008-2012), were retrospectively analyzed. Lobar patients were classified as isolated or overlapping ICH according to affected lobes. Demographic, clinical, and radiological characteristics were recorded and compared among lobar ICH patients using above subclassification. Functional outcome-dichotomized into favorable (modified Rankin Scale, 0-3) and unfavorable (modified Rankin Scale, 4-6)-was assessed after 3 and 12 months. Multivariate regression analysis was performed to identify predictors for favorable outcome. RESULTS: Of overall 553 patients, 260 had lobar ICH. In isolated lobar ICH, median hematoma-volume decreased from rostral (frontal, 22.4 mL [7.3-55.5 mL]) to caudal (occipital, 7.1 mL [5.2-16.4 mL]; P=0.045), whereas the proportion of patients with favorable outcome increased (frontal: 23/63 [36.5%] versus occipital: 10/12 [83.3%]; P=0.003). Patients with overlapping lobar ICH had larger ICH volumes than isolated lobar ICH (overlapping, 48.9 mL [22.6-78.5 mL] versus 15.3 mL [5.0-44.6 mL]; P<0.001) and poorer clinical status on admission (Glasgow Coma Scale and National Institutes of Health Stroke Scale). Correlations with anatomic aspects provided evidence of a rostrocaudal gradient with increasing gray/white-matter ratio and decreasing hematoma-volume and rate of hematoma enlargement from frontal to occipital ICH location. Multivariate analysis revealed affection of occipital lobe (odds ratio, 3.75 [1.38-10.22]) and affection of frontal lobe (odds ratio, 0.52 [0.28-0.94]) to be independent predictors for favorable outcome and unfavorable outcome, respectively. CONCLUSIONS: Among patients with lobar ICH radiological and outcome characteristics differed according to location. Especially affection of the frontal lobe was frequent and associated with unfavorable outcome after 3 months.

Functional Long-Term Outcome after Left- versus Right-Sided Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Hemispheric location might influence outcome after intracerebral hemorrhage (ICH). INTERACT suggested higher short-term mortality in right hemispheric ICH, yet statistical imbalances were not addressed. This study aimed at determining the differences in long-term functional outcome in patients with right- vs. left-sided ICH with a priori-defined sub-analysis of lobar vs. deep bleedings. METHODS: Data from a prospective hospital registry were analyzed including patients with ICH admitted between January 2006 and August 2014. Data were retrieved from institutional databases. Outcome was assessed using the modified Rankin Scale (mRS) score. Outcome measures (long-term mortality and functional outcome at 12 months) were correlated with ICH location and hemisphere, and the imbalances of baseline characteristics were addressed by propensity score matching. RESULTS: A total of 831 patients with supratentorial ICH (429 left and 402 right) were analyzed. Regarding clinical baseline characteristics in the unadjusted overall cohort, there were differences in disfavor of right-sided ICH (antiplatelets: 25.2% in left ICH vs. 34.3% in right ICH; p < 0.01; previous ischemic stroke: 14.7% in left ICH vs. 19.7% in right ICH; p = 0.057; and presence/extent of intraventricular hemorrhage: 45.0% in left ICH vs. 53.0% in right ICH; p = 0.021; Graeb-score: 0 [0-4] in left ICH vs. 1 [0-5] in right ICH; p = 0.017). While there were no differences in mortality and in the proportion of patients with favorable vs. unfavorable outcome (mRS 0-3: 142/375 [37.9%] in left ICH vs. 117/362 [32.3%] in right ICH; p = 0.115), patients with left-sided ICH showed excellent outcome more frequently (mRS 0-1: 64/375 [17.1%] in left ICH vs. 43/362 [11.9%] in right ICH; p = 0.046) in the unadjusted analysis. After adjusting for confounding variables, a well-balanced group of patients (n = 360/hemisphere) was compared showing no differences in long-term functional outcome (mRS 0-3: 36.4% in left ICH vs. 33.9% in right ICH; p = 0.51). Sub-analyses of patients with deep vs. lobar ICH revealed also no differences in outcome measures (mRS 0-3: 53/151 [35.1%] in left deep ICH vs. 53/165 [32.1%] in right deep ICH; p = 0.58). CONCLUSION: Previously described differences in clinical end points among patients with left- vs. right-hemispheric ICH may be driven by different baseline characteristics rather than by functional deficits emerging from different hemispheric functions affected. After statistical corrections for confounding variables, there was no impact of hemispheric location on functional outcome after ICH.

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.

Impact of Hypothermia Initiation and Duration on Perihemorrhagic Edema Evolution After Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) causes high morbidity and mortality. Recently, perihemorrhagic edema (PHE) has been suggested as an important prognostic factor. Therapeutic hypothermia may be a promising therapeutic option to treat PHE. However, no data exist about the optimal timing and duration of therapeutic hypothermia in ICH. We examined the impact of therapeutic hypothermia timing and duration on PHE evolution. METHODS: In this retrospective, single-center, case-control study, we identified patients with ICH treated with mild endovascular hypothermia (target temperature 35°C) from our institutional database. Patients were grouped according to hypothermia initiation (early: days 1-2 and late: days 4-5 after admission) and hypothermia duration (short: 4-8 days and long: 9-15 days). Patients with ICH matched for ICH volume, age, ICH localization, and intraventricular hemorrhage were identified as controls. Relative PHE, temperature, and intracranial pressure course were analyzed. Clinical outcome on day 90 was assessed using the modified Rankin scale (0-3=favorable and 4-6=poor). RESULTS: Thirty-three patients with ICH treated with hypothermia and 37 control patients were included. Early hypothermia initiation led to relative PHE decrease between admission and day 3, whereas median relative PHE increased in control patients (-0.05 [interquartile range, -0.4 to 0.07] and 0.07 [interquartile range, -0.07 to 0.26], respectively; P=0.007) and patients with late hypothermia initiation (0.22 [interquartile range 0.12-0.27]; P=0.037). After day 3, relative PHE increased in all groups without difference. Outcome was not different between patients treated with hypothermia and controls. CONCLUSIONS: Early hypothermia initiation after ICH onset seems to have an important impact on PHE evolution, whereas our data suggest only limited impact later than day 3 after onset.

Is Hypothermia Helpful in Severe Subarachnoid Hemorrhage? An Exploratory Study on Macro Vascular Spasm, Delayed Cerebral Infarction and Functional Outcome after Prolonged Hypothermia.

BACKGROUND: Therapeutic hypothermia (TH) is an established treatment after cardiac arrest and growing evidence supports its use as neuroprotective treatment in stroke. Only few and heterogeneous studies exist on the effect of hypothermia in subarachnoid hemorrhage (SAH). A novel approach of early and prolonged TH and its influence on key complications in poor-grade SAH, vasospasm and delayed cerebral ischemia (DCI) was evaluated. METHODS: This observational matched controlled study included 36 poor-grade (Hunt and Hess Scale >3 and World Federation of Neurosurgical Societies Scale >3) SAH patients. Twelve patients received early TH (<48 h after ictus), mild (35°C), prolonged (7 ± 1 days) and were matched to 24 patients from the prospective SAH database. Vasospasm was diagnosed by angiography, macrovascular spasm serially evaluated by Doppler sonography and DCI was defined as new infarction on follow-up CT. Functional outcome was assessed at 6 months by modified Rankin Scale (mRS) and categorized as favorable (mRS score 0-2) versus unfavorable (mRS score 3-6) outcome. RESULTS: Angiographic vasospasm was present in 71.0% of patients. TH neither influenced occurrence nor duration, but the degree of macrovascular spasm as well as peak spastic velocities were significantly reduced (p < 0.05). Frequency of DCI was 87.5% in non-TH vs. 50% in TH-treated patients, translating into a relative risk reduction of 43% and preventive risk ratio of 0.33 (95% CI 0.14-0.77, p = 0.036). Favorable functional outcome was twice as frequent in TH-treated patients 66.7 vs. 33.3% of non-TH (p = 0.06). CONCLUSION: Early and prolonged TH was associated with a reduced degree of macrovascular spasm and significantly decreased occurrence of DCI, possibly ameliorating functional outcome. TH may represent a promising neuroprotective therapy possibly targeting multiple pathways of DCI development, notably macrovascular spasm, which strongly warrants further evaluation of its clinical impact.

Anticoagulant reversal, blood pressure levels, and anticoagulant resumption in patients with anticoagulation-related intracerebral hemorrhage.

IMPORTANCE: Although use of oral anticoagulants (OACs) is increasing, there is a substantial lack of data on how to treat OAC-associated intracerebral hemorrhage (ICH). OBJECTIVE: To assess the association of anticoagulation reversal and blood pressure (BP) with hematoma enlargement and the effects of OAC resumption. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study at 19 German tertiary care centers (2006-2012) including 1176 individuals for analysis of long-term functional outcome, 853 for analysis of hematoma enlargement, and 719 for analysis of OAC resumption. EXPOSURES: Reversal of anticoagulation during acute phase, systolic BP at 4 hours, and reinitiation of OAC for long-term treatment. MAIN OUTCOMES AND MEASURES: Frequency of hematoma enlargement in relation to international normalized ratio (INR) and BP. Incidence analysis of ischemic and hemorrhagic events with or without OAC resumption. Factors associated with favorable (modified Rankin Scale score, 0-3) vs unfavorable functional outcome. RESULTS: Hemorrhage enlargement occurred in 307 of 853 patients (36.0%). Reduced rates of hematoma enlargement were associated with reversal of INR levels <1.3 within 4 hours after admission (43/217 [19.8%]) vs INR of ≥1.3 (264/636 [41.5%]; P < .001) and systolic BP <160 mm Hg at 4 hours (167/504 [33.1%]) vs ≥160 mm Hg (98/187 [52.4%]; P < .001). The combination of INR reversal <1.3 within 4 hours and systolic BP of <160 mm Hg at 4 hours was associated with lower rates of hematoma enlargement (35/193 [18.1%] vs 220/498 [44.2%] not achieving these values; OR, 0.28; 95% CI, 0.19-0.42; P < .001) and lower rates of in-hospital mortality (26/193 [13.5%] vs 103/498 [20.7%]; OR, 0.60; 95% CI, 0.37-0.95; P = .03). OAC was resumed in 172 of 719 survivors (23.9%). OAC resumption showed fewer ischemic complications (OAC: 9/172 [5.2%] vs no OAC: 82/547 [15.0%]; P < .001) and not significantly different hemorrhagic complications (OAC: 14/172 [8.1%] vs no OAC: 36/547 [6.6%]; P = .48). Propensity-matched survival analysis in patients with atrial fibrillation who restarted OAC showed a decreased HR of 0.258 (95% CI, 0.125-0.534; P < .001) for long-term mortality. Functional long-term outcome was unfavorable in 786 of 1083 patients (72.6%). CONCLUSIONS AND RELEVANCE: Among patients with OAC-associated ICH, reversal of INR <1.3 within 4 hours and systolic BP <160 mm Hg at 4 hours were associated with lower rates of hematoma enlargement, and resumption of OAC therapy was associated with lower risk of ischemic events. These findings require replication and assessment in prospective studies. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01829581.

Hyponatremia is an independent predictor of in-hospital mortality in spontaneous intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Hyponatremia is the most frequent electrolyte disturbance in critical care. Across various disciplines, hyponatremia is associated with increased mortality and longer hospital stay, yet in intracerebral hemorrhage (ICH) no data are available. This the first study that investigated the prevalence and clinical associations of hyponatremia in patients with ICH. METHODS: This observational study included all consecutive spontaneous ICH patients (n=464) admitted during a 5-year period to the Department of Neurology. Patient characteristics, in-hospital measures, mortality, and functional outcome (90 days and 1 year) were analyzed to determine the effects of hyponatremia (Na<135 mEq/L). Multivariable regression analyses were calculated for factors associated with hyponatremia and predictors of in-hospital mortality. RESULTS: The prevalence of hyponatremia on hospital admission was 15.6% (n=66). Normonatremia was achieved and maintained in almost all hyponatremia patients<48 hours. In-hospital mortality was roughly doubled in hyponatremia compared with nonhyponatremia patients (40.9%; n=27 versus 21.1%; n=75), translating into a 2.5-fold increased odds ratio (P<0.001). Multivariable analyses identified hyponatremia as an independent predictor of in-hospital mortality (odds ratio, 2.2; 95% confidence interval, 1.05-4.62; P=0.037). Within 90 days after ICH, hyponatremia patients surviving hospital stay were also at greater risk of death (odds ratio, 4.8; 95% confidence interval, 2.1-10.6; P<0.001); thereafter, mortality rates were similar. CONCLUSIONS: Hyponatremia was identified as an independent predictor of in-hospital mortality with a fairly high prevalence in spontaneous ICH patients. The presence of hyponatremia at hospital admission is related to an increased short-term mortality in patients surviving acute care, possibly reflecting a preexisting condition that is linked to worse outcome due to greater comorbidity. Correction of hyponatremia does not seem to compensate its influence on mortality, which strongly warrants future research.

Intraventricular fibrinolysis has no effects on shunt dependency and functional outcome in endovascular-treated aneurysmal SAH.

BACKGROUND: Intraventricular fibrinolysis (IVF) in subarachnoid hemorrhage (SAH) is an emerging strategy aiming to hasten clot lysis, treat hydrocephalus, and reduce permanent shunt rates. Because of clinical heterogeneity of investigated patient effects of IVF on permanent shunt incidence and functional outcome are widely debated. The present study is the first to investigate solely endovascular-treated SAH patients. METHODS: Overall, 88 consecutive patients with aneurysmal SAH requiring external ventricular drain placement and endovascular aneurysm closure were included. Functional outcome and shunt dependency were assessed 90 days after event. A matched controlled sub-analysis was carried out to investigate the effects of IVF treatment (n = 14; matching criteria: age, neuro-status and imaging). Multivariate modeling was performed to identify independent predictors for permanent shunt dependency. RESULTS: In IVF-patients neurological status was significantly poorer [Hunt&Hess: IVF = 4(3-5) vs. non-IVF = 3(1-5); p = 0.035] and the extent of ventricular hemorrhage was increased [Graeb Score: IVF = 7(6-8) vs. non-IVF = 3(1-4); p ≤ 0.001]. Consecutive matched controlled sub-analysis revealed no significant therapeutic effect of IVF with respect to shunt dependency rate and functional outcome. Multivariate analysis revealed Graeb score [OR = 1.34(1.02-1.76); p = 0.035] and sepsis [OR = 11.23(2.28-55.27); p = 0.003] as independent predictors for shunt dependency, whereas IVF did not exert significant effects (p = 0.820). CONCLUSIONS: In endovascular-treated SAH patients IVF neither reduced permanent shunt dependency nor influenced functional outcome. Despite established effects on intraventricular clot resolution IVF appears less powerful in SAH as compared to ICH. Given the reported positive effects of lumbar drainage (LD) in SAH, a prospective analysis of a combined treatment approach of IVF and subsequent lumbar drain sOeems warranted aiming to reduce permanent shunting and improve functional outcome.

Seizures among long-term survivors of conservatively treated ICH patients: incidence, risk factors, and impact on functional outcome.

BACKGROUND: Seizures are a common complication after intracerebral hemorrhage (ICH) but there is a substantial lack of information on the long-term incidence in ICH survivors and whether post-ICH seizures affect functional long-term outcome. METHODS: Over a five-year period 464 consecutive patients with spontaneous ICH were analyzed. Focussing on 1-year ICH survivors, clinical, and radiological parameters were retrieved from institutional prospective databases. The occurrence of seizures was categorized as early (≤7 days) or late (>7 days). Functional outcome was assessed by mailed questionnaires and telephone interviews, and was categorized into good vs. poor (mRS: 0-2 vs. 3-5) and favorable vs. unfavorable (mRS: 0-3 vs. 4-5). Multivariate regression models were calculated to investigate risk factors associated with post-ICH seizures including an a priori defined subgroup analysis of lobar ICH patients. RESULTS: Among 203 long-term ICH survivors, 19.7 % developed seizures of which 55 % occurred late. Factors associated with seizures were lobar location (OR 8.10; 95 % CI 3.04-21.59; p < 0.001), sepsis (OR 4.59; 95 % CI 1.20-17.53; p = 0.026), and history of alcohol abuse (OR 3.36; 95 % CI 1.25-9.06; p = 0.017). Subgroup analysis of lobar ICH patients revealed history of alcohol abuse as the only independent predictor of post-ICH seizures (OR 5.22; 95 % CI 1.25-21.78; p = 0.024). Functional long-term outcome among survivors was slightly worse in patients with post-ICH seizures (p = 0.059). In multivariate regression modeling for prediction of poor outcome, the parameter "post-ICH seizures" again reached a statistical trend (p = 0.065), and established parameters such as age, GCS, and hemorrhage volume were independently related to poor outcome. CONCLUSIONS: Post-ICH seizures among long-term ICH survivors are common and may contribute to unfavorable functional outcome. Especially lobar ICH patients with a history of alcohol abuse are at risk to develop post-ICH seizures. Therefore, this subgroup may represent a target population for a prophylactic anticonvulsive treatment approach, preferably investigated in a prospective randomized trial.

Anemia is an independent prognostic factor in intracerebral hemorrhage: an observational cohort study.

INTRODUCTION: To date only two studies have evaluated anemia status in acute intracerebral hemorrhage (ICH) reporting that on admission anemia (OAA) was associated with larger hematoma volume, and lower hemoglobin levels during hospital stay, which related to poorer outcome. The question remains whether anemia influences outcome through related volume-effects or itself has an independent impact? METHODS: This single-center investigation included 435 consecutive patients with spontaneous ICH admitted to the Department of Neurology over five years. Functional short- and long-term outcome (3 months and 1 year) were analyzed for anemia status. Multivariate logistic and graphical regression analyses were calculated for associations of anemia and to determine independent effects on functional outcome. It was decided to perform a separate analysis for patients with ICH-volume <30 cm³ (minor-volume-ICH). RESULTS: Overall short-term-outcome was worse in anemic patients (mRS[4-6] OAA = 93.3% vs. non-OAA = 61.2%, P < 0.01), and there was a further shift towards an increased long-term mortality (P = 0.02). The probability of unfavorable long-term-outcome (mRS[4-6]) in OAA was elevated 7-fold (OR:7.5; P < 0.01). Receiver operating characteristics curve (ROC) analysis revealed a positive but poor association of ICH-volume and anemia (AUC = 0.67) suggesting volume-undriven outcome-effects of anemia (AUC = 0.75). Multivariate regression analyses revealed that anemia, besides established parameters, has the strongest relation to unfavorable outcome (OR:3.0; P < 0.01). This is even more pronounced in minor-volume-ICH (OR:5.6; P < 0.01). CONCLUSIONS: Anemia seems to be a previously unrecognized significant predictor of unfavorable functional outcome with independent effects beyond its association with larger hemorrhage volumes. The recognition of anemia and its treatment may possibly influence outcome after ICH and as such prospective interventional studies are warranted.

Neuroendocrine changes in patients with spontaneous supratentorial intracerebral hemorrhage.

BACKGROUND: Neuroendocrine changes have been reported after ischemic stroke, subarachnoid hemorrhage, and brain trauma. As there are no corresponding data in patients with intracerebral hemorrhage (ICH) we analyzed various neuroendocrine parameters to investigate possible alterations in hormone profiles of patients with ICH. METHODS: Twenty patients with ICH were prospectively enrolled in the study. Patients were a priori parted into two groups: Ten non-ventilated patients treated on the stroke-unit (hemorrhage volumes <20 ml, "small ICH"), and 10 ventilated patients treated on the neurocritical care unit (hematoma volumes >20 ml with possible additional ventricular involvement ("large ICH"). Neuroendocrine parameters were compared between both groups referring to reference values. The following parameters were obtained over a period of 9 days in 20 patients with spontaneous supratentorial ICH: thyrotropin, free thiiodothyronine and thyroxine, human growth hormone, insulin-like growth factor 1, luteinizing hormone, follicle-stimulating hormone, testosterone, prolactin, adrenocorticotropic hormone, and cortisol. RESULTS: Small ICH patients were in a median 71 (54-88) years old and had a mean ICH volume of 9.5 ± 6.5 ml, whereas large ICH patients were 65 (47-80) years old and showed a mean volume of 56 ± 30.2 ml. None of the patients revealed pathological alterations for thyrotropin, free thiiodothyronine, thyroxine, human growth hormone, insulin-like growth factor 1, and testosterone. There was only a mild decrease of adrenocorticotropic hormone and cortisol on day 3 in large ICH patients. Small ICH patients showed pathologically elevated levels of luteinizing and follicle-stimulating hormone throughout the observation period. Large ICH patients showed a marked increase of prolactin that developed during the course. CONCLUSIONS: Overall, neuroendocrine changes in ICH patients are not as profound as reported for ischemic stroke or subarachnoid hemorrhage. The clinical significance of increased LH and FSH levels in small ICH is unclear, whereas elevation of prolactin in large ICH was anticipated. Future randomized controlled trials should also focus on neuroendocrine parameters to clarify the impact of possible hormonal alterations on functional outcome.

Correlation of age and haematoma volume in patients with spontaneous lobar intracerebral haemorrhage.

BACKGROUND: Lobar intracerebral haemorrhage (LH) is gaining importance in the ageing population, but there are only limited data regarding specific clinical characteristics and risk factors of older patients with LH. METHODS: This retrospective analysis of patients with spontaneous supratentorial haemorrhage included 174 consecutive patients (78 LH and 96 deep ICH (DH)). Clinical data including the preadmission status, neuroradiological findings, initial presentation, treatment and outcome were evaluated using institutional databases, patients' medical charts and mailed questionnaires. Logistic regression analyses were calculated for initial parameters predisposing LH and for treatment and outcome parameters associated with LH. RESULTS: Age-stratified volume analysis revealed increasing haematoma volumes for LH (≤70 years: 26.2 ml; 70-80 years: 37 ml; >80 years: 61.3 ml), whereas DH showed no relation between volume and age (≤70 years: 10.1 ml; 70-80 years: 23.2 ml; >80 years: 12.1 ml). DH patients had significantly higher HbA1c levels. Post-ICH seizures were more frequent after LH. Logistic regression analyses identified the parameters: age, haematoma volume and post-ICH seizures to be associated with LH, whereas intraventricular haemorrhage, extraventricular drainages and elevated HbA1c were related to DH. CONCLUSION: Haematoma volumes are substantially increasing in LH patients who are older than 70 years. Pathological HbA1c levels are significantly associated and predisposing for DH. These findings further support the ongoing debate of different disease entities for supratentorial ICH (ie, association of cerebral amyloid angiopathy and lobar ICH versus diabetes induced atherosclerosis in deep ICH). Future studies should focus on identifying specific pathological characteristics and risk factors for both bleeding sites to implement specific preventive measures, that is amyloid angiopathy modulating therapies for LH, and to avoid risk factors that are specific for each haemorrhage location.

Evaluation After Cochlear Implant Surgery : Correlation of Clinical Outcome and Imaging Findings using Flat-detector CT.

PURPOSE: Assessment of the cochlear implant (CI) electrode array position using flat-detector computed tomography (FDCT) to test dependence of postoperative outcome on intracochlear electrode position. METHODS: A total of 102 patients implanted with 107 CIs underwent FDCT. Electrode position was rated as 1) scala tympani, 2) scala vestibuli, 3) scalar dislocation and 4) no deconvolution. Two independent neuroradiologists rated all image data sets twice and the scalar position was verified by a third neuroradiologist. Presurgical and postsurgical speech audiometry by the Freiburg monosyllabic test was used to evaluate auditory outcome after 6 months of speech rehabilitation. RESULTS: Electrode array position was assessed by FDCT in 107 CIs. Of the electrodes 60 were detected in the scala tympani, 21 in the scala vestibuli, 24 electrode arrays showed scalar dislocation and 2 electrodes were not placed in an intracochlear position. There was no significant difference in rehabilitation outcomes between scala tympani and scala vestibuli inserted patients. Rehabilitation was also possible in patients with dislocated electrodes. CONCLUSION: The use of FDCT is a reliable diagnostic method to determine the position of the electrode array. In our study cohort, the electrode position had no significant impact on postoperative outcome except for non-deconvoluted electrode arrays.

Prospective study of access site complications of automated contrast injection with peripheral venous access in MDCT.

OBJECTIVE: The purpose of this article is to prospectively assess the frequency and type of IV injection site complications associated with high-flow power injection of nonionic contrast medium in MDCT. SUBJECTS AND METHODS: Contrast-enhanced (300-370 mg iodine/mL) MDCT examinations with high flow rates (up to 8 mL/s) using automatic CT injectors were performed according to standardized MDCT protocols. The location, type, and size (16-24 gauge) of IV catheters and volumes, iodine concentration, and flow rates of contrast medium were documented. Patients were questioned about associated discomfort, IV catheter sites were checked, and adverse effects were recorded. RESULTS: Prospectively, 4,457 patients were studied. The injection rate ranged from 1-2.9 mL/s (group 1; n = 1,140) to 3-4.9 mL/s (group 2; n = 2,536) to 5-8 mL/s (group 3; n = 781); 1.2% of the patients experienced extravasations (n = 52). Contrast medium iodine concentration, flow rates, and volumes were not related to the frequency of extravasation. The extravasation rate was highest with 22-gauge IV catheters (2.2%; p < 0.05) independently of the anatomic location. For 20-gauge IV catheters, extravasation rates were significantly higher in the dorsum of the hand than in the antecubital fossa (1.8% vs 0.8%; p = 0.018). Extravasation rates were higher in older patients (≥ 50 vs < 50 years, 0.6% vs 1.4%; p = 0.019). Different iodine concentrations did not trigger significant differences in contrast material reactions (p = 0.782). CONCLUSION: Automated IV contrast injection applying high flow rates (i.e., up to 8 mL/s) is performed without increased risk of extravasation. The overall extravasation rate was 1.2% and showed no correlation with iodine concentration, flow rates, or contrast material reactions. Performing high flow rates with low-diameter IV catheters (e.g., 22-gauge catheters) and a location of IV catheter in the hand is associated with a higher extravasation rate.

Acute stroke magnetic resonance imaging: current status and future perspective.

Cerebral stroke is one of the most frequent causes of permanent disability or death in the western world and a major burden in healthcare system. The major portion is caused by acute ischemia due to cerebral artery occlusion by a clot. The minority of strokes is related to intracerebral hemorrhage or other sources. To limit the permanent disability in ischemic stroke patients resulting from irreversible infarction of ischemic brain tissue, major efforts were made in the last decade. To extend the time window for thrombolysis, which is the only approved therapy, several imaging parameters in computed tomography and magnetic resonance imaging (MRI) have been investigated. However, the current guidelines neglect the fact that the portion of potentially salvageable ischemic tissue (penumbra) is not dependent on the time window but the individual collateral blood flow. Within the last years, the differentiation of infarct core and penumbra with MRI using diffusion-weighted images (DWI) and perfusion imaging (PI) with parameter maps was established. Current trials transform these technical advances to a redefined patient selection based on physiological parameters determined by MRI. This review article presents the current status of MRI for acute stroke imaging. A special focus is the ischemic stroke. In dependence on the pathophysiology of cerebral ischemia, the basic principle and diagnostic value of different MRI sequences are illustrated. MRI techniques for imaging of the main differential diagnoses of ischemic stroke are mentioned. Moreover, perspectives of MRI for imaging-based acute stroke treatment as well as monitoring of restorative stroke therapy from recent trials are discussed.

Craniosynostosis in patients with Noonan syndrome caused by germline KRAS mutations.

Craniosynostosis, the premature fusion of one or more cranial sutures, is a developmental defect that disrupts the cranial morphogenetic program, leading to variable dysmorphic craniofacial features and associated functional abnormalities. Craniosynostosis is frequently observed as an associated feature in a number of clinically and genetically heterogeneous syndromic conditions, including a group of disorders caused by activating mutations in genes coding for the fibroblast growth factor receptor family members FGFR1, FGFR2, and FGFR3. In these disorders, dysregulation of intracellular signaling promoted by the aberrant FGFR function is mediated, at least in part, by the RAS-MAPK transduction pathway. Mutations in KRAS, HRAS, and other genes coding for proteins participating in this signaling cascade have recently been identified as underlying Noonan syndrome (NS) and related disorders. While cardinal features of these syndromes include distinctive dysmorphic facial features, reduced growth, congenital heart defects, and variable ectodermal anomalies and cognitive impairment, craniosynostosis is not a recognized feature. Here, we report on the occurrence of premature closure of cranial sutures in subjects with NS, and their specific association with mutations in the KRAS gene. These findings highlight the pathogenetic significance of aberrant signaling mediated by the RAS signaling pathway in other known forms of craniosynostosis, and suggest that, even in the absence of radiologically demonstrable synostosis of the calvarian sutures, dysregulated growth and/or suture closure at specific craniofacial sites might contribute to the craniofacial anomalies occurring in NS.

Sonographic follow-up of the access site after arterial angiography: Impact on the detected complication rate.

OBJECTIVE: This study prospectively evaluated the impact of sonographic follow-up on the detection rate of access site complications in arterial angiography and determined parameters associated with major complications of the access site after arterial angiography. METHODS: Sonographic follow-up (mean +/- SD, 1.46 +/- 1.11 days after) of the access site (transfemoral, n = 896; and transbrachial, n = 44) was obtained prospectively in 940 arterial angiographies and included evaluations for hematoma, pseudoaneurysm, arteriovenous fistula, arterial dissection, and venous/arterial thrombosis. Clotting parameters, anticoagulation therapy, and several patient and procedure characteristics were recorded. Univariate and multivariate logistic regression analyses were performed. RESULTS: Sonography depicted major access site complications in 39 of 940 angiographies (4.2%). Major access site complications (major local hematoma, n = 13; retroperitoneal hematoma, n = 1; pseudoaneurysm, n = 18; arterial dissection, n = 1; arteriovenous fistula, n = 1; arterial thrombosis, n = 2; and venous thrombosis, n = 3) required conservative (n = 32 [3.4%]) or surgical (n = 7 [0.7%]) treatment. Independent factors significantly associated with major access site complications were age older than 60.33 years and sheath size greater than 5F (P < .05). CONCLUSIONS: Major access site complications were detected in 4.2% of cases and were significantly associated with age and sheath size.

Noninvasive Collateral Flow Velocity Imaging in Acute Ischemic Stroke: Intraindividual Comparison of 4D-CT Angiography with Digital Subtraction Angiography.

PURPOSE: The collateral status can be defined not only by its morphological extent but also by the velocity of collateral filling characterized by the relative filling time delay (rFTD). The aim of our study was to compare different methods of noninvasive visualization of rFTD derived from 4D-CT angiography (4D-CTA) with digital substraction angiography (DSA) and to investigate the correlation between functional and morphological collateral status on timing-invariant CTA. MATERIALS AND METHODS: 50 consecutive patients with acute occlusion in the M1 segment who underwent DSA for subsequent mechanical recanalization after multimodal CT were retrospectively analyzed. 4D-CTA data were used to assess the relative filling time delay between the A1 segment of the affected hemisphere and the sylvian branches distal to the occluded M1 segment using source images (4D-CTA-SI) and color-coded flow velocity visualization with prototype software (fv-CTA) in comparison to DSA. The morphological extent of collaterals was assessed on the basis of the Collateral Score (CS) on temporal maximum intensity projections (tMIP) derived from CT perfusion data. RESULTS: There was very good correlation of rFTD between fv-CTA and DSA (n = 50, r = 0.9, p < 0.05). Differences of absolute rFTD values were not significant. 4D-CTA-SI and DSA also showed good correlation (n = 50, r = 0.6, p < 0.05), but mean values of rFTD were significantly different (p < 0.05). rFTD derived from fvCTA and CS derived from timing-invariant CTA showed a negative association (R = - 0.5; P = 0.000). In patients with a favorable radiological outcome defined by a TICI score of 2b or 3, there was a significant negative correlation of CS and mRS at 3 months (R = - 0.4, P = 0.006). CONCLUSION: Collateral status plays an important role in the outcome in stroke patients. rFTD derived from 4D-CTA is a suitable parameter for noninvasive imaging of collateral velocity, which correlates with the morphological extent of collaterals. Further studies are needed to define valid thresholds for rFTD and to evaluate the diagnostic and prognostic value. KEY POINTS: · Collateral supply in anterior circulation stroke can be defined by the velocity of collateral filling. · Relative filling time delay (rFTD) can serve for quantitative measurement of collateral flow and correlates with the morphological extent of collaterals. · 4D-CTA is a suitable noninvasive imaging technique. CITATION FORMAT: · Muehlen I, Kloska SP, Gölitz P et al. Noninvasive Collateral Flow Velocity Imaging in Acute Ischemic Stroke: Intraindividual Comparison of 4D-CT Angiography with Digital Subtraction Angiography. Fortschr Röntgenstr 2019; 191: 827 - 835.