الفهرس 
OUTCOME OF ANEURYSMAL SUBARACHNOID HEMORRHAGEOnly 14 pages are availabe for public view
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Abstract
Fifteen percent of intracranial hemorrhages and 5 % of all strokes are due to aneurysmal subarachnoid hemorrhage (aSAH) from acute rupture of an intracranial aneurysm, affecting 145/100,000 persons annually.
Once the aneurysm has been treated, cerebral vasospasm (CV) is the leading cause of morbidity and mortality associated with aSAH despite tremendous efforts over the last decade to develop early diagnostic tools and aggressive treatment paradigms. Nearly 30%-70% of aSAH patients will experience vasospasm, and roughly one third of these patients will have a transient or permanent neurologic deficit as a result of delayed cerebral ischemia.
Cerebral vasospasm and delayed cerebral ischemia could represent separate clinical entities both occurring in aSAH patients, but with different pathophysiology, different relevance in the outcome and possibly different genetic predisposing factors.
After aneurysmal SAH, a multifaceted cascade of events is initiated, ultimately leading to vasospasm. Breakdown products of blood in the subarachnoid space probably are the triggering factor, while Ca-dependent and -independent vasoconstriction is taking place during CV. Lipid peroxides, an imbalance between endothelium-derived vasoconstrictor and vasodilator substances, NO toxicity, arachidonic acid metabolites, inflammatory cascades, a disruption of neuronal mechanisms that regulate vascular tone, endothelial proliferation, and apoptosis, are among those factors that, acting through interconnected pathways, result in the development of vasospasm.
In the current era of personalized medicine, which relies on quantifiable molecular and genetic information, identifying and understanding the key mechanisms underlying delayed cerebral vasospasm has the potential to transform the field and make an immediate impact on the outcomes of these patients.
As a theoretical model, an “omic signature” could incorporate an individual’s genetic, proteomic, and metabolomic phenotype into a powerful predictive tool. Genetic information such as haptoglobin genotypes could be used to stratify risk of subsequent CV and DCI, provide prognostic information based on published outcome probabilities, and prompt implementation of novel treatments based on individual pathophysiological models.
Haptoglobin (Hp) is a plasma a2-glycoprotein which binds free haemoglobin (Hb), thus preventing oxidative damage. After aSAH, blood is extravasated into subarachnoid space, leading to the breakdown of erythrocytes and subsequent release of Hb. The Hp-Hb complex is rapidly removed from the circulation by a specific receptor (CD163) found on macrophages. The binding and clearance of Hb neutralizes its oxidative and inflammatory potential. Three major subtypes, Hp1-1, Hp2-1 and Hp2-2 are the product of two closely related genes HP1 and HP2. The frequency of the HP1 and HP2 genes varies worldwide depending on racial origin. There are functional differences between the Hp 1 and Hp 2 protein products in protecting against hemoglobin-driven oxidative stress that appear to have important clinical significance.
In current study, 50 patients with acute aSAH were prospectively recruited and followed up clinically and radiologically by TCD examination for 14 days following aneurysmal rupture to early detect hemodynamic changes associated with CV and also occurrence of DCI secondary to CV. In this study, we attempt to analyze clinical features, neuroimaging findings, clinical scores and measurements and Hp genotyping to discover the potential risk factors that are predictive of CV and DCI during the acute phase of aneurysmal SAH.
Patients with aSAH were treated following a standardized protocol. Upon admission, all patients underwent DSA or CTA, and CT scan on admission. Based on clinical symptoms and neuroimaging findings on admission, the clinical condition of aSAH patients was graded according to Hunt and Hess and the severity of aSAH was radiologically classified according to Fisher scale.
The study was carried out at Matariya Teaching Hospital, Cairo, Egypt. As part of result analyses, about 34 patients (68%) developed CV among them 19 patients (38%) developed DCI. Only history of hypertension [RR= 1.6 (OR= 4)], diabetes mellitus [RR= 1.5 (OR= 3.4)] and smoking [RR= 1.5 (OR= 3.6)] had a significant independent relationship (P <0.05) with short term risk to develop CV following aSAH. While, Age, sex, hyperlipidemia, cardiovascular disease and peripheral vascular disease, intracranial aneurysm site and size did not achieve significant association for developing CV. Regrading poor Fisher scale and poor Hunt and Hess score, it showed significant association with CV (P <0.05).
Genotyping of Hp protein among our study cohort revealed that the relative distribution of the three common haptoglobin genotypes (Hp1-1, HP2-I & HP2-2) among Egyptian patients of aSAH is 14%, 40% and 46%, respectively; (gene proportion being 0.34 for Hp1 and 0.66 for Hp2).
Furthermore; Hp 2 allele was associated with radiographic vasospasm detected by TCD among our study patients (2-2 & 2-1 Vs 1-1: RR =5.4, OR =19.8, P <0.001).
Moreover, searching for relationship between CV & Hp genotype and risk for development of DCI; both variables failed to achieve significant relationship (P >0.05). but did not reach significance for DIND.
In a regression model; Hp genotype with α2-chain (Hp 2.2 & Hp 1.2) express a higher than normal significant risk to develop CV after aSAH. Among other factors, smokers also have a higher risk to develop CV after aSAH when controlled for other factors.
Finally, the Hp genotype may determine the susceptibility to cerebral vasospasm after acute aSAH. This has the potential for use in risk stratification by allowing for the identification of those patients requiring increased vigilance due to their inherent genetic risk for developing CV. Identifying SAH patients who are at high risk for development of vasospasm would allow for the selective administration of aggressive treatments to those patients who clearly would benefit from them.