====== Aneurysmal subarachnoid hemorrhage pathophysiology ======


A unifying theory for the pathophysiological changes following [[subarachnoid hemorrhage]] has yet not been described. Some of these changes may be causally connected or present themselves as an epiphenomenon of an associated process. A causal connection between [[DCI]] and early [[brain injury]] (EBI) would mean that future therapies should address EBI more specifically. If the mechanisms following SAH display no causal pathophysiological connection but are rather evoked by the subarachnoid blood and its degradation production, multiple treatment strategies addressing the different pathophysiological mechanisms are required. The discrepancy between experimental and clinical SAH could be one reason for unsuccessful translational results
((van Lieshout JH, Dibué-Adjei M, Cornelius JF, Slotty PJ, Schneider T, Restin
T, Boogaarts HD, Steiger HJ, Petridis AK, Kamp MA. An introduction to the
pathophysiology of aneurysmal subarachnoid hemorrhage. Neurosurg Rev. 2017 Feb
18. doi: 10.1007/s10143-017-0827-y. [Epub ahead of print] Review. PubMed PMID:
28215029.
)).


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Many pathological mechanisms ensue after cerebral aneurysm rupture, including [[hydrocephalus]], [[apoptosis]] of [[endothelial cell]]s and [[neuron]]s, [[cerebral edema]], loss of [[blood brain barrier]], abnormal [[cerebral autoregulation]], microthrombosis, [[cortical spreading depression]] and macrovascular vasospasm. 

There is significant theoretical evidence for the potential role of [[estrogen]] and [[progesterone]] use in altering the [[pathogenesis]] of [[SAH]]. Nevertheless, this has received mixed reviews in both case controlled studies and cohort analysis within the literature
((Young AM, Karri SK, Ogilvy CS. Exploring the use of estrogen & progesterone
replacement therapy in subarachnoid hemorrhage. Curr Drug Saf. 2012
Jul;7(3):202-6. Review. PubMed PMID: 22950381.
)). 
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[[Gas chromatography]], [[time-of-flight mass spectrometry]] was applied to [[CSF]] samples collected from 15 consecutive high-grade [[aneurysmal subarachnoid hemorrhage]] patients (modified Fisher grade 3 or 4). Collected CSF samples were analyzed at two time points (admission and the anticipated [[vasospasm]] timeframe). [[Metabolite]] levels at both time points were compared and correlated with vasospasm status and [[Glasgow Outcome Scale]] (GOS) of patients at 1 year post-aSAH. Significance level was defined as p < 0.05 with false discovery rate correction for multiple comparisons.

Of 97 metabolites identified, 16 metabolites, primarily free amino acids, significantly changed between the two time points. These changes were magnified in modified Fisher grade 4 compared with grade 3. Six metabolites ([[2-hydroxyglutarate]], [[tryptophan]], [[glycine]], [[proline]], [[isoleucine]], and [[alanine]]) correlated with [[GOS]] at 1 year post-aSAH independent of vasospasm status. When predicting patients who had low disability (GOS 5 vs. GOS ≤4), 2-hydroxyglutarate had a sensitivity and specificity of 0.89 and 0.83 respectively.

This preliminary study suggests that specific [[metabolite]] changes occur in the [[brain]] during the course of aSAH and that quantification of specific CSF metabolites may be used to predict long-term outcome in patients with aSAH. This is the first study to implicate [[2-hydroxyglutarate]], a known marker of tissue hypoxia, in [[aneurysmal subarachnoid hemorrhage]] [[pathogenesis]]
((Lu AY, Damisah EC, Winkler EA, Grant RA, Eid T, Bulsara KR. Cerebrospinal
fluid untargeted metabolomic profiling of aneurysmal subarachnoid hemorrhage: an 
exploratory study. Br J Neurosurg. 2018 Dec 26:1-5. doi:
10.1080/02688697.2018.1519107. [Epub ahead of print] PubMed PMID: 30585503.)).