Neurosurgical Management of Aneurysmal Subarachnoid Haemorrhage (Acta Neurochirurgica Supplement)

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A recent clinical study found increased cyclooxygenase within the walls of ruptured and unruptured aneurysms [ 33 ] and the same group has shown that aspirin may reduce the rate of aneurysm rupture due to its anti-inflammatory properties [ 34 , 35 ]. E-selectin has also been found at elevated levels in the walls of aneurysms [ 36 ].

Additionally, environmental factors that contribute to a proinflammatory state may contribute to aneurysm formation [ 37 ]. A detailed discussion of the contribution of inflammation to aneurysm formation is outside the scope of this review and was reviewed recently elsewhere [ 38 ]. Animal models have been utilized to establish a causative relationship between inflammation and brain injury after SAH.

Several animal models for SAH exist, each with their own advantages and drawbacks [ 39 ].

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Common models include blood injection into the basal cisterns of animals or endovascular perforation, both of which produce vasospasm and an inflammatory response [ 40 — 42 ]. As in human SAH studies, there is considerable variability between subjects when inflammatory responses are quantified [ 43 , 44 ]. Animal studies of SAH have found evidence of inflammation in all intracerebral compartments: CSF, brain parenchyma, and vasculature [ 45 — 49 ].

Animal studies have been used to link inflammation, cerebral edema, and cell death after SAH. Furthermore, there is not even a consensus that neuronal death occurs in SAH, with some groups reporting no neuronal apoptosis after SAH while others observe neuronal death throughout the brain after SAH [ 54 — 56 ].

Regardless of whether or not neuronal death occurs after SAH, there are other pathological events that could explain neurological dysfunction after SAH, such as synaptic injury, loss of long term potentiation, and white matter injury [ 57 ]. Both synaptic loss and white matter injury are mediated by inflammation in models of other neurological diseases; however, more work is needed to understand the precise role of inflammation on cell death and injury after SAH [ 58 , 59 ]. Animal models of SAH have also found evidence for inflammation playing a role in injury outside of the brain.

In a study using endovascular perforation as a model of SAH in rats, systemic anti-inflammatory treatment was able to reduce lung injury after SAH [ 60 ]. This is relevant to SAH treatment as many patients experience cardiopulmonary complications as part of a systemic reaction to SAH [ 61 ].

Animal models of SAH have played an essential role in linking inflammation to vasospasm after SAH and will be discussed in more detail below. Early clinical studies showing a correlation between vasospasm and fever in the absence of infection established a link between inflammation and vasospasm [ 77 — 86 ]. Several proinflammatory agents such as talc crystallized hydrous magnesium sulfate [ 87 , 88 ], latex, polystyrene, and dextran beads [ 89 , 90 ], lipopolysaccharide LPS [ 91 ], and tenascin-C [ 92 ] have been administered intracisternally to show that vasospasm can occur in the absence of blood.

These studies provided proof that vasospasm is not dependent on red blood cells RBCs or hemoglobin Hgb and confirmed the role of inflammation in the development of vasospasm. Among inflammatory molecules linked to cerebral vasospasm, the selectin family, which consists of three members: E-selectin, platelet- P- selectin, and leukocyte- L- selectin, has been extensively studied.

These molecules facilitate leukocyte binding and migration through vascular endothelium towards injured tissue. L-selectin and E-selectin are constitutively expressed on cell surfaces whereas P-selectin expression requires activation by histamine or thrombin [ 93 ]. E-selectin is elevated in the CSF of SAH patients with higher concentrations seen in patients who develop moderate or severe vasospasm [ 3 ]. Inhibition of E-selectin with an inhibitory antibody [ 62 ] and E-selectin tolerization via intranasal administration have decreased vasospasm in rodent SAH models [ 63 ].

However, not all data point to selectins having deleterious effects after SAH: Integrins are cell surface proteins that facilitate cell-cell adhesion and interaction. Systemically administered anti-LFA-1 and Mac-1 monoclonal antibodies reduce vasospasm in rat [ 64 ], rabbit [ 65 ], and primate [ 66 ] SAH models. Immunoglobulin superfamily proteins, such as ICAM-1, play a role in leukocyte adhesion and are upregulated in patients who develop clinical vasospasm [ 3 ] as well as in rabbit [ 70 ] and canine SAH models [ 47 ].

Anti-ICAM-1 monoclonal antibodies were shown to decrease femoral artery vasospasm and inhibit infiltration of macrophages and neutrophils into blood vessel adventitia in a rodent model [ 95 ] and reduce vasospasm in a rabbit model of SAH [ 71 ]. IL-6 has been shown to peak early after SAH, suggesting that it may be an early marker for predicting vasospasm development [ 9 , 11 , 47 , 96 — ]. Several studies have examined intracellular signaling pathways activated during inflammation and their role in vasospasm. Poly ADP-ribose polymerase PARP is a nuclear enzyme that regulates adhesion molecule expression and neutrophil recruitment during inflammation [ ].

The complement pathway of antibacterial proteins also affects vasospasm after SAH. Complement depletion by treatment with cobra venom [ ] and prevention of complement activation with nafamostat mesilate, a serine protease inhibitor, reduced vasospasm in experimental models [ 90 , ] and human subjects [ , ]. Moreover, expression of the membrane attack complex MAC is increased in a rat model of SAH and can be responsible for lysis of extravasated erythrocytes and release of hemoglobin after SAH [ ].

Oxidative signaling and oxidative stress are effectors of the immune response in many central nervous system diseases [ ], and it is likely that the balance of oxidative stress and antioxidants influences response to and recovery from SAH. Its main action is to bind free hemoglobin and facilitate its uptake and clearance.

This has a net effect of reducing oxidative stress caused by free hemoglobin [ , ]. Three phenotypes of haptoglobin Hp have been identified in humans: Hp , Hp , and Hp [ ]. Similarly, genetically modified Hp mice experience increased macrophage infiltration in the subarachnoid space, more severe vasospasm, and worse functional outcome after SAH [ ]. Recently, Hp phenotype was associated with neurological deterioration but not cerebral infarction or unfavorable outcome in one clinical SAH study [ ]; however, another recent study did find worse clinical outcomes in patients with the phenotype [ ].

Ongoing work in this area will further clarify the role of haptoglobin phenotype in SAH. Under physiologic conditions, NO affects signaling pathways for vasodilation and cytoprotection among many others [ , ]. On the other hand, genetic elimination of eNOS in knockout mice reduces the incidence of vasospasm and reduces oxidative stress as measured by superoxide production but has no effect on iNOS [ ].

Endothelins, which are potent vasoconstrictors and proinflammatory mediators expressed by vascular endothelial cells and vascular smooth muscle cells [ ], are thought to contribute to tissue inflammation and cerebral edema. Several studies have documented increased ET-1 levels in SAH patients with symptomatic vasospasm and that the amount of blood within the cisterns correlated with the level of ET-1 in CSF [ 73 , 76 , ].

However, other studies have failed to find significant elevation of ET-1 after SAH or a correlation between ET-1 levels and vasospasm [ 16 , 73 ]. Inhibition of ET-1 by administration of anti-ET-1 monoclonal antibodies [ ], anti-ET receptor antibodies [ 74 , ], ET activation enzyme inhibitors [ ], and levosimendan which antagonizes the ET receptor [ ] was effective in decreasing vasospasm in some [ 74 , ] but not all studies [ , ].

Transgenic mice overexpressing ET-1 experienced more pronounced vasospasm and cerebral edema and an ET-A receptor antagonist decreased vasospasm and edema in the same study [ ]. As subarachnoid blood is thought to generate much of the acute inflammation in SAH, faster clearance of subarachnoid clot could potentially improve outcomes after SAH. This theory has been tested, and intrathecal administration of thrombolytic agents has decreased vasospasm and improved outcomes in primates [ ] and humans [ — ] after SAH.

A meta-analysis showed a beneficial effect of thrombolytic treatment, with absolute risk reductions of In a recent clinical study by Yamamoto et al. Kim and colleagues recently demonstrated that cisternal irrigation with papaverine, a phosphodiesterase inhibitor and potent vasodilator, was similar in effectiveness compared to the thrombolytic urokinase, both of which decreased incidence of vasospasm [ ]. Corticosteroids are potent anti-inflammatories and have been used in several human SAH trials. Experimental administration of high-dose methylprednisolone has been shown to reduce angiographic vasospasm and ameliorate arterial wall abnormalities in dog models [ — ].

Human clinical studies by Chyatte and colleagues [ ] showed that high-dose methylprednisolone treatment improved neurological outcomes, reduced mortality, and delayed cerebral ischemia. A multicenter study of intravenous hydrocortisone administration after SAH showed improved mental status, speech, and motor function at 1 month after treatment [ ]. However, another randomized controlled trial of hydrocortisone did not show any effect on neurological outcome after SAH [ ]. On the other hand, hydrocortisone has been shown to support hypervolemic therapy by attenuating natriuresis [ ], inducing hypervolemia, and improving the efficiency of hypervolemic therapy [ ].

However, a large double blind randomized control trial demonstrated a beneficial effect of methylprednisolone in functional outcome one year after SAH but no effect on vasospasm [ ]. These studies underscore the fact that outcomes in SAH are not solely dependent upon the development of vasospasm. Nonsteroidal anti-inflammatory drugs NSAIDs also have potent anti-inflammatory properties, mediated in part by inhibition of cyclooxygenase expression, which reduces prostaglandin synthesis [ ]. Ibuprofen inhibits femoral artery vasospasm and decreases periadventitial monocytes and macrophages after, in a rodent model of SAH, and can increase cerebrovascular diameter in monkeys and rabbits [ — ].

Chyatte and colleagues also demonstrated that ibuprofen prevented ultrastructural changes in the cerebral vessel walls of dogs after blood injection [ ]. The nonsteroidal anti-inflammatory drugs parecoxib and celecoxib have also shown promise as treatment options for vasospasm [ — ]. As these drugs are relatively safe and well studied in humans, they hold promise for clinically applicable treatment options for vasospasm. Immunosuppressants such as cyclosporine cause T-cell dysfunction by inhibiting interleukin-2 IL-2 transcription [ ] and have been tested in experimental SAH with varied success [ , ].

Clinical studies with cyclosporine are also varied, showing no beneficial effect of cyclosporine in the outcome patients with severe SAH [ ], but showing improved outcome in patients who underwent early clipping after SAH when combined with nimodipine [ — ]. Tacrolimus FK , a newer immunosuppressant, did not prevent vasoconstriction and lymphocytic infiltrations in experimental SAH models [ — ].

Statins are 3-hydroxymethylglutaryl coenzyme A reductase inhibitors clinically used as cholesterol-reducing agents. Their ability to reduce the expression of proinflammatory cytokines and inhibit leukocyte integrins confers their potent anti-inflammatory activity [ , ]. Preconditioning of rats with atorvastatin has been shown to reduce the level of ET-1 while attenuating vasospasm, which could be a mechanism of antivasospastic effects of statins after SAH [ ].

Simvastatin treatment before or after SAH was also shown to attenuate cerebral vasospasm and neurological deficits, possibly via endothelial nitric oxide upregulation [ ], and decrease perivascular granulocyte migration [ 40 ]. Several clinical studies have shown that statins decrease serum ICAM-1 levels in hypercholesterolemic patients [ , , — ], which could explain the experimental findings associated with decreased leukocyte migration.

However, clinical studies with statins have yielded mixed results. While one study showed improved day functional outcomes and cerebral vasospasm in patients receiving statins prior to their SAH [ ], more recent studies [ , ] did not find significant differences in the severity of angiographic or clinical vasospasm or neurologic outcomes of patients receiving statins after SAH. Another case-control study showed that oral atorvastatin treatment decreased vasospasm and cerebral ischemia but did not lead to significant functional improvement 1 year after SAH [ ].

Subsequently, pravastatin was also effective at sustaining the improved neurological outcome at 6 months after the treatment [ ]. A Cochrane review of clinical trials on statins after SAH concluded that, in the only clinical trial that met criteria, although simvastatin improved vasospasm, mortality, and functional outcome, these benefits were not statistically significant [ ]. Currently, clinical trials including simvastatin in aneurysmal subarachnoid hemorrhage STASH trial are ongoing http: Nitric oxide NO depletion contributes to the pathogenesis of cerebral vasospasm after SAH [ , ].

Therefore, several NO donors have been investigated for treatment of vasospasm. Intrathecal NO supplementation via controlled-released polymers was shown to prevent vasospasm in rat and rabbit models of SAH [ , ] and delayed polymer implantation 24 or 48 hours after SAH has been shown to be still effective at ameliorating vasospasm [ ]. Several other studies have also shown that selective intracerebral NO injection, [ ] intraventricular NO injection [ ], and systemic nitrite infusions can improve the severity or decrease the incidence of vasospasm in experimental and clinical studies [ ].

Intravenous sodium nitrate NaNO 2 was also shown to reduce the degree of vasospasm and nitrite, nitrate, and S-nitrosothiols concentrations in CSF were found to be increased compared to controls in primate model of SAH [ ]. L-citrulline is an amino acid that when converted to L-arginine increases nitric oxide NO production by NO synthase NOS , leading to vasodilation [ ]. L-citrulline administration has been shown to prevent posthemorrhagic cerebral vasospasm in the transgenic Hp model of SAH, improve neurological function as determined by PGA posture, grooming, and ambulation scores, and reverse the decrease in upregulation of iNOS and eNOS expression in Hp animals compared with baseline levels in mice [ ].

Besides vasodilation, NO supplementation can have anti-inflammatory effects through modulating leukocyte-endothelial cell interactions in the acute inflammatory response. Inhibitors of NO production increase leukocyte adherence [ ], and NO modulates oxidative stress [ ] and microvascular permeability [ , ]. The anti-inflammatory effects of NO through prevention of leukocyte adhesion have been linked with its ability to inactivate the superoxide anion [ ].

Besides ameliorating vasospasm, whether NO donors including citrulline can help recoupling of eNOS, decrease the inflammatory infiltration, and decrease neuronal apoptosis requires further investigation. Other NO donors such as sodium nitroprusside and nitroglycerin are not considered as potential candidates due to their side effects such as dose-limiting hypotension, cyanide toxicity, and tolerance development [ ].

Clazosentan, a synthetic endothelin receptor antagonist ETRA , has been investigated as a potential treatment for vasospasm after subarachnoid hemorrhage [ ].

Cerebral Vasospasm in Traumatic Brain Injury

In CONSCIOUS-2, a phase-III randomized controlled trial, including 1, patients, clazosentan infusion up to 14 days after hemorrhage did not reduce vasospasm-related morbidity and mortality or improve functional outcome [ 75 ]. A meta-analysis of randomized controlled trials for ETRAs for the treatment of vasospasm, including 5 trials with patients, showed that ETRAs decreased incidence of angiographic vasospasm; however, they did not improve functional outcome, vasospasm-related cerebral infarction, or mortality [ ].

These studies reinforce that vasospasm alone cannot be accounted for the neurological deficits and functional outcome after SAH and treatment strategies that only target improving or preventing vasospasm are not likely to succeed. Cilostazol is a selective phosphodiesterase III inhibitor that is used to treat ischemic peripheral vascular disease and exhibits anti-inflammatory properties including inhibiting microglial activation [ , ].

Oral cilostazol administration prevented vasospasm in a rat model of SAH [ ] and reduced endothelial damage in a canine model of SAH [ ]. Clinical studies have demonstrated effectiveness of cilostazol in decreasing incidence and severity of vasospasm [ , ]. A multicenter randomized clinical trial of cilostazol has shown a decrease in angiographic vasospasm but no improvement in outcomes 6 months after SAH [ ]. While there is no doubt that inflammation occurs after SAH, a link must be made between inflammation and poor outcomes after SAH for it to be considered an important therapeutic target.

As demonstrated by several of the trials discussed above, vasospasm is not the only determinant of outcome after SAH. It is likely that inflammation plays multiple roles after SAH, mediating vasospasm as tissue damage as well as leading to regeneration or recovery as has been shown in other neurological conditions [ ].

Inflammation, Vasospasm, and Brain Injury after Subarachnoid Hemorrhage

There is a vast literature in ischemic stroke that ties the inflammatory response to deleterious effects such as edema and neuronal loss. Many experimental studies in stroke have shown blood brain barrier breakdown to be mediated by inflammatory cytokines [ ] and that inhibiting inflammation reduces cerebral edema and neurological injury [ , ].

However, despite the vast literature on inflammation in ischemic stroke, there have been no successful clinical trials using anti-inflammatory agents. Early brain injury includes cell death, cerebral edema, and neuronal dysfunction that occur after SAH. Although vasospasm is a major cause of clinical deterioration after SAH, recent thinking has focused on the fact that vasospasm is not the only phenomenon contributing to poor patient outcomes after SAH [ , ]. A key example of this is that nimodipine, the only pharmaceutical treatment shown to improve outcomes in SAH, appears to manifest its effects without affecting the rate of vasospasm [ , ].

Many patients also undergo neurological deterioration in a delayed fashion after SAH. This can be due to cerebral vasospasm, which typically peaks 7 to 14 days after SAH, but also occurs in the absence of vasospasm.

Additionally, it is likely that the events of early brain injury occur along a continuum with DND and are likely mediated by many of the same factors. As in ischemic stroke, there is no accepted use of anti-inflammatory treatments for improving outcome after SAH. As discussed earlier, corticosteroids have been used to block inflammation after SAH, but there is no clear therapeutic benefit of this strategy [ ].

However, there is experimental evidence from animal studies showing that blocking inflammatory pathways can improve both blood brain barrier breakdown and neuronal survival after SAH [ , ]. Clinically, the presence of cell death, cerebral edema, and vasospasm all contribute to poor outcomes after SAH. Though it is difficult to measure cell loss in humans, there is evidence for hippocampal neuronal loss after SAH based on MRI imaging, and elevated neurofilament levels in CSF correlate with functional outcome after SAH, indicating a link between axonal breakdown and clinical outcome [ , ].

As in ischemic stroke, proinflammatory cytokines have gained attention as biomarkers for outcome in SAH, and the recent literature is well reviewed by Lad and colleagues [ ]. Genetic differences in inflammatory cytokine expression and haptoglobin phenotype discussed previously have also been used to prognosticate outcome in patients with SAH, without definitive results [ 69 ].

This points to a possible dual role for inflammation in both acute injury and recovery, as has been proposed in other neurological diseases [ ]. There is already experimental support for this dual role of inflammation in SAH, as the cytokine MCP-1 that has been associated with poor outcomes and vasospasm after SAH has recently been used to promote repair of experimental aneurysms [ 21 , ]. Evidence from both clinical and animal studies indicates that inflammation contributes to aneurysm formation, brain injury, and vasospasm after SAH and that many of the same molecules contribute to vasospasm and brain injury after SAH Figure 1 , Table 1.

Much of the data from human studies linking inflammation to worse outcomes after SAH is correlative and studies examining different inflammatory molecules at different time points after SAH make it difficult to make direct comparisons Table 1. This would suggest anti-inflammatory treatment to be a robust treatment strategy for SAH, as in other diseases. For example, the possibility that aspirin could reduce chronic inflammation within the walls of aneurysms and decrease the risk of rupture [ 34 , 35 ] is akin to the paradigm of human cardiovascular disease in which the anti-inflammatory actions of aspirin and statins may protect against cardiovascular disease [ , , ].

Unfortunately, this strategy has not borne out reliably in clinical trials. One potential reason for this is that animal studies of homogenous populations may not be an accurate model of SAH in humans where individual responses to a given insult could be quite variable. Schematic of a coronal projection of a ruptured cerebral aneurysm and contributing factors that result in cerebral vasospasm after SAH and delayed ischemic injury. Many inflammatory factors are hypothesized to contribute to brain injury and vasospasm after SAH.

The interface between subarachnoid blood, brain parenchyma, and the cerebral vasculature is the likely location for induction of inflammatory cascades that lead to brain injury and vasospasm after SAH. Clinicians who care for patients with SAH understand that there is a wide range of physiologic responses to SAH, even in patients who present with the same initial grade of hemorrhage. While this is doubtlessly influenced by many factors such as SAH blood volume , the intensity of an individual's inflammatory response to SAH may also determine if a patient develops delayed clinical deterioration or vasospasm.

While this could be influenced by factors such as haptoglobin genotype [ ], there are probably other genetic and environmental factors that influence patients' production of, and tolerance to, a post-SAH inflammatory response. Evidence from animal studies has shown that inflammatory stimuli can both exacerbate and reduce vasospasm, depending on the intensity of the stimulus [ ]. A recent clinical study implied that preexisting atherosclerotic disease could have a protective effect on patients who suffer SAH, possibly by modifying neuroinflammation [ , , ]. In the future, treatment for SAH may involve tailoring therapy to match the timing and intensity of an individual patient's inflammatory response.

In order for this approach to be implemented, successful validation of inflammatory biomarkers and outcome measures for SAH would need to be developed. The immune response within and possibly outside of the CNS is clearly a driving force behind many of the pathological events of SAH, including both vasospasm and early brain injury. Though much experimental and clinical work has linked increased inflammation to poor outcome after SAH, there is still no proven anti-inflammatory treatment that can be offered to patients who have suffered SAH.

The volume of research on inflammation and SAH is rapidly expanding and will likely lead to new clinical trials, development of biomarkers, and hopefully anti-inflammatory treatments for SAH. Though anti-inflammatory treatments will likely improve the lives of patients with SAH, it must be remembered that neuroinflammation has beneficial effects as well and could also play a role in recovery after SAH. Dempsey Cerebrovascular Section Award. The authors declare that there is no conflict of interests regarding the publication of this paper. National Center for Biotechnology Information , U.

Journal List Biomed Res Int v. Published online Jul 3. Author information Article notes Copyright and License information Disclaimer. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. This article has been cited by other articles in PMC.

Abstract Subarachnoid hemorrhage SAH can lead to devastating neurological outcomes, and there are few pharmacologic treatments available for treating this condition.

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Introduction Subarachnoid hemorrhage SAH remains a devastating disease, leaving survivors with neurological injuries that range from subtle cognitive deficits to disabling cerebral infarctions. Evidence for Acute Inflammation after Subarachnoid Hemorrhage 2. Inflammation and Aneurysm Formation Inflammation may also play a role in aneurysm formation. Induction of Vasospasm with Proinflammatory Agents Early clinical studies showing a correlation between vasospasm and fever in the absence of infection established a link between inflammation and vasospasm [ 77 — 86 ].

Inflammatory Molecules Linked to Development of Vasospasm Among inflammatory molecules linked to cerebral vasospasm, the selectin family, which consists of three members: Trials of Anti-Inflammatory Agents for Treatment of Vasospasm As subarachnoid blood is thought to generate much of the acute inflammation in SAH, faster clearance of subarachnoid clot could potentially improve outcomes after SAH. Discussion Evidence from both clinical and animal studies indicates that inflammation contributes to aneurysm formation, brain injury, and vasospasm after SAH and that many of the same molecules contribute to vasospasm and brain injury after SAH Figure 1 , Table 1.

Open in a separate window. Table 1 Key inflammatory molecules implicated in the pathology of SAH. Conclusion The immune response within and possibly outside of the CNS is clearly a driving force behind many of the pathological events of SAH, including both vasospasm and early brain injury. Conflict of Interests The authors declare that there is no conflict of interests regarding the publication of this paper.

Detection of soluble intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in both cerebrospinal fluid and serum of patients after aneurysmal subarachnoid hemorrhage. Cytokine production in cerebrospinal fluid after subarachnoid haemorrhage. Inflammatory mechanisms after ischemia and stroke.

Journal of Neuropathology and Experimental Neurology. Thrombolysis with tissue plasminogen activator alters adhesion molecule expression in the ischemic rat brain. Inflammatory cell adhesion molecules in ischemic cerebrovascular disease. Functional analysis of Pro-inflammatory properties within the cerebrospinal fluid after subarachnoid hemorrhage in vivo and in vitro.

Serum and cerebrospinal fluid concentrations of E-selectin in patients with aneurysmal subarachnoid hemorrhage. Brazilian Journal of Medical and Biological Research. Cisternal CSF levels of cytokines after subarachnoid hemorrhage. Inflammatory cytokines in subarachnoid haemorrhage: Journal of Neurology Neurosurgery and Psychiatry. Cerebrospinal fluid and plasma cytokines after subarachnoid haemorrhage: CSF interleukin-6 may be an early marker of infection. Endothelin-1 in subarachnoid hemorrhage: Raised plasma endothelin in aneurysmal subarachnoid haemorrhage.

Long term monitoring of immunoreactive endothelin-1 and endothelin-3 in ventricular cerebrospinal fluid, plasma, and h urine of patients with subarachnoid hemorrhage. Research in Experimental Medicine. Absence of elevation of big endothelin in subarachnoid hemorrhage. Immunological response in early brain injury after SAH. Global cerebral edema after subarachnoid hemorrhage: Journal of the Neurological Sciences. Rise in serum soluble intercellular adhesion molecule-1 levels with vasospasm following aneurysmal subarachnoid hemorrhage.

Monocyte chemoattractant protein-1 predicts outcome and vasospasm following aneurysmal subarachnoid hemorrhage. Outcome prediction with serum intercellular adhesion molecule-1 levels after aneurysmal subarachnoid hemorrhage. Serum inflammatory adhesion molecules and high-sensitivity C-reactive protein correlates with delayed ischemic neurologic deficits after subarachnoid hemorrhage.

Dhar R, Diringer MN. The burden of the systemic inflammatory response predicts vasospasm and outcome after subarachnoid hemorrhage. Impact of systemic inflammatory response syndrome on vasospasm, cerebral infarction, and outcome after subarachnoid hemorrhage: Correlation among systemic inflammatory parameter, occurrence of delayed neurological deficits, and outcome after aneurysmal subarachnoid hemorrhage.

Circulating sICAM-1 and sE-Selectin as biomarker of infection and prognosis in patients with systemic inflammatory response syndrome. European Journal of Internal Medicine. Inflammatory cytokine cascade released by leukocytes in cerebrospinal fluid after subarachnoid hemorrhage. Increased interleukin-6 levels in cerebrospinal fluid following subarachnoid hemorrhage.

Aoki T, Nishimura M. Targeting chronic inflammation in cerebral aneurysms: Expert Opinion on Therapeutic Targets. Impact of monocyte chemoattractant protein-1 deficiency on cerebral aneurysm formation. Imaging aspirin effect on macrophages in the wall of human cerebral aneurysms using ferumoxytol-enhanced MRI: Aspirin as a promising agent for decreasing incidence of cerebral aneurysm rupture.

E-selectin expression increased in human ruptured cerebral aneurysm tissues. Canadian Journal of Neurological Sciences. Cigarette smoke and inflammation: Review of cerebral aneurysm formation, growth, and rupture. Standard intracranial in vivo animal models of delayed cerebral vasospasm. British Journal of Neurosurgery. Systemic administration of simvastatin after the onset of experimental subarachnoid hemorrhage attenuates cerebral vasospasm. Phosphodiesterase 5 inhibition attenuates cerebral vasospasm and improves functional recovery after experimental subarachnoid hemorrhage.

Isoflurane delays the development of early brain injury after subarachnoid hemorrhage through sphingosine-related pathway activation in mice. Inflammation in the brain after experimental subarachnoid hemorrhage. The rodent endovascular puncture model of subarachnoid hemorrhage: Glibenclamide reduces inflammation, vasogenic edema, and caspase-3 activation after subarachnoid hemorrhage.

Journal of Cerebral Blood Flow and Metabolism. Expression of intercellular adhesion molecule 1 ICAM-1 on the cerebral artery following subarachnoid haemorrhage in rats. Quantitative analysis of gene expressions related to inflammation in canine spastic artery after subarachnoid hemorrhage. Expression of Toll-like receptor 4 in the basilar artery after experimental subarachnoid hemorrhage in rabbits: Isoflurane on brain inflammation. Isoflurane attenuates blood-brain barrier disruption in ipsilateral hemisphere after subarachnoid hemorrhage in mice.

Neuroprotective effects of anti-tumor necrosis factor-alpha antibody on apoptosis following subarachnoid hemorrhage in a rat model. Journal of Clinical Neuroscience. Irish Journal of Medical Science. Cell death starts early after subarachnoid hemorrhage. Loss of long-term potentiation in the hippocampus after experimental subarachnoid hemorrhage in rats.

Learning deficits after experimental subarachnoid hemorrhage in rats. Molecular alterations in the hippocampus after experimental subarachnoid hemorrhage. Heparin reduces neuroinflammation and transsynaptic neuronal apoptosis in a model of subarachnoid hemorrhage. Medical complications after subarachnoid hemorrhage. Neurosurgery Clinics of North America. Monoclonal antibody against E selectin attenuates subarachnoid hemorrhage-induced cerebral vasospasm.

Intranasal administration of E-selectin to induce immunological tolerization can suppress subarachnoid hemorrhage-induced vasospasm implicating immune and inflammatory mechanisms in its genesis.

1. Introduction

There are separate chapters by world leading surgeons on transcranial doppler, treatment in intensive care unit, mechanisms, diagnoses and treatment of vasospasms, titanium aneurysm clips, surgical methods for treating aneurysms in the cavernous sinus, surgical methods for posterior circulation of aneurysms, surgical methods for anterior circulation aneurysms, and methods for giant aneurysms, as well as long-term follow-up and neuropsychological consequences. The small neck of the aneurysm afforded an easy surgical attack.

An ordinary flat silver clip was placed over the sac and tightly compressed obliterated it completely. The clip was flush with the wall of the carotid artery. The sac, lateral to the silver clip, was then picked up with the forceps and thrombosed by the electocautery. Walter Dandy reporting his successful operation of a posterior communicating aneurysm on March 23, Walter Dandy's patient left the hospital in good health 2 weeks later, and from his report one may gain the impression that the operation was an easy task.

Despite continuous developments during the following decades, it was not until the introduction of the operating microscope and microsurgical techniques that surgical treatment was generally accepted. Endovascular obliteration has become an important treatment alternative but this has not been included in this particular volume.

Professor Helge Nornes has been a major force in the development of new techniques and research strategies in this area for a number of years and has recently retired from the National Hospital in Oslo. Read more Read less. Credit offered by NewDay Ltd, over 18s only, subject to status. See all free Kindle reading apps.

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