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.

     

Coagulopathy Disproportionately Predisposes to Lobar Intracerebral Hemorrhage

Background

Anticoagulation increases the risk of intracerebral hemorrhage (ICH), yet whether different underlying disease processes are equally affected is unknown. We tested the hypothesis that coagulopathy, measured by admission international normalized ratio (INR), disproportionately increases the risk for lobar hemorrhages.

Methods

Patients with primary ICH were enrolled into a registry between December 2006 and February 2012 with prospective data acquisition and systematic follow up. Logistic regression was used to test whether lobar versus deep ICH location was independently associated with INR, and then whether INR had an influence on mortality. Spearman’s correlation coefficient was used to test for an association between INR and hematoma volume separately in the lobar and deep ICH groups.

Results

221 patients were studied. Patients with lobar ICH were older (71 vs. 62 years old, p < 0.001) and more likely to have prior ICH (10 vs. 0 %, p < 0.001). INR >1.4 was observed on admission more frequently in lobar versus deep ICH (19 vs. 8 %, p = 0.02). Lobar ICH location was independently associated with INR >1.4 (OR: 2.51, 95 % CI: 1.03–6.14, p = 0.043). ICH volume correlated with INR in lobar ICH (p = 0.009), but not deep ICH (p = 0.8). Death at 1 month was independently associated with INR >1.4 (OR: 7.6, 95 % CI: 2.4–24.1, p = 0.001) after correction for the ICH Score.

Conclusions

Abnormal coagulation occurs disproportionally in lobar versus deep ICH, and is associated with larger ICH volumes and higher mortality. These findings suggest a unique risk interaction between coagulopathy and underlying brain pathology due to cerebral amyloid angiopathy.     

Prophylactic Anticonvulsants in Intracerebral Hemorrhage

Background and Purpose

Prophylactic anticonvulsants are routinely prescribed in the acute setting for intracerebral hemorrhage (ICH) patients, but some studies have reported an association with worse outcomes. We sought to characterize the prevalence and predictors of prophylactic anticonvulsant administration after ICH as well as guideline adherence. We also sought to determine whether prophylactic anticonvulsants were independently associated with poor outcome.

Methods

We performed a retrospective study of primary ICH in our two academic centers. We used a propensity matching approach to make treated and non-treated groups comparable. We conducted multiple logistic regression analysis to identify independent predictors of prophylactic anticonvulsant initiation and its association with poor outcome as measured by modified Rankin score.

Results

We identified 610 patients with primary ICH, of whom 98 were started on prophylactic anticonvulsants. Levetiracetam (97%) was most commonly prescribed. Age (OR 0.97, 95% CI 0.95–0.99, p < .001), lobar location (OR 2.94, 95% CI 1.76–4.91, p < .001), higher initial National Institutes of Health Stroke Scale (NIHSS) score (OR 2.31, 95% CI 1.40–3.79, p = .001), craniotomy (OR 3.06, 95% CI 1.51–6.20, p = .002), and prior ICH (OR 2.36, 95% CI 1.10–5.07, p = .028) were independently associated with prophylactic anticonvulsant initiation. Prophylactic anticonvulsant use was not associated with worse functional outcome [modified Rankin score (mRS) 4–6] at hospital discharge or with increased case-fatality. There was no difference in prescribing patterns after 2010 guideline publication.

Discussion

Levetiracetam was routinely prescribed following ICH and was not associated with worse outcomes. Future investigations should examine the effect of prophylactic levetiracetam on cost and neuropsychological outcomes as well as the role of continuous EEG in identifying subclinical seizures.

     

Integrins AV and B8 Gene Polymorphisms and Risk for Intracerebral Hemorrhage in Greek and Polish Populations

Α limited number of genetic variants have been linked to the development of intracerebral hemorrhage (ICH). Ιntegrin AV and/or B8-deficient mice were found to develop ICH. The present candidate gene association study was designed to investigate possible influence of integrin AV (ITGAV) and integrin B8 (ITGB8) gene region polymorphisms on the risk of ICH. 1015 participants (250 Greek and 193 Polish patients with primary ICH and 250 Greek and 322 Polish controls) were included in the study. Using logistic regression analyses, 11 tag single nucleotide polymorphisms (SNPs) for ITGAV and 11 for ITGB8 gene were tested for associations with ICH risk, lobar ICH risk and non-lobar ICH after adjustment for age, gender, history of hypertension and country of origin. Linear regression models were used to test the effect of tag SNPs on the ICH age of onset. Correction for multiple comparisons was carried out. The rs7565633 tag SNP of the ITGAV gene was independently associated with the risk of lobar ICH in the codominant model of inheritance [odds ratio (95 % confidence interval (CI)) 0.56 (0.36–0.86), p = 0.0013]. Furthermore, heterozygous individuals of the rs10251386 and the rs10239099 of the ITGB8 gene had significantly lower age of ICH onset compared to the wild-type genotypes [regression coefficient (b) ?3.884 (95 % CI ?6.519, ?1.249), p = 0.0039 and b = ?4.502 (95 % CI ?7.159, ?1.845), p = 0.0009, respectively]. The present study provides preliminary indication for an influence of ITGAV gene tag SNP in the development of lobar ICH and of ITGB8 gene variants in the age of ICH onset.     

Men Experience Higher Risk of Pneumonia and Death After Intracerebral Hemorrhage

Background

Infectious complications worsen outcome after intracerebral hemorrhage (ICH). We investigated the impact of sex on post-ICH infections and mortality.

Methods

Consecutive ICH patients (admitted to a single hospital between 1994 and 2015) were retrospectively assessed via chart review to ascertain the following in-hospital infections: urinary tract infection (UTI), pneumonia, and sepsis. Adjusted logistic regression was performed to identify associations between sex, infection, and mortality at 90 days.

Results

Two thousand and four patients were investigated, 1071 (53.7%) males. Men were more likely to develop pneumonia (21.9 vs 15.5% p < 0.001) and sepsis (3.4 vs 1.6%, p = 0.009), whereas women had higher risk of UTI (19.9 vs 11.7% p < 0.001). Multivariate analyses confirmed association between male sex and pneumonia (Odds Ratio (OR) 1.37, 95% confidence interval (CI) 1.08–1.74, p = 0.011). Male sex (OR 1.40; CI 1.07–1.85; p = 0.015) and infection (OR 1.56; CI 1.11–1.85; p = 0.011) were independently associated with higher 90-day mortality.

Conclusions

Types and rates of infection following ICH differ by sex. Male sex independently increases pneumonia risk, which subsequently increases 90-day mortality. Sex-specific preventive strategies to reduce the risk of these complications may be one strategy to improve ICH outcomes.

     

Clinical Value of Neutrophil to Lymphocyte and Platelet to Lymphocyte Ratio After Aneurysmal Subarachnoid Hemorrhage

Background

Inflammation and thrombosis are associated with the pathogenesis of aneurysmal subarachnoid hemorrhage (aSAH) and neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) are emerging as novel inflammatory markers in stroke. We aimed to identify the association of NLR and PLR with delayed cerebral ischemia (DCI) and 3-month outcome after aSAH.

Methods

Two hundred and forty-seven patients diagnosed with aSAH within 24 h of symptoms onset were enrolled. Clinical, neuroradiological, laboratory, and follow-up data were collected from electronic database. Functional outcome was assessed by modified Rankin Scale. Admission NLR, PLR, and combined NLR-PLR associated with outcomes were evaluated by logistic regression analysis, and we used receiver operating characteristic curves to detect the overall predictive accuracy of these markers.

Results

Fifty-five (22.3 %) patients had unfavorable outcome and 47 (19 %) developed DCI. Both NLR and PLR were correlated with WFNS grade (ρ = 0.35[p < 0.001], ρ = 0.28[p < 0.001]) and modified Fisher grade (ρ = 0.25[p = 0.001], ρ = 0.28[p = 0.003]) and independently related to DCI (OR 2.18, 95 %CI 1.51–3.15, p = 0.016; OR 2.21, 95 %CI 1.61–3.32, p = 0.008) and functional outcome (OR 1.89, 95 %CI 1.52–3.17, p = 0.015; OR 1.77, 95 %CI 1.48–3.21, p = 0.018) at 3 months after aneurysm repair. They had comparable predictive ability in DCI occurrence (area under the curve [AUC] 0.65, 95 %CI 0.55–0.74, p = 0.002; AUC 0.68, 95 %CI 0.60–0.76, p < 0.001) and poor outcome (AUC 0.70, 95 %CI 0.63–0.77, p < 0.001; AUC 0.65, 95 %CI 0.58–0.72, p = 0.001). However, combination of the two indexes showed a better predictive value than each alone (AUC 0.73, 95 %CI 0.66–0.81, p < 0.001 for DCI; AUC 0.76, 95 %CI 0.70–0.83, p < 0.001 for poor outcome).

Conclusions

NLR and PLR as novel inflammatory biomarkers are independent predictors of DCI development and functional outcome after acute aSAH. When combined together, they may help to identify high-risk patients more powerfully.

     

Safety of Chemical DVT Prophylaxis in Severe Traumatic Brain Injury with Invasive Monitoring Devices

Background

Patients with traumatic brain injuries (TBIs) have an increased risk of developing a deep vein thrombosis (DVT), but the risk of hemorrhage expansion with intracranial monitoring devices remains unknown. We sought to determine the safety of chemical DVT prophylaxis in severe TBI patients with invasive intracranial pressure monitors.

Methods

We retrospectively reviewed all patients with severe TBI admitted to the neurosurgical intensive care unit of a large tertiary care center over a three-year period.

Results

155 patients were included with an incidence of DVT of 12 %. The median length of time to a stable head CT was 2 days, and the median time to initiation of chemical DVT prophylaxis was 3.6 days. The odds of DVT increased with intraparenchymal hemorrhage [OR 7.21, 95 % CI (1.43–36.47), p = 0.0169], non-White ethnicity [OR 7.86, 95 % CI (1.23–50.35), p = 0.0295], female gender [OR 13.93, 95 % CI (2.47–78.73), p = 0.0029], smoking [OR 4.32, 95 % CI (1.07–17.51), p = 0.0405], no anticoagulation [OR 25.39, 95 % CI (4.26–151.48), p < 0.001], and an IVC filter [OR 15.82, 95 % CI (3.14–79.76), p < 0.001]. Twenty-eight (18 %) of these subjects experienced in-hospital mortality. The risk of in-hospital death was significantly increased among those who did not receive anticoagulation. This study found no association between DVT formation, hemorrhage expansion, or increased risk from invasive monitoring devices between various doses of unfractionated heparin (UH) and low-molecular-weight heparin (LMWH).

Conclusion

We conclude that DVT prophylaxis with either LMWH or UH is safe with intracranial pressure monitors in place.

     

Factors Associated with the Need for Intensive Care Unit Admission Following Supratentorial Intracerebral Hemorrhage: The Triage ICH Model

Background

Providing the correct level of care for patients with intracerebral hemorrhage (ICH) is crucial, but the level of care needed at initial presentation may not be clear. This study evaluated factors associated with admission to intensive care unit (ICU) level of care.

Methods

This is an observational study of all adult patients admitted to our institution with non-traumatic supratentorial ICH presenting within 72 h of symptom onset between 2009–2012 (derivation cohort) and 2005–2008 (validation cohort). Factors associated with neuroscience ICU admission were identified via logistic regression analysis, from which a triage model was derived, refined, and retrospectively validated.

Results

For the derivation cohort, 229 patients were included, of whom 70 patients (31 %) required ICU care. Predictors of neuroscience ICU admission were: younger age [odds ratio (OR) 0.94, 95 % CI 0.91–0.97; p = 0.0004], lower Full Outline of UnResponsiveness (FOUR) score (0.39, 0.28–0.54; p < 0.0001) or Glasgow Coma Scale (GCS) score (0.55, 0.45–0.67; p < 0.0001), and larger ICH volume (1.04, 1.03–1.06; p < 0.0001). The model was further refined with clinician input and the addition of intraventricular hemorrhage (IVH). GCS was chosen for the model rather than the FOUR score as it is more widely used. The proposed triage ICH model utilizes three variables: ICH volume ≥30 cc, GCS score <13, and IVH. The triage ICH model predicted the need for ICU admission with a sensitivity of 94.3 % in the derivation cohort [area under the curve (AUC) = 0.88; p < 0.001] and 97.8 % (AUC = 0.88) in the validation cohort.

Conclusions

Presented are the derivation, refinement, and validation of the triage ICH model. This model requires prospective validation, but may be a useful tool to aid clinicians in determining the appropriate level of care at the time of initial presentation for a patient with a supratentorial ICH.

     

Multiple sclerosis and environmental risk factors: a case-control study in Iran

Studies have shown an increase in the incidence of MS in Iran. The aim of our study was to evaluate the relationship between environmental exposure and MS in Iran. This case-control study was conducted on 660 MS patients and 421 controls. Many environmental factors are compared between the two groups. Our findings demonstrated that prematurity ([OR = 4.99 (95% CI 1.34–18.68), P = 0.017]), history of measles and mumps ([OR = 1.60 (95% CI 1.05–2.45), P = 0.029; OR = 1.85 (95% CI 1.22–2.78), P = 0.003, respectively]), breast feeding [OR = 2.90 (95% CI 1.49–5.65), P = 0.002], head trauma in childhood ([OR = 8.21 (95% CI 1.56–43.06), P = 0.013]), vaccination in adulthood ([OR = 4.57 (95% CI 1.14–18.41), P = 0.032, respectively]), migraine ([OR = 3.50 (95% CI 1.61–7.59), P = 0.002]), family history of MS, IBD, migraine, and collagen vascular diseases ([OR = 2.73 (95% CI 1.56–4.78), P < 0.001], [OR = 3.14 (95% CI 1.460–6.78), P = 0.004; OR = 3.18 (95% CI 1.83–5.53), P < 0.001; OR = 1.81 (95% CI 1.03–3.20), P = 0.040, respectively]), stressful events ([OR = 32.57 (95% CI 17.21–61.64), P < 0.001]), and microwave exposure ([OR = 3.55 (95% CI 2.24–5.63), P ≤0.001]) were more in the MS group. Sun exposure ([OR = 0.09 (95% CI 0.02–0.38), P = 0.001]), dairy and calcium consumption ([OR = 0.44 (95% CI 0.27–0.71), P = 0.001]), diabetes mellitus ([OR = 0.11 (95% CI 0.01–00.99), P = 0.049], and complete vaccination during childhood appeared to decreased MS risk. Our results investigated many risk factors and protective factors in Iran.     

Lymphopenia,Infectious Complications,and Outcome in Spontaneous Intracerebral Hemorrhage

Background

Lymphopenia is increasingly recognized as a consequence of acute illness and may predispose to infections. We investigated whether admission lymphopenia (AL) is associated with increased risk of infectious complications and poor outcome in patients with spontaneous intracerebral hemorrhage (ICH).

Methods

We retrospectively analyzed a prospectively collected cohort of ICH patients ascertained between 1994 and 2015. We identified subjects with lymphocyte count obtained within 24 h from onset, and AL was defined as lymphocyte count <1000/μL. Infectious complications were assessed through retrospective chart review. Association between AL, infections, and mortality was investigated using multivariable logistic regression.

Results

Of the 2014 patients meeting inclusion criteria, 548 (27.2%) had AL and 605 (30.0%) developed an infectious complication. Case-fatality at 90 days was 36.9%. Patients with AL had larger hematoma volumes, higher frequency of intraventricular hemorrhage, and lower Glasgow Coma Scale score on presentation (all p < 0.001). AL was independently associated with increased risk of pneumonia [odds ratio (OR) 1.97, 95% confidence interval (CI) 1.50–2.58, p < 0.001] and multiple infections (OR 1.84, 95% CI 1.24–2.71, p = 0.003). AL was also an independent predictor of 90-day mortality (OR 1.55, 95% CI 1.18–2.04, p = 0.002) after adjusting for confounders.

Conclusions

AL is common in ICH patients and independently associated with increased risk of infectious complications and poor outcome. Further studies will be needed to determine whether prophylactic antibiotics in ICH patients with AL can improve outcome.

     

Nosocomial Infections and Outcomes after Intracerebral Hemorrhage: A Population-Based Study

Background

Infections after intracerebral hemorrhage (ICH) may be associated with worse outcomes. We aimed to evaluate the association between nosocomial infections (>48 h) and outcomes of ICH at a population level.

Methods

We identified patients with ICH using ICD-9-CM codes in the 2002–2011 Nationwide Inpatient Sample. Demographics, comorbidities, surgical procedures, and hospital characteristics were compared between patients with and without concomitant nosocomial infections. Primary outcomes were in-hospital mortality and home discharge. Secondary outcome was permanent cerebrospinal shunt placement. Logistic regression analyses were used to analyze the association between infections and outcomes.

Results

Among 509,516 ICH patients, infections occurred in 117,636 (23.1 %). Rates of infections gradually increased from 18.7 % in 2002–2003 to 24.1 % in 2010–2011. Pneumonia was the most common nosocomial infection (15.4 %) followed by urinary tract infection (UTI) (7.9 %). Patients with infections were older (p < 0.001), predominantly female (56.9 % vs. 47.9 %, p < 0.001), and more often black (15.0 % vs. 13.4 %, p < 0.001). Nosocomial infection was associated with longer hospital stay (11 vs. 5 days, p < 0.001) and a more than twofold higher cost of care (p < 0.001). In the adjusted regression analysis, patients with infection had higher odds of mortality [odds ratio (OR) 2.11, 95 % CI 2.08–2.14] and cerebrospinal shunt placement (OR 2.19, 95 % CI 2.06–2.33) and lower odds of home discharge (OR 0.49, 95 % CI 0.47–0.51). Similar results were observed in subgroup analyses of individual infections.

Conclusions

In a nationally representative cohort of ICH patients, nosocomial infection was associated with worse outcomes and greater resource utilization.

     

Impact of Perihemorrhagic Edema on Short-Term Outcome After Intracerebral Hemorrhage

Background

Intracerebral hemorrhage (ICH) is a devastating disease with ICH volume being the main predictor of poor outcome. The prognostic role of perihemorrhagic edema (PHE) is still unclear; however, available data are mainly derived from analyses during the first days after symptom onset. As PHE growth may continue up to 14 days after ICH, we evaluated PHE over a longer period of time and investigated its impact on short-term clinical outcome.

Methods

In this monocentric retrospective cohort study, patients with spontaneous supratentorial ICH were identified from our institutional data base. Different time points of CT scans were merged to time clusters for better comparison (day 1, 2–3, 4–6, 7–9, 10–12). Absolute volumes of ICH and PHE were obtained using a validated semiautomatic volumetric algorithm. Clinical outcome at discharge was assessed using the modified Rankin Scale (0–3 = favorable, 4–6 = poor).

Results

220 patients (83 with favorable, 137 with poor outcome) were included in the final analysis. Mean ICH volume on admission was 22.8 [standard deviation (SD) 24.6] cm³. Mean absolute PHE volume on admission was 22.5 (SD 20.8) cm³ and increased to a mean peak volume of 38.1 (SD 31.4) cm³ during 6.7 (SD 4.1) days on average. Besides GCS on admission, functional status before ICH, peak hematoma volume, lobar localization and fever burden, and high peak PHE volume predicted poor outcome at discharge [OR 0.977 (95 % CI 0.957–0.998)] in the multivariable analysis.

Conclusions

PHE may have a negative impact on short-term functional outcome after ICH and therefore represent a possible treatment target.

     

Acutely Trapped Ventricle: Clinical Significance and Benefit from Surgical Decompression

Background

Focal ventricular obstruction—trapped ventricle—results in cerebrospinal fluid accumulation, mass effect and possible clinical deterioration. There are no systematic studies on the benefit of surgical decompression in adults.

Methods

We reviewed patients admitted with acutely trapped ventricle on brain imaging to assess their prognosis and the effect of surgical intervention on 30-day mortality.

Results

Of the 392 patients with trapped ventricle, the most common causes were brain tumor (45 %), intracerebral hemorrhage (ICH) (20 %), and subdural hematoma (SDH) (14 %). Lateral ventricle trapping accounted for 97 % of cases. Two hundred and twenty-one patients (56 %) received a surgical intervention for trapped ventricle or its causes; 126 (83 %) were treated with craniotomy, 26 (17 %) with craniectomy, 30 (14 %) with external ventricular drain (EVD) alone, 23 (10 %) with ventriculoperitoneal shunt alone, and 16 (7 %) with endoscopic fenestration of the septum pellucidum. Surgical intervention was associated with mortality reduction from 95 % (n = 54) to 48 % (n = 11) in the ICH group, from 47 % (n = 27) to 12 % (n = 15) in the tumor group and from 90 % (n = 18) to 20 % (n = 7) in the SDH group (p < 0.001 for all comparisons). Univariate logistic analysis showed that surgical intervention and tumor etiology were associated with decreased mortality while age, ICH etiology, intraventricular hemorrhage, midline shift, and anticoagulation were associated with increased mortality. On multivariate logistic regression, surgical intervention remained associated with decreased mortality (p < 0.0001; OR 0.20, 95 % CI 0.09–0.42). On subgroup analysis of the ICH cohort, surgical intervention was also associated with decreased mortality (p = 0.028).

Conclusions

Neurosurgical intervention for decompression in patients with trapped ventricle can have a measurable beneficial effect on early mortality.

     

ApoA1, ApoJ and ApoE Plasma Levels and Genotype Frequencies in Cerebral Amyloid Angiopathy

The involvement of apolipoproteins, such as the ApoE4 isoform, in Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA) highlights the fact that certain lipid carriers may participate in soluble β-amyloid (Aβ) transport. Our general aim was to characterize the soluble levels of the apolipoproteins apoE, apoA1 and apoJ/clusterin and their genotype status in patients with CAA. We analyzed the genotypes frequency of APOA1 (rs5069, rs670), CLU (rs11136000, rs1532278, rs7012010, rs9331888) and APOE (rs429358, rs7412) in a cohort of patients with CAA-associated intracerebral hemorrhage (ICH) (n = 59) and compared the results with those from hypertension-associated ICH (n = 42), AD patients (n = 73) and controls (n = 88). In a subgroup of patients, we also determined the plasma concentrations of apoE, apoA1 and apoJ/clusterin. We found increased plasma apoJ/clusterin levels in CAA patients compared to AD patients or controls after adjusting for sex and age (CAA vs. controls, p = 0.033; CAA vs. AD, p = 0.013). ApoA1 levels were not altered between groups, although a strong correlation was observed between plasma Aβ(1-40) and apoA1 among CAA patients (r = 0.583, p = 0.007). Regarding plasma apoE concentration, a robust association between circulating levels and genotype status was confirmed (p < 0.001). Whereas the APOE4 frequency was higher in AD (p < 0.001) and CAA (p = 0.013), the APOA1 and CLU genotypes were not different among groups. In the CAA cohort, the risk-linked CLU variant (C) rs11136000 was associated with white matter hyperintensities (p = 0.045) and the presence of lobar microbleeds (p = 0.023) on MRI. In summary, our findings suggest that apoA1 may act as a physiological transporter of Aβ(1-40) and that apoJ/clusterin appears to be a chaperone related to distinctive lesions in CAA brains.     

Joint Effects of GWAS SNPs in Coagulation System Confer Risk to Hypertensive Intracerebral Hemorrhage

Recent genome-wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) associated with coagulation system, including hemostatic factors and hematological phenotypes. However, few articles described the relationships between these SNPs and the risk of hemorrhagic stroke. The aim of our study was to evaluate the roles of these SNPs as risk factors and survival predictors for hemorrhagic stroke. Thirteen SNPs from GWAS in coagulation system were genotyped in a Chinese Han population including 1000 patients with hemorrhagic stroke (intracerebral hemorrhage, ICH = 743; subarachnoid hemorrhage, SAH = 257) and 1044 population-based controls. The associations between the genetics risk score (GRS) and risk of hemorrhagic stroke as well as post-stroke adverse outcomes were determined. No individual SNP was associated with the risk of hemorrhagic stroke. The GRS was calculated by summing the number of risk alleles of each SNP, and a total of 13 SNPs were included. Meanwhile, the GRS cutoffs values were defined to be close to quartiles or tertiles in control subjects. For quartiles, individuals with GRS about 8–9, 10–11, ≥12 had 1.28 (OR 1.28, 95% CI 0.98–1.68, p = 0.067)-, 1.36 (OR 1.36, 95% CI 1.04–1.79, p = 0.026)-, 1.53 (OR 1.53, 95% CI 1.13–2.07, p = 0.006)-fold increase in ICH risk compared to those with GRS ≤7, respectively; for tertiles, individuals with GRS about GRS 9–10, ≥11 had 0.98 (OR 0.98, 95% CI 0.78–1.23, p = 0.067)- and 1.26 (OR 1.26, 95% CI 1.00–1.59, p = 0.048)-fold increase in ICH risk compared to those with GRS ≤8, respectively. Further stratification analyses indicated that this association was only found in hypertensive ICH subjects. However, no statistical difference was found in the volume of hematoma, activities of daily living scale as well as hospital death in the ICH patients based on GRS values. Joint effects of SNPs associated with low coagulation factor levels might confer risk to ICH patients with hypertension. However, the clinical value on risk stratification and survival prediction was limited.     

<Emphasis Type="Italic">ABCC8</Emphasis> Single Nucleotide Polymorphisms are Associated with Cerebral Edema in Severe TBI

Objective

Cerebral edema (CE) in traumatic brain injury (TBI) is the consequence of multiple underlying mechanisms and is associated with unfavorable outcomes. Genetic variability in these pathways likely explains some of the clinical heterogeneity observed in edema development. A role for sulfonylurea receptor-1 (Sur1) in CE is supported. However, there are no prior studies examining the effect of genetic variability in the Sur1 gene (ABCC8) on the development of CE. We hypothesize that ABCC8 single nucleotide polymorphisms (SNPs) are predictive of CE.

Methods

DNA was extracted from 385 patients. SNPs in ABCC8 were genotyped using the Human Core Exome v1.2 (Illumina). CE measurements included acute CT edema, mean and peak intracranial pressure (ICP), and need for decompressive craniotomy.

Results

Fourteen SNPs with minor allele frequency >0.2 were identified. Four SNPS rs2283261, rs3819521, rs2283258, and rs1799857 were associated with CE measures. In multiple regression models, homozygote-variant genotypes in rs2283261, rs3819521, and rs2283258 had increased odds of CT edema (OR 2.45, p = 0.007; OR 2.95, p = 0.025; OR 3.00, p = 0.013), had higher mean (β = 3.13, p = 0.000; β = 2.95, p = 0.005; β = 3.20, p = 0.008), and peak ICP (β = 8.00, p = 0.001; β = 7.64, p = 0.007; β = 6.89, p = 0.034). The homozygote wild-type genotype of rs1799857 had decreased odds of decompressive craniotomy (OR 0.47, p = 0.004).

Conclusions

This is the first report assessing the impact of ABCC8 genetic variability on CE development in TBI. Minor allele ABCC8 SNP genotypes had increased risk of CE, while major SNP alleles were protective—potentially suggesting an evolutionary advantage. These findings could guide risk stratification, treatment responders, and the development of novel targeted or gene-based therapies against CE in TBI and other neurological disorders.

     

Cerebral small vessel disease burden and functional and radiographic outcomes in intracerebral hemorrhage

Objective

To examine the effect of individual cerebral small vessel disease (CSVD) markers and cumulative CSVD burden on functional independence, ambulation and hematoma expansion in spontaneous intracerebral hemorrhage (ICH).

Methods

Retrospective analysis of prospectively collected data from an observational study of consecutive patients with spontaneous ICH, brain MRI within 1 month from ictus, premorbid modified Rankin Scale (mRS) score?≤?2, available imaging data and 90-day functional status in a tertiary academic center. Functional outcomes included 90-day functional independence (mRS?≤?2) and independent ambulation; radiographic outcome was hematoma expansion (>?12.5 ml absolute or >?33% relative increase in ICH volume). We identified the presence and burden of individual CSVD markers (cerebral microbleeds (CMBs), enlarged perivascular spaces, lacunes, white matter hyperintensities) and composite CSVD burden score and explored their association with outcomes of interest in multivariable models adjusting for well-established confounders.

Results

111 patients were included, 65% lobar ICH, with a median volume 20.8 ml. 43 (38.7%) achieved functional independence and 71 (64%) independent ambulation. In multivariable adjusted models, there was higher total CSVD burden (OR 0.61, 95% CI 0.37–0.96, p?=?0.03) and CMBs presence (OR 0.32, 95% CI 0.1–0.88, p?=?0.04) remained independently inversely associated with functional independence. Individual CSVD markers or total CSVD score had no significant relation with ambulation and ICH expansion. Larger ICH volume and deep ICH location were the major determinants of lack of independent ambulation.

Conclusions

Our findings suggest that in ICH patients without previous functional dependence, total CSVD burden and particularly presence of CMBs significantly affect functional recovery. The latter is a novel finding and merits further exploration.

     

Prevalence and clinical characteristics of cortical superficial siderosis in patients with acute stroke

Cortical superficial siderosis (cSS) is a pathologic and radiologic diagnosis of hemosiderin deposition in subpial brain layers. However, cSS has not been fully studied in patients with acute stroke. Here, we investigated the prevalence of cSS in patients with acute stroke and analyzed the relationship between cSS and different clinical and neuroimaging characteristics. From September 2014 through June 2016, consecutive patients with acute stroke who were admitted to our department were retrospectively investigated. We analyzed the prevalence of cSS and the associations between cSS and risk factors, the topographic distribution of cerebral microbleeds (CMBs), and the severity of white matter lesions (WMLs). In total, 739 patients (589 patients with ischemic stroke/transient ischemic stroke [IS/TIA] and 150 with intracerebral hemorrhage [ICH]; mean age, 71.4 years) were enrolled. We identified cSS in six (1.0%) patients with IS/TIA and seven (4.7%) patients with ICH. The presence of cSS was associated with ICH (P < 0.0001), WMLs (P = 0.0105), and lobar and non-lobar CMBs (both P < 0.0001); no associations between cSS and age, sex, cardiovascular risk factors, IS subtype classification, or antiplatelet and anticoagulant therapy were found. In a multivariable logistic regression analysis, high numbers of lobar CMBs (≥ 2; odds ratio, 11.03; 95% confidence interval, 2.03–205.40; P = 0.0029) were independently associated with cSS. Furthermore, cSS was often located near lobar CMBs. Our results suggest that cSS is prevalent in ICH and is independently associated with lobar CMBs; however, no associations between cSS and other risk factors or comorbidities were observed.     

TURN Score Predicts 24-Hour Cerebral Edema After IV Thrombolysis

Background and Purpose

Cerebral edema is associated with poor outcome after IV thrombolysis. We recently described the TURN score (Thrombolysis risk Using mRS and NIHSS), a predictor of severe outcome after IV thrombolysis. Our purpose was to evaluate its ability to predict 24-h cerebral edema.

Methods

We retrospectively analyzed data from 303 patients who received IV rt-PA during the NINDS rt-PA trial. Measures of brain swelling included edema, mass effect and midline shift assessed at baseline, at 24 h and new onset at 24 h. Outcome was assessed using intracerebral hemorrhage (ICH), symptomatic intracerebral hemorrhage (sICH), 90-day severe outcome, and 90-day mortality. Statistical associations were assessed by logistic regression reporting odds ratios (OR) and by areas under the receiver operating characteristic curves (AUROC).

Results

Baseline brain swelling did not predict poor outcome; however, 24-h brain swelling predicted ICH (OR 5.69, P < 0.001), sICH (OR 9.50, P = 0.01), 90-day severe outcome (OR 7.10, P < 0.001), and 90-day mortality (OR 5.65, P = 0.01). Similar results were seen for new brain swelling at 24 h. TURN predicted 24-hour brain swelling (OR 2.5, P < 0.001; AUROC 0.69, 95 % CI 0.63–0.75) and new brain swelling at 24 h (OR 2.1, P < 0.001; AUROC 0.67, 95 % CI 0.61–0.73).

Conclusions

Cerebral edema at 24 h is associated with poor outcome and 90-day mortality. TURN predicts ischemic stroke patients who will develop 24-h cerebral edema after IV thrombolysis.

     

The Role of FEIBA in Reversing Novel Oral Anticoagulants in Intracerebral Hemorrhage

Background

Activated prothrombin complex concentrates factor eight inhibitor bypassing activity (FEIBA) has been recommended for reversing novel oral anticoagulants (NOAC) in the context of intracerebral hemorrhage (ICH), though few clinical studies report its use.

Methods

A prospective study of patients with spontaneous ICH was conducted from May 2013 to May 2015. Hospital complications including hemorrhage (gastrointestinal bleeding, anemia requiring transfusion, and surgical site bleeding) and thrombosis (pulmonary embolus, deep vein thrombosis, ischemic stroke, and myocardial infarction) were recorded. All ICH patients underwent baseline head CT and a follow-up stability scan in 6 h. NOAC taken within 48 h of presentation was reversed with FEIBA (50 u/kg) per protocol. Three-month outcomes were assessed using the modified rankin score (mRS).

Results

Of 127 ICH patients enrolled, 6 (5 %) had NOAC-related ICH including: oral factor XA inhibitor N = 5 (4 %; N = 4 rivaroxaban, N = 1 apixaban] and direct thrombin inhibitor N = 1 (0.8 %; dabigatran). The indication for NOAC was atrial fibrillation in all patients and the median CHADS2–VASC score was 4 (range 2–5). The median admission NIHSS was 2 (range 0–14) and the median ICH volume was 8 mL (range 1–20). Five patients (3 rivaroxaban, 1 apixaban, 1 dabigatran) presented within 48 h and received FEIBA within a median of 13 h (range 10–29 h) from their last NOAC dose and 8 h (range 4.5–20) from the time last known well. None of the patients had ICH expansion, hemorrhagic, or thrombotic complications. Three-month median mRS was 1 (range 0–6).

Conclusion

In this small case series, reversal of NOAC with FEIBA was not associated with ICH expansion or any thrombotic or hemorrhagic complications.