Delayed Cerebral Ischemia in Patients with Aneurysmal Subarachnoid Hemorrhage – Serum D-dimer and C-reactive Protein as Early Markers

BackgroundIdentifying patients at risk for delayed cerebral ischemia after an aneurysmal subarachnoid hemorrhage remains challenging and both delayed treatment and over-treatment are reasonable concerns.ObjectiveTo evaluate the role of the serum markers C-reactive protein, white blood count, and d-dimer as prognostic factors for the occurrence of delayed cerebral ischemia.MethodsAll patients admitted within 24 hours after an aneurysmal subarachnoid hemorrhage were included over a 6-year period. The World Federation of Neurosurgery and Fisher grading scales as well as the extended Glasgow Outcome Scale were documented at discharge and after a 3-to-6-month follow-up period. C-reactive protein, d-dimer, white blood count, and procalcitonin were assessed on admission, day 1, day 4, day 9, day 14, and at discharge. Radiologically confirmed delayed cerebral ischemia before discharge was the primary endpoint. Severe angiographic vasospasm and outcome were used as secondary endpoints.ResultsDelayed cerebral ischemia occurred in 19.6% of the 138 patients included. Delayed cerebral ischemia correlated with severe vasospasm and with a worse outcome. Serum C-reactive protein levels were higher in patients with severe vasospasm during the period of vasospasm. D-dimer levels on admission correlated with Fisher grades. Delayed cerebral ischemia occurred more frequently in patients with Fisher grade IV hemorrhage, if d-dimer levels were higher on admission. The cut-off was .445 µg/ml.ConclusionOur observations support a multifactorial genesis for delayed cerebral ischemia, including vasospasm and microthrombotic and inflammatory processes. Serum d-dimer levels greater than .445 µg/ml might be a predictor for the occurrence of delayed cerebral ischemia in patients with a Fisher grade IV aneurysmal subarachnoid hemorrhage.     

SANGUINATE™ (PEGylated Carboxyhemoglobin Bovine) Improves Cerebral Blood Flow to Vulnerable Brain Regions at Risk of Delayed Cerebral Ischemia After Subarachnoid Hemorrhage

Background

Delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) has been linked to focal reductions in cerebral blood flow (CBF) and microvascular impairments in oxygen delivery. Effective therapies that restore flow and oxygen transport to vulnerable brain regions are currently lacking. SANGUINATE is a dual-action carbon monoxide-releasing and hemoglobin-based oxygen transfer agent with efficacy in animal models of focal brain ischemia and tolerability in patients with sickle cell disease.

Methods

We performed a safety and proof-of-principle study in 12 SAH patients at risk of DCI across three escalating doses (160, 240, and 320 mg/kg). We used ¹⁵O-PET (performed at baseline, after SANGUINATE and at 24 h) to evaluate efficacy for improving CBF and restoring flow–metabolism balance (assessed by oxygen extraction fraction [OEF]) to vulnerable regions (defined as baseline OEF ≥ 0.50).

Results

SANGUINATE resulted in a transient rise in mean arterial pressure (116 ± 15–127 ± 13 mm Hg, p = 0.001) that normalized by 24 h and allowed three patients with DCI to be weaned off vasopressors. No adverse events were noted during infusion. Global CBF did not rise (43 ± 8–46 ± 9 ml/100 g/min) although a trend was seen at the highest dose (45 ± 7–51 ± 9, p = 0.044). However, a significant 16% rise in regional CBF associated with reduction in OEF was seen in vulnerable regions, but did not persist at 24 h.

Conclusions

We demonstrated that this novel agent can improve regional CBF and may improve oxygen supply–demand balance. Clinical studies (likely with repeat dosing) are required to evaluate whether this effect can prevent DCI or cerebral infarction.

     

“Optimal Cerebral Perfusion Pressure” in Poor Grade Patients After Subarachnoid Hemorrhage

Background  

Cerebrovascular pressure reactivity depends on cerebral perfusion pressure (CPP), with the optimal CPP (CPPopt) defined as pressure at which cerebrovascular reactivity is functioning optimally, reaching minimal value of pressure reactivity index (PRx). The study investigates the association between vasospasm, PRx, and CPPopt in poor grade patients (WFNS 4&5) after subarachnoid hemorrhage (SAH).     

Effect of Interferon-β on Neuroinflammation, Brain Injury and Neurological Outcome After Experimental Subarachnoid Hemorrhage

Introduction

Aneurysmal subarachnoid hemorrhage (SAH) has a poor outcome, particularly attributed to progressive injury after the initial incident. Several studies suggest a critical role for inflammation in lesion progression after SAH. Our goal was to test whether treatment with anti-inflammatory interferon-β, which has shown promise as a therapeutic agent in experimental ischaemic stroke, can protect the brain after SAH.

Methods

SAH was induced in adult male Wistar rats by puncturing the intracranial bifurcation of the right internal carotid artery. Treatment effects of daily interferon-β (n = 16) or vehicle (n = 14) injections were serially evaluated with multiparametric MRI and behavioral tests from day 0 to 7, in compliance with recent recommendations for pre-clinical drug testing. Outcome measures included neurological status, brain lesion volume, blood–brain barrier (BBB) leakage, and levels of inflammatory markers.

Results

In animals that survived up to 7 days post-SAH, we found no significant differences between vehicle- and interferon-β-treated animals with respect to final neurological score (14.3 ± 1.0 vs. 13.0 ± 2.2), brain lesion size on T₂-weighted MR images (59 ± 83 vs. 124 ± 99 mm³), BBB leakage (0.26 ± 0.05 vs. 0.22 ± 0.08 contrast-induced relative MR signal change), upregulation of brain RNA for cytokines, chemokines and cell adhesion molecules, and increased neutrophil activation.

Conclusions

In contrast to previously published findings in experimental ischemic stroke models, interferon-β has no clear efficacy to protect the brain after SAH. In line with recent highlighting of the significance of negative findings, our data currently do not recommend clinical testing of interferon-β to prevent neurological damage in SAH patients.     

Serum TNF-α and neurodegeneration in isolated REM sleep behavior disorder

ObjectiveTo investigate serum inflammatory cytokine profiles in patients with isolated REM sleep behavior disorder (iRBD) and to explore whether these markers are associated with phenoconversion risk to α-synucleinopathies.MethodsIn this prospective cohort study, we analyzed serum samples from patients with polysomnography-confirmed iRBD (n = 30) and healthy controls (n = 12). We measured the following cytokines: interleukin (IL)-1β, IL-2, IL-6, IL-10, and tumor necrosis factor-α (TNF-α). All patients underwent motor and non-motor evaluations and dopamine transporter imaging at baseline for predicting the phenoconversion risk. We followed the patients quarterly over up to 6 years to identify disease conversion. We also assessed longitudinal changes in cytokine levels from baseline at the 2- and 4-year follow-up visits.ResultsThe baseline cytokine levels did not differ between the patients and controls. However, the TNF-α levels were significantly increased in a subgroup of the patients with multiple markers (≥3) for phenoconversion risk compared to those without (p = 0.008) and controls (p = 0.003). At longitudinal analyses, patients with TNF-α levels above the median showed a higher incidence of phenoconversion than those with lower TNF-α levels (47% vs. 7%; p = 0.008), and this significant association persisted after adjusting for covariates (p = 0.026). The cytokine levels over 4 years of follow-up period did not change significantly.ConclusionsOur data suggest a possible link between serum TNF-α and phenoconversion risk in iRBD. Further studies are warranted to confirm the role of peripheral TNF-α in the pathogenesis of neurodegeneration in this disorder.     

Beneficial Effects of a CaMKIIα Inhibitor TatCN21 Peptide in Global Cerebral Ischemia

Aberrant calcium influx is a common feature following ischemic reperfusion (I/R) in transient global cerebral ischemia (GCI) and causes delayed neuronal cell death in the CA1 region of the hippocampus. Activation of calcium-calmodulin (CaM)-dependent protein kinase IIα (CaMKIIα) is a key event in calcium signaling in ischemic injury. The present study examined the effects of intracerebroventricular (icv) injection of tatCN21 in ischemic rats 3 h after GCI reperfusion. Cresyl violet and NeuN staining revealed that tatCN21 exerted neuroprotective effects against delayed neuronal cell death of hippocampal CA1 pyramidal neurons 10 days post-GCI. In addition, TatCN21 administration ameliorated GCI-induced spatial memory deficits in the Barnes maze task as well as anxiety-like behaviors and spontaneous motor activity in the elevated plus maze and open field test, respectively. Mechanistic studies showed that the administration of tatCN21 decreased GCI-induced phosphorylation, translocation, and membrane targeting of CaMKIIα. Treatment with tatCN21 also inhibited the level of CaMKIIα-NR2B interaction and NR2B phosphorylation. Our results revealed an important role of tatCN21 in inhibiting CaMKIIα activation and its beneficial effects in neuroprotection and memory preservation in an ischemic brain injury model.     

Long-Term Outcome and Economic Burden of Aneurysmal Subarachnoid Hemorrhage: Are we Only Seeing the Tip of the Iceberg?

Neurocritical Care -     

Serum BDNF, TNF-α and IL-1β levels in dementia patients

Neurotrophins such as the brain-derived neurotrophic factor (BDNF) are reportedly related to the pathogenesis of Alzheimer's disease (AD). Several studies have revealed an alteration in BDNF expression in the postmortem brains of AD patients. BDNF has great potential as a therapeutic agent because of its ability to cross the blood-brain barrier and due to its wide in vivo distribution. However, little is known about in vivo BDNF in dementia patients. Moreover, the immunological function of neurotrophins such as BDNF has received great interest. Therefore, we investigated the serum levels of BDNF and cytokines such as TNF-alpha and IL-1beta in dementia patients by the enzyme-linked immunosorbent assay (ELISA). The following subjects were included in this study: 60 AD patients, 60 vascular dementia (VaD) patients and 33 healthy controls. AD and VaD patients were matched for age, gender and severity of dementia. Serum BDNF levels in AD patients were significantly lower than those in VaD patients and controls. TNF-alpha and IL-1beta levels showed no significant difference among the three groups. In the dementia groups, neither the TNF-alpha nor the IL-1beta levels correlated with the BDNF levels. Our results suggest that BDNF may play a pathological role in some cases of AD.     

Serum concentrations of CRP, IL-6, TNF-α and cortisol in major depressive disorder with melancholic or atypical features

The aim of the present study was to explore possible differences between serum C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and cortisol concentration in patients with major depressive disorder (MDD) with melancholic features, and MDD with atypical features. As secondary aim, we investigated possible associations with clinical features such as suicidal ideation, number of episodes, duration of depression and symptomatology severity. We included 55 MDD patients (32 with melancholic features and 23 with atypical features) and 18 healthy controls. When compared to healthy controls, MDD with melancholic or atypical features showed higher CRP and IL-6, but not TNF-α. Cortisol concentration was higher in MDD with melancholic type, in comparison to the atypical type of MDD or controls. A positive correlation was found between the severity of depressive symptoms, concentrations of IL-6 and cortisol in the MDD group with melancholic features, while a negative correlation was observed between IL-6 and CRP in the MDD group with atypical feature. Also, in the MDD group with atypical features, there was a correlation between the severity of anxiety symptoms based on the Hamilton Rating Scale for Anxiety (HARS), concentration of CRP, and the duration of symptoms. In conclusion, we observed several differences in serum CRP, IL-6, and cortisol concentrations in MDD patients considering clinical features as well.     

Best Motor Response Predicts Favorable Outcome for “True” WFNS Grade V Patients with Aneurysmal Subarachnoid Hemorrhage

BackgroundThe universal application of ultra-early surgery for World Federation of Neurological Societies (WFNS) grade V aneurysmal subarachnoid hemorrhage (aSAH) patients may lead to the increased implementation of unnecessary treatment. Therefore, this study aimed to refine the patient selection process for timely definitive treatment.MethodsFrom January 2011 to March 2020, a total of 517 aSAH patients were treated at our institution. Among these, 177 aSAH patients with WFNS grade V on admission were identified from our database. Patients with improved grades in response to the initial supportive treatment, with clinical or radiological signs of herniation, and with irreversible signs of brain damage such as bilaterally dilated pupils and global ischemia on follow-up CT scan were excluded. The outcome of definitive treatment for 54 patients without herniation who remained with WFNS grade V after the initial supportive treatment were analyzed to seek any factor for a favorable outcome (modified Rankin scale 0–2).ResultsAmong 54 patients, 19 (35.2%) had a favorable outcome after a definitive treatment. Multivariate logistic regression analysis showed that the best motor response (BMR) 4 on Glasgow Coma Scale was significantly associated with favorable outcomes (odds ratio, 3.76; 95% confidence interval, 1.09–13.0, p = 0.03). The positive predictive value of BMR 4 was 48.3%.ConclusionsAlbeit being simple, BMR 4 may facilitate the prompt aggressive treatment for patients with WFNS grade V including those with “true” grade V who do not have any clinical and radiological signs of herniation.     

Variation in Early Developmental Course in Autism and its Relation with Behavioral Outcome at 3–4 Years of Age

The aims of the present study were to describe variations in the early course of development in autism by utilizing an in-depth parent interview that incorporated techniques to improve accuracy of parent recall, and to examine the relation between variations in early developmental course in autism and behavioral outcome at 3–4 years of age. The Early Development Interview, which consisted of questions about child’s behavior in several domains from birth through 2 years of age, was created and administered to parents of 72 3–4-year-old children with autism spectrum disorder and 34 3–4-year-old children with developmental delay, who were matched on mental and chronological age, and 39 1–4-year-old typically developing children, who were matched to the clinical groups on mental age. At 3–4 years of age, children were administered standardized measures (some clinician administered and some parent report); these included verbal and nonverbal IQ, autism symptom severity, and adaptive and aberrant behavior. Based on the Early Development Interview, children with autism spectrum disorder (ASD) were reported to have elevated symptoms in the social and regulatory domains by 3–6 months. By 12–15 months, parents of children with ASD reported significantly higher levels of social symptoms than parents of children with developmental delay. At 3–4 years of age, children with autism with early vs. late onset of symptoms, and with vs. without a history of loss of skills (regression) were not found to differ on standardized tests of verbal and nonverbal IQ and observational measures of autism symptom severity.     

TNF-α and TNF-β gene polymorphisms in cerebral infarction

Tumor necrosis factor (TNF) is an important cytokine in the inflammation process of atherosclerosis. Two biallelic polymorphisms in the TNF-α (TNF-α-308) and TNF-β (TNF-β +252) genes have been reported to be associated with TNF production and susceptibility to inflammatory diseases. We investigated two genetic polymorphisms in the TNF locus (TNF-α-308 G→A and TNF-β +252 A→G) as risk factors for cerebral infarction (CI) by determining its prevalence in 294 survivors of CI, and in 581 age-, gender-, and race-matched controls. A significant association was found for the TNF-α and TNF-β genotypes in CI patients compared with controls. A significant increase was found for the TNF-α A allele in controls compared with CI patients (X ²=7.593, p=0.006, odds ratio =1.74, confidence interval =1.17-2.59). In addition, the TNF-α GG genotype increased the relative risk for CI in subjects with the TNF-β AA genotype (X ² = 4.998, P=0.025). As a result, compared to controls, the frequency of the TNF-α AA genotype was decreased, whereas that of TNF-β AA was increased in CI patients. The former implies an association with resistance, whereas the latter suggests an association with susceptibility to the disease. These results show that the TNF-α-308 and TNF-β + 252 locus plays an important role in the etiopathogenesis of CI.     

Fatigue in irritable bowel syndrome is associated with plasma levels of TNF-α and mesocorticolimbic connectivity

Irritable bowel syndrome (IBS) is a symptom-based disorder of gut-brain interactions generating abdominal pain. It is also associated with a vulnerability to develop extraintestinal symptoms, with fatigue often reported as one of the most disturbing. Fatigue is related to brain function and inflammation in several disorders, however, the mechanisms of such relations in IBS remain elusive. This study aimed to elucidate fatigue and its association with a resting state network of mesocorticolimbic regions of known importance in fatigue, and to explore the possible role of circulating TNF-α levels in IBS and healthy controls (HC). Resting state functional magnetic resonance imaging (fMRI) was conducted in 88 IBS patients and 47 HC of similar age and gender to investigate functional connectivity between mesocorticolimbic regions. Further, fatigue impact on daily life and plasma levels of the proinflammatory cytokine tumor necrosis factor-α (TNF-α), of known relevance to immune activation in IBS, were also measured. The selected mesocorticolimbic regions indeed formed a functionally connected network in all participants. The nucleus accumbens (NAc), in particular, exhibited functional connectivity to all other regions of interest. In IBS, fatigue impact on daily life was negatively correlated with the connectivity between NAc and dorsolateral prefrontal cortex bilaterally (left p = 0.019; right p = 0.038, corrected for multiple comparisons), while in HC, fatigue impact on daily life was positively correlated to the connectivity between the right NAc and anterior middle insula in both hemispheres (left p = 0.009; right p = 0.011). We found significantly higher levels of TNF-α in IBS patients compared to HC (p = 0.001) as well as a positive correlation between TNF-α and fatigue impact on daily life in IBS patients (rho = 0.25, p = 0.02) but not in HC (rho = −0.13, p = 0.37). There was no association between functional connectivity in the mesocorticolimbic network and plasma levels of TNF-α in either group In summary, this novel multimodal study provides the first evidence that the vulnerability to fatigue in IBS is associated with connectivity within a mesocorticolimbic network as well as immune activation. These findings warrant further investigation, both peripherally and potentially with measurements of central immune activation as well.     

Does Serum Tau Protein Predict the Outcome of Patients with Ischemic Stroke?

The prediction of outcome after ischemic stroke (IS) is currently based on indirect data from clinical and radiological evaluation. We evaluated the usefulness of serum Tau protein as possible prognostic markers for IS. Fifty-six patients with computed tomography-confirmed IS were enrolled. Blood samples were obtained on days 1, 3, 5, and 10 after stroke onset. Tau and S100BB serum levels were measured by commercially available enzyme-linked immunosorbent assay. Neurological deficits were quantified by the National Institute of Health Stroke Scale on days 1, 3, 5, and 10 of stroke. Functional disability was rated with the Barthel Index and Rankin Scale on days 1, 3, 5, and 10 and additionally 3 months after the stroke. Computed tomography scan was performed to calculate infarct volume on admission to hospital and on day 10 from the diagnosis of IS onset. Tau protein was detected in the serum of 47.8% patients with IS. Patients in whom Tau protein was detected in serum, when compared with patients without Tau protein, developed more severe neurological deficits, had worse functional status measured in the early and late phase of IS, and were found to have larger volume of infarction. However, Tau protein concentrations measured within the early phase of IS did not correlate with degrees of neurological deficit and disability in the early phase and also after 3 months of IS. Detection of Tau protein in the serum of patients with IS but not its concentration can be considered as a bad prognostic factor for the clinical outcome in early and late phase of IS.