The presence of tandem endothelial nitric oxide synthase gene polymorphisms identifying brain aneurysms more prone to rupture

OBJECT: It is becoming apparent that the presence of certain genetic variations (polymorphisms) may increase the individual's susceptibility to cardiovascular diseases, even in the absence of a family history. We hypothesized that brain aneurysms more prone to rupture may be identified on the basis of an individual's genotype for endothelial nitric oxide synthase (eNOS), a critical vasomodulatory protein found to be increasingly relevant to the pathobiology of aneurysms. METHODS: Patients' clinical data were recorded prospectively. Genomic DNA was isolated from blood samples obtained from individuals presenting consecutively to the Mayo Clinic with ruptured (58 patients) or unruptured (49 patients) intracranial saccular aneurysms. Using polymerase chain reaction and gene microarray technology, the following eNOS genetic polymorphisms were studied: intron-4 27-base pair variable number of tandem repeats (27 VNTR); promoter single nucleotide polymorphism (T-786C SNP); and exon-7 SNP (G894T SNP). Both groups of patients had similar demographic and clinical characteristics. For all three polymorphisms, variant alleles (p < or = 0.003) and their corresponding genotypes (p < or = 0.006) were found two to four times more frequently in patients with ruptured aneurysms than in patients with unruptured aneurysms. Strikingly, the odds ratio for presenting with a ruptured brain aneurysm among individuals demonstrating the copresence of all three variant alleles was 11.4 (95% confidence interval 1.7-75.9, p = 0.004). CONCLUSIONS: The authors have uniquely identified a set of tandem eNOS gene variations whose presence can be used to identify patients with aneurysms likely to rupture. We believe that if this finding is reproducible in a large multicenter study, in addition to known anatomical factors a rapid and cost-effective screening tool will become available to clinicians as a genetic aid to predict the risks of rupture in patients presenting with unruptured intracranial aneurysms.     

Influence of endothelial nitric oxide synthase T-786C single nucleotide polymorphism on aneurysm size

OBJECT: Among patients with aneurysms, those with heterozygous (T/C) endothelial nitric oxide synthase (eNOS) T-786C single nucleotide polymorphism (SNP), a mutation reducing endothelial nitric oxide synthesis, are reported to have larger ruptured intracranial aneurysms (IAs) than those with homozygous (C/C or T/T) genotype. The authors tested patients harboring aneurysms for eNOS T-786C SNP in two populations--Japanese and Korean. METHODS: The eNOS T-786C SNP was genotyped through direct sequencing in genomic DNA obtained from 336 Japanese and 191 Korean patients with lAs and 214 Japanese and 191 Korean control volunteers. Differences in genotype frequencies among the various aneurysm sizes were evaluated using the Fisher exact test. There was no significant difference in heterozygous (T/C) eNOS T-786C SNP between aneurysms 5 mm or smaller and those from 6 to 9 mm, and between lesions 5 mm or smaller and those 10 mm or larger in 336 Japanese patients harboring aneurysms--220 with ruptured and 116 with unruptured lesions--and in 191 Korean patients with ruptured aneurysms. CONCLUSION: The eNOS T-786C SNP genotype does not influence the size of aneurysms.     

Unruptured intracranial aneurysms: an assessment of the annual risk of rupture based on epidemiological and clinical data

From autopsy and neuroradiological studies a maximum prevalence of unruptured intracranial aneurysms (UA) of 0.5% in the general population is revealed. Studies concerning the incidence of aneurysmal subarachnoid haemorrhage (SAH) revealed 10 cases per 100,000 inhabitants per year. From these epidemiological parameters a minimum annual risk of 2% of rupture of an UA is calculated. It is in accordance with clinical studies, which also demonstrated an annual risk of UA rupture of at least 2%. No critical size of the UA predisposing to rupture has been found. Operation on diagnosed UA is recommended because of the serious prognosis after aneurysmal SAH (morbidity 20%-25% and mortality 50%-60%) and because the morbidity (4%) and the mortality (0%) after operative treatment of UA are very low.     

Screening for intracranial aneurysms in autosomal dominant polycystic kidney disease

SUMMARY:   Screening patients with autosomal dominant polycystic kidney disease (ADPKD) for asymptomatic intracranial aneurysms has been proposed as a method of reducing the morbidity and mortality associated with aneurysm rupture. However, recent studies have shown lower spontaneous rupture rates of small aneurysms and higher risks of significant complications with interventions than previously reported. Risk-benefit analysis has not demonstrated any benefit of screening ADPKD patients without a history of subarachnoid haemorrhage (SAH) for intracranial aneurysms, and has suggested that screening might cause harm.     

Cerebral arterial fenestrations: a common phenomenon in unexplained subarachnoid haemorrhage

Background

Fenestrations of intracranial arteries are variants resulting from incomplete fusion of vessels during development with unknown clinical significance. They are best visualised with 3D rotational angiography (3DRA).

Objective

In a prospective consecutive series of patients with suspected aneurysms, 3DRA was performed to identify not only the potential bleeding source but also to assess the frequency and location of any fenestrations of intracranial arteries.

Methods

In 287 consecutive patients with possible intracranial aneurysms (accidental discovery or previous history of SAH), 3DRAs were prospectively performed, and the location of subarachnoid haemorrhage was assessed by CT.

Results

Of 174 patients presenting with SAH, 153 had saccular aneurysms, and in 21 cases (12.1 %), no source of bleeding was found. In 20 of these 21 patients with "unexplained SAH" (95.2 %) an arterial fenestration was detected in the neighbourhood of the clot. The incidence of fenestration in the 153 aneurysmal SAH patients was 22.9 %, and it was 23.3 % in 266 patients with intracranial aneurysms (113 accidental and 153 ruptured).

Conclusions

Arterial fenestration was detected in 22.9 % of ruptured cerebral aneurysms, in contrast with 95.2 % in patients with unexplained SAH, the difference being statisctically significant (p?<?0.01). Fenestration is a developmental defect, a structural wall weakness possibly making the vessel prone to rupture. Its incidence of nearly 100 % may suggest a connection with idiopathic SAH. The presented data indicate that arterial fenestrations are generally overlooked, and they can be considered as one of the candidates for the source of idiopathic SAH.     

Rupture of intracranial aneurysms during treatment with Guglielmi detachable coils: incidence, outcome, and risk factors

OBJECT: The aim of this study was to assess the incidence and outcome of procedure-related rupture of intracranial aneurysms in patients treated with Guglielmi detachable coils (GDCs) and to identify risk factors for this complication. METHODS: Procedure-related rupture occurred in seven of 264 treated aneurysms in 239 consecutive patients. Aneurysm size, history of previous subarachnoid hemorrhage (SAH) caused by the treated aneurysm, timing of treatment after SAH, and the use of a temporary occlusion balloon in the seven procedures in which rupture occurred were compared with the remaining 257 procedures, and these findings were correlated with data from 13 studies in the literature, in which results of 2030 aneurysm treatments were reported. CONCLUSIONS: Procedure-related rupture of intracranial aneurysms during GDC treatment occurs in 2.5% of cases and is responsible for 1% of treatment-related deaths. Risk factors are as follows: small aneurysm size, previous SAH, and probably the use of a temporary occlusion balloon.     

Screening of risk groups for discovering intracranial aneurysms before rupture

In development of intracranial aneurysms contribute genetic factors together with smoking, hypertension, diabetes mellitus. Epidemiology studies suggest that as many as 5% of people harbour a cerebral aneurysm by age 75. Rupture of cerebral aneurysm is the most frequent cause of spontaneous subarachnoid haemorrhage (up to 80%.) Annual incidence of SAH is 10-14/100 000, but only 15-20% of aneurysms will rupture, and that will happen probably between 40-60 years. The morbidity and mortality of aneurismal subarachnoid (SAH) continues to be high. It is not possible to predict who has aneurysm and is it going to bleed or not, but it is possible to reveal high risk groups (polycystic kidney disease, Ehlers-Danlos sy, Marphan sy, family history of cerebral aneurysms, suspect de novo aneurysm formation in patients with prior history of cerebral aneurysm). Reviewing data from literature and reporting cases from each group with high risk, that have been screened and aneurysms discovered, authors wish to focus interest on this matter and propose screening program for these groups of patients. The mortality and morbidity in cases treated before rupture is significantly lower than after SAH, so screening programs could save many lives. According to our preliminara data, mostly based on control angiographies after 8-10 zears in patients previouslz operated for intracranial aneurysmas, from 15 angipgraphies 4 revealed new aneurysms (26% in 10 years period) with total number of 6 de novo formed aneurysms, which is not valid due to small number of patients but strongly suggests the importancy of screening program for risk groups.     

The significance of early operation in the management of ruptured intracranial aneurysms—An analysis of 251 cases hospitalized within 24 hours after subarachnoid haemorrhage

Summary An analysis of 251 patients who were hospitalized within 24 hours after rupture of supratentorial aneurysms and were not comatose during the very early stage was carried out. The patients were divided into three groups in relation to timing and methods of surgery. In 61 patients of Group A, the operation was planned to be delayed more than 10 days from subarachnoid haemorrhage (SAH). In 91 patients of Group B, clipping of aneurysms was performed within 48 hours of SAH and subarachnoid blood clots were simultaneously removed while approaching the aneurysms. In 99 patients of Group C, clipping of aneurysms was performed within 48 hours of SAH and radical and extensive removal of any subarachnoid blood clot identified on the computerized tomographic scan was tried at the same time. The outcome at 3 months after SAH was the most favourable in Group C patients and the least favourable in Group A patients.Early operation combined with radical removal of subarachnoid clots minimizes the overall mortality and morbidity in patients with ruptured intracranial aneurysms by preventing rebleeding and probably by avoiding vasospasm.     

Fusion of subarachnoid hemorrhage data and computed tomography angiography data is helpful to identify the rupture source in patients with multiple intracranial aneurysms

Neurosurgical Review - Determining the rupture source is imperative in patient with aneurysmal subarachnoid hemorrhage (SAH). About one third of SAH cases with multiple intracranial aneurysms...     

The role of constitutive and inducible nitric oxide synthase in the human brain after subarachnoid hemorrhage

AIM: Results of prior experimental studies show that nitric oxide (NO) plays an important role in the pathogenesis of vasospasm. In the present study, the expression of endothelial NO synthase (eNOS), neuronal NO synthase (nNOS) and of inducible NO synthase (iNOS) in the human brain after subarachnoid haemorrhage were studied. METHODS: Twenty-three samples of gyrus rectus or temporal operculum that were obtained during a surgical approach to anterior circulation aneurysms were used for this study. Seven samples were obtained during surgery from patients who underwent operation for unruptured aneurysms (control group). eNOS-mRNA, nNOS-mRNA and iNOS-mRNA were extracted and amplified by RT-PCR. Patients were subdivided for intergroup comparison by: age < 60 / > 60 years; source of sample; clinical grading; extent of subarachnoid clot; presence of intracerebral/intraventricular hematoma; surgical timing; vasospasm; outcome. RESULTS: There was a significant increase in the expression of eNOS between SAH and control groups (P=0.046); eNOS hyperexpression was higher in the patients in poor clinical conditions (P=0.002) and lasted until the late phase of haemorrhage. nNOS overall expression was unchanged but hyperexpression was observed in the patients in poor clinical conditions (P=0.008). There was a significant hyperexpression of iNOS in SAH group (P=0.026), and in patients with vasospasm (P=0.0024); the expression was significantly reduced in the late phase of haemorrhage (P=0.0038). CONCLUSIONS: The acute decrease of NO after SAH is not determined by reduced constitutive NOS expression and iNOS induction is a consequence of SAH and plays a major role in the pathogenesis of vasospasm.     

Prospective risk of hemorrhage in patients with vertebrobasilar nonsaccular intracranial aneurysm

OBJECT: Nonsaccular intracranial aneurysms (NIAs) are characterized by dilation, elongation, and tortuosity of intracranial arteries. Dilemmas in management exist due to the limited regarding the natural history of this disease entity. The objective of this study was to determine the prospective risk of subarachnoid hemorrhage (SAH) in patients with vertebrobasilar NIAs. METHODS: All patients with vertebrobasilar fusiform or dolichoectatic aneurysms that had been radiographically demonstrated between 1989 and 2001 were identified. These patients' medical records were retrospectively reviewed. A prospective follow-up survey was sent and death certificates were requested. Based on results of neuroimaging studies, the maximal diameter of the involved artery, presence of SAH, and measurements of arterial tortuosity were recorded. Nonsaccular intracranial aneurysms were classified according to their radiographic appearance: fusiform, dolichoectatic, and transitional. Dissecting aneurysms were excluded. The aneurysm rupture rate was calculated based on person-years of follow up. Predictive factors for rupture were evaluated using univariate analysis (p < 0.05). One hundred fifty-nine patients, 74% of whom were men, were identified. The mean age at diagnosis was 64 years (range 20-87 years). Five patients (3%) initially presented with hemorrhage; four of these patients died during follow up. The mean duration of follow up was 4.4 years (692 person-years). Nine patients (6%) experienced hemorrhage after presentation; six hemorrhages were definitely related to the NIA. The prospective annual rupture rate was 0.9% (six patients/692 person-years) overall and 2.3% in those with transitional or fusiform aneurysm subtypes. Evidence of aneurysm enlargement or transitional type of NIA was a significant predictor of lesion rupture. Six patients died within 1 week of experiencing lesion rupture. CONCLUSIONS: Risk of hemorrhage in patients harboring vertebrobasilar NIAs is more common in those with evidence of aneurysm enlargement or a transitional type of aneurysm and carries a significant risk of death.     

Does a safe size-limit exist for unruptured intracranial aneurysms?

Summary Of 1076 patients with intracranial ruptured aneurysms (RA) included in the Danish Aneurysm Study, 948 had the RA verified by angiography. Of these cases 908 RA had a maximum diameter less than 25 mm. 162 RA were <5 mm, 474 and 272 were between 5–10 mm and 11–24 mm, respectively. The average diameter of the RA according to the day of angiography after the aneurysm rupture did not differ significantly within the first 10 days. In these circumstances, using this indirect method for estimation of aneurysm rupture according to the size, we also recommend that unruptured aneurysms with a size 10 mm or less should be seriously considerated for operation.     

Endothelial Nitric Oxide Synthase Gene [G894T] polymorphism as a possible risk factor in aneurysmal subarachnoid haemorrhage

Summary Background. The exact aetiology, growth and rupture of intracranial aneurysms is unclear. In this study we investigated a possible association between intracranial aneurysm rupture and polymorphism of the endothelial nitric oxide synthase gene G894T. Methods. Endothelial nitric oxide synthase gene polymorphism of 53 patients with ruptured intracranial aneurysms and 60 control subjects were analysed by the polymerase chain reaction-restriction fragment length polymorphism technique. The genotype distribution and allele frequencies of endothelial nitric oxide synthase gene polymorphism in patients with ruptured intracranial aneurysm and healthy subjects were compared. Findings. The homozygous (TT) genotype frequency was significantly higher in patients with ruptured intracranial aneurysms. It was also found that the presence of eNOS 894TT genotype was significantly associated with the risk of intracranial aneurysm rupture (p < 0.05). Conclusion. Polymorphism in exon 7 of the endothelial nitric oxide synthase gene G894T seems to be a possible risk factor for intracranial aneurysm rupture. Correspondence: ünal ?züm, MD, PhD, Department of Neurosurgery. Cumhuriyet University School of Medicine, 58140 Sivas, Turkey.     

Familial aggregation of intracranial aneurysms in an Inuit patient population in Kalaallit Nunaat (Greenland)

OBJECTIVE: The incidence of subarachnoid hemorrhage (SAH) and intracranial aneurysm (IA) has been reported to be higher in Greenlandic Inuits than in Caucasian Danes, but the rate of familial aggregation in Inuits is unknown. METHODS: This study retrospectively compared the rate of familial aggregation of SAH and IA (at least one first- or second-degree relative with presumed SAH and/or IA) in 120 Inuit patients from Greenland admitted to the Copenhagen University Hospital in Copenhagen, Denmark, from 1978 to 1998 with a diagnosis of ruptured IA with that in 1,037 Caucasian Danes admitted from 1978 to 1983. RESULTS: Inuit patients had a much higher rate of familial history of SAH (23.1%) and of IA (9.6%) than Danish patients (4.3 and 1.6%, respectively). In both populations, familial SAH was associated with lower age at the time of aneurysm rupture. Danish patients with familial SAH showed a higher rate of middle cerebral artery aneurysms (40 versus 26% in sporadic SAH). In Inuit patients with familial and nonfamilial SAH, 42 and 38% of the aneurysms originated from the middle cerebral artery. The overall rate of multiple aneurysms was highest among Inuits, and in both populations, it was increased in the presence of a positive family history. CONCLUSION: The rate of a positive family history of presumed SAH and IA is high among Inuits who present with SAH compared with Caucasian Danes who present with SAH. This finding, coupled with a higher rate of multiple aneurysms and younger age at presentation, suggests a potential genetic influence among Inuit families.     

Relationship between endothelial nitric oxide synthase (eNOS) and natural history of intracranial aneurysms: meta-analysis

The aneurysmal subarachnoid hemorrhage is a major public health problem described as a sudden drastic event with no warning symptoms and high morbidity and mortality rates. The role of the endothelial isoform of nitric oxide synthase gene polymorphism in intracranial aneurysms (IAs) is still a matter of controversy with divergent findings among European, American, and Asian populations. Our study purposed to test the association between intracranial aneurysms formation and nitric oxide gene polymorphisms through a systematic review and meta-analysis. Systematic search on Medline, Lilacs, and EMBASE was performed. The primary search resulted in 139 papers, out of which 9 met our inclusion criteria after a full text analysis. The dominant T786C model found a significant association with IA (OR 1.22, 95 % CI 1.04–1.44, p?=?0.01), so did studies of the recessive T786C model (OR 0.37, 95 % CI 0.30–0.45, p?<?0.0001) but with opposite effect. Our findings support the presence of the T786C polymorphism as a predictor for the development of intracranial aneurysm in the cerebral vascular system. More studies are necessary in order to elucidate the pathways of the endothelial nitric oxide synthase (eNOS) in cerebrovascular diseases and in defining how different allelic combinations of the eNOS gene single-nucleotide polymorphism (SNP) could favor this pathological process.     

Is vascular angiopathy following intracranial aneurysm rupture immunologically mediated?

Summary Immunofluorescence studies showed the presence of IgM and/ or C3 in the endothelium of intracranial aneurysms in 5 out of 6 patients with subarachnoid haemorrhage (SAH). In none of them were the immune deposits found in the gyrus rectus. Cortical tissue of 4 epileptic patients which served as a control give negative results. Serum studies on femoral artery wall used as an antigenic substrate did not reveal circulating antibodies of the IgM or IgG class.Our studies strongly suggest that the IgM and/or C3 immune deposits located in the endothelium of intracranial arteries may play a role in post SAH neurological complications.     

Surgical management of unruptured aneurysms: prognostic indicators

BACKGROUND: The treatment of unruptured aneurysms (UA) remains controversial. Therefore, it has become necessary to define various prognostic indicators in the surgical treatment of unruptured aneurysms not associated with previously ruptured aneurysms. METHODS: During a 6-year period, 78 unruptured aneurysms were managed. The results of management were retrospectively reviewed to define the prognostic indicators. RESULTS: There were 104 patients with unruptured aneurysms who underwent surgical treatment. Seventy-five patients without previous subarachnoid hemorrhage (SAH) were selected for data analysis. Eighty-seven percent of the aneurysms were on the anterior circulation. The most common location was the middle cerebral artery (MCA) followed by the posterior communicating artery (PCom), ophthalmic artery, and anterior communicating artery (ACom). Six percent were found on the basilar artery. The mean size of aneurysms was 12.5 mm (range = 3-30 mm, SD = 7.4). At surgery, rupture of the aneurysm was encountered in eight cases with temporary control of the parent vessel being required in 31 procedures. In four cases, intraoperative angiography warranted clip reapplication. The Glasgow Outcome Scale (GOS) was used as an outcome measure. Surgical treatment resulted in good outcome (GOS 1) in 87% and 10.7% had fair outcome; 2.3% were in GOS 3 (severe disability) at 6 month follow-up. There was no mortality. Logistic regression identified significant relationships between GOS and intraoperative rupture (p < 0.0002), rupture and size (p < 0.003), and size and age (p < 0.01). CONCLUSIONS: Large size aneurysms were associated with intraoperative rupture, which had a strong correlation with poor outcome. Increased age showed a linear relationship with the size of the aneurysm. Overall results of treatment for UA are gratifying. There was no mortality. Early diagnosis and surgical extirpation of UA may reduce both intraoperative difficulties as well as poor outcome probability.     

Subarachnoid haemorrhage of unknown origin

Summary This study concerns 64 patients with angiographically negative subarachnoid haemorrhage (SAH) hospitalized in the period 1970–1982. Requisites for inclusion in the study were adequate angiographic demonstration of the carotid and vertebrobasilar systems and no clinical signs of spinal SAH or spontaneous intracerebral haematoma. The clinical data on the 64 cases confirm the close similarity, except for the prognostic factors, between angiographically negative SAH and SAH secondary to rupture of an intracranial saccular aneurysm. The study underlines the benign character of the clinical course and of the medium and long-term prognosis of the condition under study. In view of this, the hypothesis advanced sometime ago relating angiographically negative SAH to the rupture of microaneurysms (Ø<2 mm) of the large cerebral arteries with subsequent complete repair of the artery wall, or to the spontaneous thrombosis of intracranial saccular aneurysms, with the possibility of subsequent recanalization and risk of fresh rupture, would appear to be a reasonable one.     

Comparison of postoperative cognitive function in patients undergoing surgery for ruptured and unruptured intracranial aneurysm

Background

Patients with SAH often experience cognitive decline. Previous studies used normal volunteers, published normal test values, and orthopedic patients as controls to identify factors for postoperative cognitive decline. The present study excluded the effects of surgery by comparing cognitive function after surgical repair in patients with aneurysmal SAH and patients with unruptured intracranial aneurysm.

Methods

This study recruited 117 patients with SAH due to ruptured aneurysm and 39 patients with incidentally found unruptured intracranial aneurysms. The cognitive test battery consisted of the Japanese translation of the WAIS-R, the Japanese translation of the WMS, and the recall trial of the ROCF. Postoperative neuropsychological test scores for the patients with SAH and control subjects were compared using group-rate and event-rate analysis. The relationship between clinical variable and postoperative cognitive decline in the patients with SAH was evaluated by univariate analysis using the Mann-Whitney U test or χ² test.

Results

Group-rate analysis showed that the WAIS-R and ROCF scores were significantly lower in the SAH group than in the control group. Event-rate analysis demonstrated that the incidence of cognitive decline in the patients with SAH (73 [62.4%] of the 117 patients) was significantly higher than that in the control subjects (12 [30.8%] of 39 patients). The Hunt and Hess grade was significantly higher in patients with postoperative cognitive decline.

Conclusion

The cognitive function after SAH was significantly correlated with Hunt and Hess grade on admission when using patients with postoperative unruptured intracranial aneurysm as the control group.     

Epidemiological features and diagnostic evaluation of intracranial aneurysms

Female gender and cigarette smoking appear to be risk factors for the development of multiple intracranial aneurysms. An acquired nature is likely in this form. The mechanism of aneurysm formation in patients with sickle cell anemia is apparently different. These patients also present multiple aneurysms that show propensity for vertebrobasilar territory and appear at a younger age. Familial cerebral aneurysms are diagnosed once heritable connective tissue disorders have been excluded. The age of patients tends to be lower and the size of aneurysm to be smaller at the time of rupture in the familial form. These aneurysms are less frequently found in the anterior communicating artery than the sporadic aneurysms. A high incidence of asymptomatic familial aneurysms was detected in people with family histories of intracranial aneurysms studied by means of magnetic resonance angiography. Furthermore, familial aneurysms are more likely to rupture in families having members with aneurysmal subarachnoid hemorrhage (SAH) than in those without. The results of an interesting study using color "power" transcranial Doppler ultrasound in patients with aneurysmal SAH suggest that as the intracranial pressure diminished, the size of the aneurysm increased, and there was relatively little change between maximum and minimum dimensions during the cardiac cycle, i.e., the pulsatility is reduced. The use of postoperative angiography after clipping is a matter of debate. The indication more widely accepted is in large aneurysms with a wide neck, in which incomplete clipping can be suspected. Taking into account the current low risk of angiography in centers of excellence, its routine use may be recommended. Aneurysm remnants, vessel occlusion, vasospasm, and newly identified aneurysms are the main findings that were reported.