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.     

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.     

Effects of apolipoprotein E genotype on outcome after ischaemic stroke, intracerebral haemorrhage and subarachnoid haemorrhage

Background

Rodent models of acute ischaemic stroke and head injury suggest that apolipoprotein E (APOE) genotype influences neuronal repair, regeneration and survival after brain injury. Possession of an APOE ε4 allele is associated with poor outcome after head injury in clinical studies. APOE might therefore influence outcome after acute stroke in humans.

Objective and methods

To comprehensively search, identify, assess and carry out meta‐analyses of studies reporting on the association between APOE and the combined outcome of death or dependency, or death alone, several months after ischaemic stroke, intracerebral haemorrhage (ICH) or subarachnoid haemorrhage (SAH).

Results

Main analyses included data from nine studies on 2262 patients (1453 with ischaemic stroke, 199 with ICH and 610 with SAH). Overall, ε4+ genotypes were not significantly associated with risk of death or dependency several months after stroke. However, there was significant heterogeneity between studies, and between the three pathological types of stroke. ε4+ genotypes were associated with increased death or dependency after SAH (relative risk (RR) 1.40, 95% confidence interval (CI) 1.06 to 1.84), with a trend towards a similar association with ICH (RR 1.38, 95% CI 0.99 to 1.92), but not with ischaemic stroke (RR 0.98, 95% CI 0.85 to 1.12). Results were similar for death alone.

Conclusions

APOE may differentially affect outcome after the three main pathological types of stroke. Further, large studies are needed to confirm or refute these findings, and to assess the possibility of an interaction between the effects of APOE and age.In contrast with the many studies assessing the role of various candidate genes in the causation of stroke and its subtypes,^1,2,3 the role of genetic factors influencing outcome after acute stroke has been relatively little studied in humans.^4,5 However, studies on animal models of stroke comparing outcomes among genetically manipulated animals with those among wild‐type animals suggest that this should be a promising subject, which may ultimately improve our understanding of the pathways of neuronal protection and recovery, and even lead to new therapeutic insights.^4,6The apolipoprotein E gene (APOE) is one of the most widely studied genes in vascular and neurodegenerative diseases. Its protein product is a 34‐kDa glycoprotein with three common isoforms, E2, E3 and E4, encoded by the alleles ε2, ε3 and ε4, respectively, giving rise to six genotypes, the ε3/ε3 genotype occurring in about 50–66% of people in most populations.⁷ APOE has a major role in lipid redistribution, which is important for membrane maintenance and repair in the brain, and in the regulation of synaptic remodelling during or after brain injury.^6,8,9,10,11 Rodent models of head injury and ischaemic stroke suggest that APOE influences neuronal repair, regeneration and survival after brain injury.^6,11 In clinical studies, possession of an APOE ε4 allele is associated with poor outcome after head injury.⁵ These observations suggest that APOE might influence outcome after acute stroke in humans, but clinical studies have produced conflicting results.⁵Here, we use systematic review and meta‐analysis methods to assess the effect of APOE on outcome after the three main pathological types of acute stroke: ischaemic stroke, intracerebral haemorrhage (ICH) and subarachnoid haemorrhage (SAH).     

Axonal damage and outcome in subarachnoid haemorrhage

Background

On the basis of preliminary evidence from patients with subarachnoid haemorrhage (SAH), axonal degeneration is thought to be an underestimated pathological feature.

Methods

A longitudinal study in 17 patients with aneurysmal SAH. Ventricular CSF was collected daily for up to 14 days. The neurofilament heavy chain^SMI35 (NfH^SMI35, a biomarker for axonal damage) was quantified using a standard ELISA (upper limit of normal 0.73 ng/ml). The primary outcome measure was the Glasgow Outcome Score (GOS) at 3 months.

Results

Of 148 samples from patients with SAH, pathologically high NfH levels in the CSF were found in 78 (52.7%) samples, compared with 20 (5%) of 416 samples from the reference population (p<0.0001). A pathological increase in NfH was observed in all patients with a bad outcome (GOS 1–3) compared with 8% of those with a good outcome (GOS 4–5, p<0.0001). This increase typically became significant 7 days after the haemorrhage (p<0.01). The result was confirmed by analysing the individual mean NfH concentrations in the CSF (3.45 v 0.37 ng/ml, p<0.01), and was reinforced by the inverse correlation of NfH in the CSF with the GOS (r = −0.65, p<0.01). Severity of injury was found to be correlated to NfH^SMI35 levels in the CSF (World Federation of Neurological Surgeons, r = 0.63, p<0.01 and Glasgow Coma Score, r = −0.61, p<0.01).

Conclusion

Patients with SAH thus have secondary axonal degeneration, which may adversely affect their outcome.The presence of axonal degeneration in patients with subarachnoid haemorrhage (SAH) has recently been suggested in a longitudinal study.¹ One important finding was that damage to axons may continue after the primary injury and extend into the period of delayed cerebral ischaemia.^1,2,3,4Presence of secondary axonal degeneration in patients with SAH may be relevant to the outcome because, despite the high mortality (32–67%) during the hyperacute phase,^2,5 a considerable proportion of mostly young and otherwise healthy patients has the potential for good recovery from a limited degree of primary injury. In these patients, it is well known that secondary brain damage caused by delayed cerebral ischaemia adversely affects the potential for recovery.^2,3,4 About 50% of patients who survive do not return to their previous level of employment.^6,7,8In this longitudinal study, we monitored the development of axonal degeneration indirectly by measuring a biomarker for axonal degeneration (neurofilaments, reviewed by Petzold⁹). Firstly, we investigated whether neurofilaments would be increased early on (eg, a single peak, indicative of primary axonal injury) or rise late (eg, secondary peaks, suggestive of secondary axonal damage) in the disease course. Secondly, we tested whether the pattern of an anticipated¹ increase in neurofilament levels over time would be related to the degree of recovery.     

The relationship between ischaemic brain lesions and cognitive outcome after aneurysmal subarachnoid haemorrhage

Journal of Neurology - Cerebral ischaemia is thought to be an important determinant of cognitive outcome after aneurysmal subarachnoid haemorrhage (aSAH), but the exact relationship is unclear. We...     

Fatigue after subarachnoid haemorrhage: a systematic review

BackgroundFatigue is common and debilitating symptom in many neurological disorders and it has been reported in patients after non-traumatic subarachnoid haemorrhage (SAH).ObjectivesWe undertook a systematic review to identify and critically appraise all published studies that have reported frequency, severity and time course of fatigue after SAH, the factors associated with its development and the impact of fatigue on patients' life after SAH.MethodsWe searched Medline, EMBASE, CINAHL, PsycINFO, AMED, PubMed and included in the review all studies published in English, recruiting at least 10 patients (> 18 years old) after SAH, which reported fatigue.ResultsWe identified 13 studies (total number of subjects 737) meeting our inclusion criteria. The frequency of fatigue ranged from 31 to 90%. Fatigue remained common even several years after the ictus. According to some studies fatigue after SAH was associated with sleep disturbances, anxiety, depression, posttraumatic stress disorder, cognitive and physical impairment, but these could not explain all cases of fatigue. Fatigue reduces quality of life and life satisfaction in patients after SAH.ConclusionsFatigue is common after SAH and seems to persist. Further research is needed to clarify its time course and identify factors associated with its development.     

Incidence and outcome of subarachnoid haemorrhage: a retrospective population based study

OBJECTIVES: The purpose was to define the incidence and case fatality rates of subarachnoid haemorrhage in the population of Devon and Cornwall. METHODS: A retrospective population based design was employed with multiple overlapping methods of case ascertainment. A strict definition of subarachnoid haemorrhage was used. Age and sex specific incidence rates and relative risks for death at different time intervals are calculated. RESULTS: Eight hundred cases of first ever subarachnoid haemorrhage were identified; 77% of cases were verified by CT, 22% by necropsy, and 1% by lumbar puncture. The incidence rates are higher than those previously reported in the United Kingdom. The age standardised incidence rate (/100 000 person-years) for females was 11.9 (95% confidence interval (95% CI) 9.5-15.0), for males 7.4 (5.4-10.0), and the total rate was 9.7 (7.5-12.6). The case fatality rates at 24 hours, 1 week, and 30 days were 21 (18-24)%, 37 (33-41)%, and 44 (40-49)% respectively. The relative risk for death at 30 days for those over 60 years:under 60 years was 2.95 (2.18-3.97). CONCLUSION: The incidence of subarachnoid haemorrhage in the United Kingdom is higher than previously reported. Three quarters of the mortality occurs within 3 days.     

Apolipoprotein E polymorphism and neuropsychological outcome following subarachnoid haemorrhage

OBJECTIVES: To investigate the association between APOE genotype and cognitive and emotional outcome following spontaneous subarachnoid haemorrhage (SAH). MATERIALS AND METHODS: Neuropsychological assessments were conducted with 70 SAH survivors derived from a consecutive series of neurosurgical admissions. Outcomes, including cognitive tests, health questionnaires and Glasgow Outcome Scale at a mean of 16 months after SAH, were compared with presence or absence of the epsilon4 allele. RESULTS: There was no evidence that SAH survivors possessing the epsilon4 allele had poorer outcome. The only suggestion of an association between the epsilon4 allele and outcome was in a subgroup of patients with a Fisher grade 4 haemorrhage, although this trend did not reach statistical significance. CONCLUSIONS: Overall, possession of the APOE epsilon4 allele is not significantly associated with neuropsychological outcome following SAH. However, there may be an effect amongst those with a Fisher grade 4 haemorrhage.     

Arachidonate metabolites and vasospasm after subarachnoid haemorrhage

A wide literature exists about the pathogenesis of cerebral arterial spasm following subarachnoid haemorrhage: several compounds have been identified in human cerebrospinal fluid as possible vasoactive agents involved in the biochemical mechanism of vasospasm onset. Many experimental evidences exist for a major involvement of arachidonate metabolites. The present work represents a review of experimental data supporting the hypothesis of cerebral arterial spasm as a result of an imbalanced vascular regulatory mechanism involving arachidonate metabolites. The authors have also monitored, in 25 cases of aneurysmal subarachnoid haemorrhage, lumbar and cisternal CSF levels of prostacyclin and PGD2, as representative of vasodilating and, respectively, vasoconstrictor compounds. In all cases CSF arachidonate metabolite levels after SAH were significantly higher than in control cases. Ten patients presented with symptomatic vasospasm: lumbar CSF PGD2 levels show fluctuations with superimposed peaks related to the neurological deterioration due to vasospasm, while lumbar CSF prostacyclin concentration-trend suggest a decreasing synthesis. In 15 patients presenting without vasospasm, lumbar CSF concentration of arachidonate metabolites are in a 'steady-state'. These data confirm the existence of an imbalanced biochemical situation promoting vasospasm, markedly in cisterns near to the ruptured aneurysmal wall. The evaluation of cisternal CSF levels of arachidonate metabolites supports the hypothesis of the clotting phenomenon around the ruptured aneurysm as an important predictive pattern of vasospasm, as shown in CT findings.     

Patterns of convexal subarachnoid haemorrhage: clinical,radiological and outcome differences between cerebral amyloid angiopathy and other causes

Journal of Neurology - Cerebral amyloid angiopathy (CAA) is a common aetiology of convexal subarachnoid haemorrhage (cSAH) but little is known about its specific characteristics in comparison with...     

A comparison of the outcome of aneurysmal subarachnoid haemorrhage before and after the introduction of an endovascular service

There has been a rapid change from predominantly surgical to endovascular treatment of ruptured intracranial aneurysms giving the opportunity to assess change in patient outcome during this transition. We identified and followed 139 patients with subarachnoid haemorrhage (SAH) treated in the year prior to (group 1) and following (group 2) the introduction of an endovascular service in a retrospective, cross-sectional study. A total of 78.7% of patients in group 1 underwent surgical treatment, 10.7% underwent endovascular treatment and 10.7% received no treatment, whereas patients in group 2 received 29.7%, 65.7% and 4.7%, respectively. MRS scores were obtained in 91% of patients in group 1 and in 89% of patients in group 2. A total of 30.7% and 24.0% of patients had a poor outcome in groups 1 and 2 respectively (p = 0.34). The overall change in the management of ruptured cerebral aneurysms in the post-International Subarachnoid Aneurysm Trial (ISAT) era has not significantly changed cross-sectional outcome, although absolute differences appear to reflect difference in outcome noted in the ISAT.     

Use of the Disability Rating Scale Recovery curve as a predictor of psychosocial outcome following closed-head injury.

Rapid rate of recovery has been associated with better outcome following closed-head injuries, but few studies have compellingly demonstrated this. This study used growth curve analyses of Disability Rating Scale (DRS) scores at acute hospitalization discharge, 1, 3, and 6 months post injury in a sample of 55 patients with a closed-head injury. Six month post-injury outcome measures were taken from significant other (SO) responses on the NYU Head Injury Family Interview (NYU-HIFI) including severity and burden ratings of affective/neurobehavioral disturbance, cognitive deficits, and physical/dependency status. Rate of recovery (linear and curvilinear recovery curve components) was significantly related to the level of affective/neurobehavioral severity, and the severity and burden of SO-perceived cognitive deficits. Only the intercept of the DRS recovery curve was associated with the SO-perceived severity and burden of physical/dependency status. Growth curve modeling is a meaningful and powerful tool in predicting head injury outcome.     

ApoE genotype and cognition after subarachnoid haemorrhage: a longitudinal study

OBJECTIVES: To investigate the effect of the apolipoprotein epsilon4 allele on cognitive functions after aneurysmal subarachnoid haemorrhage (SAH) in a longitudinal study. MATERIALS AND METHODS: Performances of 19 patients with and 27 patients without the epsilon4 allele were compared on eight cognitive test variables measured 1-4.5 years and 12-15 years after SAH. RESULTS: In the baseline examination, epsilon4 patients scored worse than non-epsilon4 patients on verbal fluency (P < 0.05). In the follow-up, a visual memory task and interference in colour naming showed more pronounced impairments from baseline in epsilon4 carriers than in non-carriers. CONCLUSION: Presence of the epsilon4 allele poses a minor risk for late cognitive impairment after the subacute phase of aneurysmal SAH.     

Visual neglect as a predictor of functional outcome one year after stroke

OBJECTIVE: The aim was to study the role of visual neglect in acute right hemisphere brain infarct as a predictor of poor functional outcome during the first year after stroke. In particular, we were interested in the additional value of neglect measures besides hemiparesis, hemianopia, cognitive deficits and age. PATIENTS AND METHODS: A consecutive series of 57 patients with a neuroradiologically verified right hemisphere infarct was examined within 10 days of the stroke. Fifty patients were followed up for 1 year. Neglect was measured with the Conventional and the Behavioural subtests of the Behavioural Inattention Test (BITC and BITB, respectively). The predictors were determined at the 10-day examination. Functional outcome was assessed 3, 6 and 12 months after the onset with the Frenchay Activities Index. RESULTS: Neglect in BITB was the best single predictor, which together with high age formed the best combination of predictors for poor functional outcome at each follow-up. Hemiparesis was also included in this prediction model at the 3-month follow-up, but hemianopia, BITC, or visuoconstructional and memory deficits showed no additional predictive value. However, neglect usually recovered soon. When neurological and cognitive deficits were assessed at the same time as the outcome, hemiparesis rather than neglect was the strongest correlate of poor outcome. CONCLUSION: Neglect in acute stroke is an important predictor of poor functional recovery. Residual neglect, which could be compensated in the follow-up tests, may nevertheless restrict patients' real-life activities and hobbies.