Genes and outcome after aneurysmal subarachnoid haemorrhage

Objectives Initial and secondary ischaemia are important determinants of outcome after subarachnoid haemorrhage (SAH). Cerebral ischaemia is a potent stimulus for expression of genes that may influence recovery.We investigated whether functional polymorphisms in the apolipoprotein E (APOE), insulin–like growth factor-1 (IGF–1), tumor necrosis factor-A (TNF–A), interleukin-1A (IL–1A), interleukin-1B (IL–1B), and interleukin-6 (IL–6) genes are related with outcome after aneurysmal SAH. Methods Genotyping of the polymorphisms was performed in a consecutive series of 167 patients with aneurysmal SAH. The risk of a poor outcome was analysed with logistic regression with adjustment for prognostic factors for outcome after SAH, using the homozygotes for the wild type alleles as a reference. Results Patients carrying any IGF–1 non–wild type allele had a lower risk of a poor outcome (OR 0.4, 95% CI 0.2–1.0), while carriers of the TNF–A non–wild type allele had a higher risk (OR 2.3, 95% CI 1.0–5.4). We could not demonstrate an association with outcome for APOE (APOE4 OR 0.4, 95% CI 0.1–1.2; APOE 2 OR 0.7, 95% CI 0.2–2.4), IL–1A (OR 1.8, 95% CI 0.8–4.0), IL–1B (OR 0.7, 95% CI 0.3–1.5) and IL–6 (OR 0.7, 95% CI 0.3–1.8) polymorphisms. Conclusions Variation in some genes that are expressed after cerebral ischaemia may partly explain the large differences in outcome between patients with aneurysmal SAH. SAH patients homozygote for the IGF–1 wild type allele or carriers of the TNF–A non–wild type allele have a higher risk of poor outcome. Additional studies in other populations are needed to assess the generalisability of our results.     

Organic psychiatric disorders after aneurysmal SAH: outcome and associations with age,bleeding severity,and arterial hypertension

OBJECTIVES: The Lindqvist & Malmgren's system was used to describe the outcome of organic psychiatric disorders (OPDs) after aneurysmal subarachnoid hemorrhage (aSAH) and their associations with age, bleeding severity, and pre-existing arterial hypertension (preAH). MATERIAL AND METHOD: OPDs were diagnosed at 3, 6, and 12 months after aSAH in a prospective cohort study (n=63). Reaction level (RLS85), World Federation of Neurological Surgeons Committee SAH scale (WFNS), Fisher, and hydrocephalus grades were assessed at admission. RESULTS: At 3/6/12 months, 60/49/38% had an Astheno-emotional disorder (AED), 4/5/5% had emotional-motivational blunting disorder (EMD) and 19/19/16% had Korsakoffs amnestic disorder (KAD). AED was associated with preAH, whereas EMD/KAD, but not AED, was associated with a higher mean age, worse median RLS85 levels, WFNS grades, and Fisher grades. CONCLUSIONS: OPDs were diagnosed in 59% of the patients at 12 months after aSAH. AED, the most common OPD, had the highest recovery rate and was associated with preAH. Use of organic psychiatric diagnoses for evaluation of outcome after aSAH and other brain injuries is encouraged.     

Early cerebral infarction as a risk factor for poor outcome after aneurysmal subarachnoid haemorrhage

Background and purpose: After aneurysmal subarachnoid haemorrhage, severity of bleeding, and occurrence of rebleeding and cerebral infarcts are the main factors predicting outcome. We investigated predictive risk factors for both early and late cerebral infarcts, and whether time of appearance of infarct is associated with outcome. Methods: Previous diseases as well as clinical, laboratory and radiological variables including serial CT scans were recorded for 173 patients admitted within 48 h after bleeding and with ruptured aneurysm occlusion by open surgery within 60 h. Factors predicting occurrence of cerebral infarct and poor outcome at 3 months according to the Glasgow Outcome Scale were tested using multiple logistic regression. Results: Of several potential predictors, poor outcome was independently predicted by patient age, rebleeding, intraventricular haemorrhage, intracerebral haematoma, delayed cerebral ischaemia with fixed symptoms and early new ischaemic lesion on CT scan appearing on the 1st post‐operative morning (P < 0.01 for each factor). After adjustment for confounding factors, occurrence of early infarct (odds ratio 12.5; 95% confidence interval 3.2–48.7; P < 0.01), both early and late infarct (6.6; 1.1–40.4; P < 0.05), and late infarct only (2.4; 0.6–9.1) increased risk for poor outcome. Adjusted independent significant risk factors for early infarction were duration of artery occlusion during surgery (1.4/min; 1.1–1.7, P < 0.01) and admission plasma glucose level (1.3 per mM; 1.0–1.6, P < 0.05) and for late infarction amount of subarachnoid blood (4.5; 1.3–14.9, P < 0.05). Conclusion: Early infarction after surgical aneurysm occlusion seems to have different risk factors and worse prognosis than late infarct which is mostly associated with delayed cerebral ischaemia.     

Impact of early surgery after aneurysmal subarachnoid haemorrhage

Objectives – To investigate the effect of early aneurysm surgery (<72 h) on outcome in patients with subarachnoid haemorrhage (SAH). Materials and methods – We studied two consecutive series of patients with aneurysmal SAH [postponed surgery (PS) cohort, n = 118, 1989–1992: surgery was planned on day 12 and early surgery (ES) cohort, n = 85, 1996–1998: ES was performed only in patients with Glasgow Coma Scale (GCS) >13]. We used multivariable logistic regression analysis to assess outcome at 3 months. Results – Favourable outcome (Glasgow Outcome Scale 4 or 5) was similar in both cohorts. Cerebral ischemia occurred significantly more often in the ES cohort. The occurrence of rebleeds was similar in both cohorts. External cerebrospinal fluid (CSF) drainage was performed more often in the ES cohort (51% vs 19%). Patients with cisternal sum score (CSS) of subarachnoid blood <15 on admission [adjusted odds ratio (OR) for favourable outcome: 6.4, 95% confidence interval (CI) 1.0–39.8] and patients with both CSS <15 and GCS > 12 on admission benefited from the strategy including ES (OR 10.5, 95% CI 1.1–99.4). Conclusions – Our results support the widely adopted practice of ES in good‐grade SAH patients.     

Outcome 1 year after aneurysmal subarachnoid hemorrhage: relation between cognitive performance and neuroimaging

OBJECTIVE: To assess the cognitive impairment and the association between neuropsychological measures and neuroimaging 1 year after aneurysmal subarachnoid hemorrhage (SAH). METHOD: Forty-two patients were examined clinically according to Glasgow Outcome Scale (GOS). Computed tomography (CT), single photon emission computed tomography (SPECT) and neuropsychological examination were performed. RESULTS: There were no association between GOS and cognitive impairment index based on the neuropsychological examination. CT showed no sign of cerebral ischemia in 17 (40%) and low attenuating areas indicating cerebral infarction(s) in 25 (60%) patients. A significant correlation (P = 0.01) was observed between the cognitive impairment index and the SPECT index (r = 0.6). SPECT measurement was the only independent predictor for cognitive impairment. CONCLUSION: GOS is a crude outcome measure and patients classified with good recoveries may have significant cognitive deficits. Neuropsychological examination is the preferred method for outcome evaluation as this method specifically addresses the disabilities affecting patients' everyday life.     

Impact of early endovascular aneurysmal occlusion on outcome of patients in poor grade after subarachnoid haemorrhage: a prospective, consecutive study

Patients in poor grade (WFNS IV and V) after aneurysmal subarachnoid hemorrhage (SAH) often have a bad outcome. To evaluate early GDC embolisation on such patients a prospective observational study, with comparison to a historical cohort was performed. From January 1996 to December 1998 113 patients were admitted to the Department of Clinical Neurosciences in poor grade after SAH (45 WFNS IV and 68 WFNS V). Eighty-one patients were managed actively with endovascular occlusion of the aneurysm (n = 42) where possible and delayed clipping (n = 16) where not. On an intention to treat basis, 46% had a favourable outcome (Glasgow Outcome Score IV or V) and 48% had died by 3 months. Compared to an historical cohort managed in the same unit between 1992 and 1995 (n = 62, 52% favourable outcome) these results suggest that early GDC aneurysmal occlusion has had a minimal impact on overall outcome.     

Risk factors and outcome of seizures after spontaneous aneurysmal subarachnoid hemorrhage

Background and purpose:  Seizures are important neurologic complications of spontaneous aneurysmal subarachnoid hemorrhage (SAH). A better understanding of the risk factors of seizures following aneurysmal SAH is needed to predict those who will require treatment.
Methods:  A total of 137 adult patients were enrolled in this two-year retrospective study. Baseline prognostic variables were analyzed based on Cox's proportional hazards model after a minimum of one-year follow-up.
Results:  Seizures occurred in 21 patients who had SAH, including acute symptomatic seizures in 11.7% (16/137) and unprovoked seizures in 3.6% (5/137). None progressed to status epilepticus during hospitalization. After a minimum of one-year follow-up, the mean Glasgow Outcome Score was 3.5 ± 1.4 for patients with seizures and 3.1 ± 1.1 for those without.
Conclusions:  Higher mean World Federation of Neurological Societies grade on presentation was predictive of seizure, but seizure itself was not a significant prognostic predictor after a minimum of one-year follow-up. Regarding potential side effects of anti-epileptic drugs, anti-epileptic therapy should be carefully administered to patients with seizures after aneurysmal SAH.     

Genetic determinants of cerebral vasospasm, delayed cerebral ischemia, and outcome after aneurysmal subarachnoid hemorrhage

Despite extensive effort to elucidate the cellular and molecular bases for delayed cerebral injury after aneurysmal subarachnoid hemorrhage (aSAH), the pathophysiology of these events remains poorly understood. Recently, much work has focused on evaluating the genetic underpinnings of various diseases in an effort to delineate the contribution of specific molecular pathways as well as to uncover novel mechanisms. The majority of subarachnoid hemorrhage genetic research has focused on gene expression and linkage studies of these markers as they relate to the development of intracranial aneurysms and their subsequent rupture. Far less work has centered on the genetic determinants of cerebral vasospasm, the predisposition to delayed cerebral injury, and the determinants of ensuing functional outcome after aSAH. The suspected genes are diverse and encompass multiple functional systems including fibrinolysis, inflammation, vascular reactivity, and neuronal repair. To this end, we present a systematic review of 21 studies suggesting a genetic basis for clinical outcome after aSAH, with a special emphasis on the pathogenesis of cerebral vasospasm and delayed cerebral ischemia. In addition, we highlight potential pitfalls in the interpretation of genetic association studies, and call for uniformity of design of larger multicenter studies in the future.     

Validity and reliability of a new instrument for assessing mood symptomatology: the Structured Clinical Interview for Mood Spectrum (SCI-MOODS)

We evaluated the internal consistency, discriminant validity, inter-rater reliability and test–retest reliability of a new instrument for the assessment of lifetime symptoms related to mood spectrum disorders: the Structured Clinical Interview for Mood Spectrum (SCI-MOODS). We report on results obtained from 491 subjects assessed across eight psychiatric centres in Italy who were given the SCI-MOODS and the Mini International Neuropsychiatric Interview (MINI). The study sample consisted of four groups: 141 students, 116 gastrointestinal (GI) patients, 112 bipolar patients and 122 patients with recurrent depression. To evaluate the inter-rater reliability and the test–retest reliability, an additional group of 30 subjects (10 non-psychiatric patients enrolled in an orthopaedic clinic, 10 unipolar patients and 10 bipolar patients) was given the SCI-MOODS at a baseline assessment and six to eight days later. At the baseline assessment, these subjects were also interviewed using the Structural Clinical Interview for DSM-IV (SCID IV) and were rated for the severity of symptomatology using the Clinical Global Impression Scale (CGI). The internal consistency of the four domains and six subdomains of the interview, expressed in terms of the Kuder–Richardson coefficient, was high, ranging from 0.79 to 0.92. Correlations of each of the domains with the others ranged from 0.63 to 0.85, indicating a strong interrelationship among the domains. Moreover, the correlations of each of the three manic subdomains with the others and each of the three depressive subdomains with the others were consistently higher than those between manic and depressive subdomains. The SCI-MOODS was found to discriminate between patients with mood disorders and subjects belonging to two control groups as well as between bipolar and unipolar patients. The inter-rater reliability for the four domains and the six subdomains was excellent, with the intra-class correlation coefficient being close to unity for each of them. Test–retest reliability was also excellent, ranging from 0.93 to 0.94 for the four domains. Test–retest reliability was slightly lower in the manic (0.86 to 0.89) than in the depressive subdomains (0.95 to 0.96), but well within the acceptable range. These findings provide strong support for the internal consistency, the discriminant validity and the reliability of the SCI-MOODS. Copyright © 1999 Whurr Publishers Ltd.     

Early circulating levels of endothelial cell activation markers in aneurysmal subarachnoid haemorrhage: associations with cerebral ischaemic events and outcome

OBJECTIVE: To investigate the relation of endothelial cell activation with delayed cerebral ischaemia (DCI) and outcome after subarachnoid haemorrhage (SAH). METHODS: Concentrations of soluble (s) intercellular adhesion molecule-1, sE-selectin, sP-selectin, ED1-fibronectin, von Willebrand Factor (vWf), and vWf propeptide were measured within three days of SAH onset. The associations with poor outcome were investigated at three months in 106 patients. In 90 patients in whom the occurrence of cerebral ischaemia could be dated accurately, two analyses were undertaken: one for all ischaemic events (n = 32), including those related to treatment, and another for spontaneous DCI (n = 11). Concentrations of markers were dichotomised at their medians. The associations of endothelial cell activation markers with outcome were expressed as odds ratios (OR) from logistic regression and those with ischaemic events as hazard ratios (HR) derived from Cox regression. RESULTS: Early vWf concentrations were associated with poor outcome (crude OR = 4.6 (95% CI, 2.0 to 10.9; adjusted OR = 3.3 (1.1 to 9.8). Early levels of vWf were also positively related to occurrence of all ischaemic events (crude HR = 2.3 (1.1 to 4.9); adjusted HR = 1.8 (0.8 to 3.9) and with occurrence of spontaneous DCI (crude HR = 3.5 (0.9 to 13.1); adjusted HR = 2.2 (0.5 to 9.8). None of the other markers showed any associations. CONCLUSIONS: Concentrations of sICAM-1, sP-selectin, sE-selectin, and ED1-fibronectin do not predict the occurrence of DCI or outcome. The positive associations of raised early vWf concentrations with ischaemic events and poor outcome after SAH may reflect a predisposition to further ischaemic injury through formation of microthrombi in the cerebral circulation.     

Lower incidence of cerebral infarction correlates with improved functional outcome after aneurysmal subarachnoid hemorrhage

Despite an undisputed association between vasospasm and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (SAH), there is debate if this association implies causality. It has been suggested that cerebral infarction is a better outcome measure than vasospasm in clinical trials and observational studies. To further investigate the relationship between infarction and outcome, we performed a systematic review and meta-analysis of all randomized, double-blind, placebo-controlled trials that studied the efficacy of pharmaceutical preventive strategies in SAH patients, and had both cerebral infarction and clinical outcome as outcome events. Effect sizes were expressed in (pooled) risk ratio (RR) estimates with corresponding 95% confidence intervals (CIs). Sensitivity analyses were performed for studies with a low risk of bias and for those who reported outcome at 3 months after SAH. Twenty-four studies including 8,552 patients were included. Pharmaceutical treatments decreased the incidence of both cerebral infarction (RR: 0.83; 95% CI: 0.74 to 0.93) and of poor functional outcome (RR: 0.92; 95% CI: 0.86 to 0.98). The sensitivity analyses did not change the results essentially. These data suggest that the previously observed association between cerebral infarction and functional outcome implies causality, and that cerebral infarction is a better outcome measure than vasospasm in clinical trials and observational studies.     

Acute hyponatremia after aneurysmal subarachnoid hemorrhage: Frequency,treatment, and outcome

We retrospectively examined the course of serum sodium levels in 180 patients with acute aneurysmal subarachnoid hemorrhage (SAH) who had been admitted to the anesthesiologic-neurosurgical intensive care unit of the University Medical Center Regensburg, Germany, between January 2014 and December 2018. Each patient file was analyzed regarding the frequency and intensity of hyponatremic episodes and the administered medication. At admission to the intensive care unit (ICU), 18 patients had shown initial hyponatremia (<135 mmol/L) and 4 patients hypernatremia (greater than145 mmol/L). 88 (48.9%) of the 158 patients with normal serum sodium levels developed at least one hyponatremic episode during ICU treatment. The number of hyponatremic episodes was similar between patients with higher-grade and lower-grade aneurysmal SAH (P = 0.848). At the end of ICU treatment, outcome did not differ between patients with and without hyponatremia (40/88, 45.5% vs. 38/70, 54.3%, P = 0.270). At 6 months after SAH, however, good outcome (Glasgow outcome scale, GOS 4–5) was more frequently observed in patients with hyponatremia (26/88, 29.5% vs. 32/70, 45.7%, P = 0.036). Medication with sodium chloride, fludrocortisone, or tolvaptan was initiated in 75.4% patients with mild hyponatremia (130–134 mmol/L) and in 92.9% with moderate hyponatremia (125–129 mmol/L). At 6 months after SAH, patients treated with tolvaptan had a lower rate of poor outcome than patients who had not received tolvaptan (1/14, 7.1% vs. 25/74, 33.8%, P = 0.045). In patients with acute aneurysmal SAH and hyponatremic episodes, consequent treatment of hyponatremia prevented impaired outcome. Because administration of tolvaptan rapidly normalized serum sodium levels, this therapy seems to be a promising treatment approach.     

Association between elevated cerebrospinal fluid D-dimer levels and delayed cerebral ischaemia after aneurysmal subarachnoid haemorrhage

Delayed cerebral ischaemia (DCI) after aneurysmal subarachnoid haemorrhage (aSAH) is a major contributor to morbidity and mortality. It is currently not possible to reliably predict patients at risk of DCI after aSAH. The aim of this study was to quantify cerebrospinal fluid (CSF) D-Dimer and plasminogen levels and to investigate any association with development of DCI. Cerebrospinal fluid (CSF) samples collected from 30 patients within 72 h post-aSAH (n = 13 DCI and n = 17 non-DCI patients) were analysed. DCI was diagnosed when angiographic vasospasm was detected in the presence of new onset neurological deficit. Enzyme-linked immunosorbent assays were used to quantify D-dimer concentrations while western blotting was used to quantify plasminogen levels. Significant differences in CSF proteins between DCI and non-DCI cohorts were verified using Mann-Whitney test. Sensitivity and specificity of these proteins for detecting DCI was examined using a ROC curve and verified with a Fischer’s exact test. CSF levels of D-dimer within 72 h post aSAH were significantly elevated in DCI patients (54.29 ng/ml, 25.35–105.88 ng/ml) compared to non-DCI patients (26.75 ng/ml, 6.9–45.08 ng/ml) [p = 0.03]. In our sample population, D-dimer levels above 41.1 ng/ml had a sensitivity of 69.2% and specificity of 75% for predicting DCI. CSF levels of plasminogen (DCI: 0.50 signal-intensity/μl, 0.20–0.73 signal-intensity/μl, non-DCI: 0.28 signal-intensity/μl, 0.22–0.54 signal-intensity/μl) did not differ between the DCI and non-DCI cohort (p > 0.05). Our study suggests that elevated D-dimer in the first 72 h after aSAH may be a potential predictive biomarker for DCI.     

The relation of cognitive control to social outcome after paediatric TBI: Implications for intervention

Hypothesis: This study postulated cognitive control is related to social outcome in children with traumatic brain injury (TBI) and orthopaedic injury (OI).

Procedure and design: This study analysed 12-month, post-injury, cross-sectional data from 52 children (7–17 years) with moderate-to-severe TBI and 41 children with OI. Cognitive control was measured with the Sternberg Task (memory) and the Flanker Task (resistance to interference). Relations to social outcome (Vineland Adaptive Behavioural Scales—Socialization and Communications domains) were measured.

Results: Reaction time (RT) on the Sternberg task was related to social outcome, with stronger relations in children of lower SES. Flanker baseline and interference RTs were related to social outcome, with the relation for interference RT more robust in children with lower SES.

Conclusions: Cognitive control is related to social outcome. Further, it is suggested that cognitive training may have positive effects on social function through improved efficiency of social information processing.     

Impact of aneurysm morphology on aneurysmal subarachnoid hemorrhage severity,cerebral infarction and functional outcome

ObjectiveAneurysmal subarachnoid hemorrhage (aSAH) is associated with high morbidity. The objective was to evaluate, whether specific morphological aneurysm characteristics could serve as predictive values for aSAH severity, disease-related complications and clinical outcome.MethodsA total of 453 aSAH patients (mean age: 54.9 ± 13.8 years, mean aneurysm size: 7.5 ± 3.6 mm) treated at a single center were retrospectively included. A morphometric analysis was performed based on angiographic image sets, determining aneurysm location, aneurysm size, neck width, aneurysm size ratios, aneurysm morphology and vessel size. The following outcome measures were defined: World Federation of Neurosurgical Societies (WFNS) grade 4 and 5, Fisher grade 4, vasospasm, cerebral infarction and unfavorable functional outcome.ResultsRegarding morphology parameters, aneurysm neck width was an independent predictor for Fisher 4 hemorrhage (OR: 1.1, 95%CI: 1.0–1.3, p = 0.048), while dome width (OR: 0.92, 95%CI: 0.86–0.97, p = 0.005) and internal carotid artery location (OR: 2.1, 95%CI: 1.1–4.2, p = 0.028) predicted vasospasm. None of the analyzed morphological characteristics prognosticated functional outcome. Patient age (OR: 0.95, 95%CI: 0.93–0.96, p < 0.001), WFNS score (OR: 4.8, 95%CI: 2.9–8.0, p < 0.001), Fisher score (OR: 2.3, 95%CI: 1.4–3.7, p < 0.001) and cerebral infarction (OR: 4.5, 95%CI: 2.7–7.8, p < 0.001) were independently associated with unfavorable outcome.ConclusionsThe findings indicate a correlation between aneurysm morphology, Fisher grade and vasospasm. Further studies will be required to reveal an independent association of aneurysm morphology with cerebral infarction and functional outcome.     

Effect of pharmaceutical treatment on vasospasm,delayed cerebral ischemia,and clinical outcome in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis

As it is often assumed that delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) is caused by vasospasm, clinical trials often focus on prevention of vasospasm with the aim to improve clinical outcome. However, the role of vasospasm in the pathogenesis of DCI and clinical outcome is possibly smaller than previously assumed. We performed a systematic review and meta-analysis on all randomized, double-blind, placebo-controlled trials that studied the effect of pharmaceutical preventive strategies on vasospasm, DCI, and clinical outcome in SAH patients to further investigate the relationship between vasospasm and clinical outcome. Effect sizes were expressed in pooled risk ratio (RR) estimates with corresponding 95% confidence intervals (CI). A total of 14 studies randomizing 4,235 patients were included. Despite a reduction of vasospasm (RR 0.80 (95% CI 0.70 to 0.92)), no statistically significant effect on poor outcome was observed (RR 0.93 (95% CI 0.85 to 1.03)). The variety of DCI definitions did not justify pooling the DCI data. We conclude that pharmaceutical treatments have significantly decreased the incidence of vasospasm, but not of poor clinical outcome. This dissociation between vasospasm and clinical outcome could result from methodological problems, sample size, insensitivity of clinical outcome measures, or from mechanisms other than vasospasm that also contribute to poor outcome.