subarachnoid hemorrhage ( sah ) is a devastating neurological insult that causes significant morbidity and mortality .
one of the greatest sources of this morbidity and mortality is cerebral vasospasm ( cvs ) , leading to delayed cerebral ischemia ( dci ) .
while angiographic vasospasm is thought to occur in approximately 70% of patients after asah , only 25% develop symptomatic cvs [ 3 , 4 ] .
morbidity remains high despite years of clinical and basic science research done on the topic , with approximately 50% infarction rates in affected patients [ 5 , 6 ] .
an antecedent inflammatory cascade is one of the many etiologies thought to be responsible for the development of cvs .
experimental studies have shown involvement of cytokines , cell adhesion molecules , and leukocytes , and early clinical studies have attempted to inhibit components of the inflammatory cascade to mitigate cvs [ 719 ] .
additionally , endothelin receptor activation , nitric oxide inhibition , thromboxane receptor modification , and many cell signaling cascades are thought to play an integral role in the development of this pathology [ 2027 ] .
currently , the primary treatment for this patient population involves hemodynamic augmentation and medically or surgically mediated intra - arterial vasodilation .
these treatments , while providing amelioration in the short term , have proved relatively ineffective in staving off neurological decline , in part due to lack of large scale analyses [ 1 , 28 ] . in our review , we hope to summarize past and current research in the area of inflammation and the development of cvs .
an appreciation of these key inflammatory intermediaries will allow for the development of clinically significant interventions in this patient population .
this decline was initially attributed to the progression of mass effect secondary to acute sah ; however , current evidence suggests that an acute brain injury with subsequent cerebral ischemia plays a primary role .
it is thought that the introduction of blood products , specifically hemoglobin , into the extravascular space initiates narrowing of the arterial vasculature within several hours , starting at approximately three days after - injury and lasting up to several weeks .
the arterial vasculature demonstrates diffuse or focal stenosis with significant restriction of blood flow visualized via angiography .
cvs presents with focal neurological dysfunction and can precipitate the development of permanent ischemia in approximately 50% of patients with cvs .
the gold standard for the diagnosis of cvs is angiography , specifically with digital subtraction angiography ( dsa ) . as an improvement to the technique described by ecker and colleagues in 1951
, dsa allows for high quality angiographic images via the digital subtraction of extraneous artifact . in its use as a diagnostic tool ,
mild vasospasm is defined by less than 25% reduction in vessel patency . a greater than 50% reduction
many authors have since espoused the utility of cta and mra as alternatives to the invasive techniques used in dsa [ 3537 ] .
in addition to being less invasive and severalfold faster than conventional angiography , cta and mra produce images of higher resolution than their predecessor [ 38 , 39 ] .
these techniques however rely heavily on digital reconstruction , and their accuracies vary depending on the vascular territory assessed and operator experience [ 31 , 35 , 39 , 40 ] .
transcranial doppler sonography ( tcd ) is currently the primary tool used in the noninvasive diagnosis of cerebral vasospasm .
it is currently the single most important noninvasive measure of cerebral vasospasm [ 42 , 43 ] . when vasospasm induces a decrease in arterial diameter , cerebral blood flow ( cbf ) velocity concomitantly increases .
cvs is most times described when cbf velocity exceeds 120  cm / s [ 44 , 45 ] .
an increased ratio of cbf velocity between intracranial vessels , the middle cerebral artery ( mca ) or anterior cerebral artery ( aca ) , and an extracranial ica can be used to indicate cvs .
the diagnostic reliability of tcd has historically been called into question since factors such as the arterial window analyzed , patient movement , and operator experience affect the reliability of the test [ 31 , 43 , 47 ] .
specifically , changes in systemic pressure , cardiac output , and other factors that affect hemodynamic homeostasis can adversely affect reliability of the tool due to its strong dependence on cerebral blood flow dynamics . in a comparative study between tcd and dsa in the assessment of aneurysmal vasospasm , okada and
colleagues highlighted the poor sensitivity of tcd for detecting vasospasm and noted that dsa was distinctly superior as a diagnostic tool .
other studies have underscored the incongruences in the diagnostic sensitivity of this tool [ 49 , 50 ] .
tools such as jugular venous oxygen saturation monitoring , xe - enhanced ct , positron emission tomography ( pet ) , single photon emission ct ( spect ) , and magnetic resonance imaging have also been used to diagnose cvs with varying sensitivities .
walton in 1955 demonstrated that febrile patients who presented with sahs fared worse than their afebrile counterparts .
several decades later , studies by rousseaux et al . confirmed a definitive relationship between the occurrence of symptomatic cvs and fever in affected patients ( table 1 ) .
it was in the late 1980 's however that spallone and colleagues demonstrated that leukocytosis , the sentinel indicator of systemic inflammation , was significantly higher in patients with asah .
these discoveries spurred interest in the role of the inflammatory response as a causative factor in the development of the pathology .
later studies substantiated these earlier findings , and additional inflammatory markers and cytokines were identified to play a pivotal role in the inflammatory process ( table 1 ) . as a result of decades of research into the inflammatory mediators of cvs , several theories explaining the pathophysiology have been proposed .
one such theory states that the extravasation of erythrocytes into the cerebral parenchyma acts as the nidus for the vasospasms that characterize acute and chronic cvs [ 11 , 18 , 55 , 56 ] .
extracorpuscular hemoglobin ( hb ) is a proinflammatory moiety as opposed to its intravascular homolog [ 5760 ] .
the presence of hb in the extravascular space liberates reactive oxygen species ( ros ) that result in the peroxidation of membrane lipids of endothelial cells and proliferation of smooth muscle [ 61 , 62 ] .
it is also thought that these oxidative stressors inhibit bradykinin mediated vascular relaxation after asah .
additionally , it has been hypothesized that the presence of subarachnoid blood is a potent stimulant for nuclear factor - kappa b ( nf-b ) mediated cytokine release augmenting the inflammatory reaction [ 11 , 64 ] .
normally , once erythrocytes have entered the extravascular space , exposed hb is rapidly bound to a hepatically produced haptoglobin ( hp ) .
hp exists in two isoforms , hp 1 - 1 and hp 2 - 2 of which hp 2 - 2 is thought to bind with less affinity and as such is relatively pro - inflammatory in comparison to its analog [ 23 , 27 , 56 , 65 ] .
macrocytes phagocytize hb bound moieties and remove them from the extravascular space . the initial pro - inflammatory effect elicited by hb and hb bound moieties
initiates an inflammatory cascade involving an increase of cytokines , leukocytes , and cell adhesion molecules ( cams ) characterizing the inflammatory process [ 7 , 13 , 18 , 56 , 66 , 67 ] .
the elevation in inflammatory cytokines and cell adhesion markers promotes the initial margination of leukocytes by cams on the endothelial surface .
of these cell adhesion markers , selectins ( l- , p- ) are most important in the initial capture [ 9 , 20 , 6871 ] .
secondly , leukocyte rolling is facilitated by p- and e - selectins in which captured leukocytes are sequentially bound and released by adjacent cams .
the end result is a sequential transmigration of leukocytes down a chemoattractant concentration gradient to the site of inflammation .
finally , firm adhesion to the endothelium effectively halts leukocyte rolling and promotes leukocyte diapedesis [ 11 , 72 ] .
this process is mediated by another class of cams , the integrins of which cam-1 , lfa-1 and other moieties play vital roles .
experimental models have successfully demonstrated the temporal relationship between the initial inciting injury and increases in cytokine concentrations [ 7678 ] .
of particular interest are il-1 , il-6 , tl-8 , and tnf-. in various studies , increases in the intraventricular concentrations of these moieties have been demonstrated to occur after injury [ 7981 ] . though the csf concentrations of these inflammatory intermediaries increase after - hemorrhage , the change in serum concentrations is not as reliable .
in fact , studies have demonstrated both elevations   and no relevant changes   in the analysis of systemic concentration of these cytokines .
it is irrefutable , however , that leukocytosis and changes in c - reactive protein levels ( crp ) correlate strongly with clinical outcomes after - injury [ 83 , 84 ] .
transendothelial migration , or diapedesis , is the final step in the recruitment of inflammatory leukocytes and encompasses a multitude of cell adhesion molecules and intracellular cell signaling pathways .
macrophages , monocytes and neutrophils are the primary cells implicated in the initial stages of injury and have been found in postinjury histological analysis to be a highly represented cell type in adjacent tissue [ 85 , 86 ] .
these inflammatory cells mediate macrocytosis of free erythrocytes as part of their natural function ; however , after asah there is a disruption of normal cerebral blood flow preventing the re - entry of macrophages and leukocytes into circulation .
ultimately , a release of inflammatory cytokines and other vasoactive compounds , which characterize the chronic vasospasm of cvs , is thought to occur approximately four days after injury .   in the final analysis , the upregulation of et-1 , destructive free radicals , no dysregulation , and spasmodic cytokines are all thought to play a substantial role in the onset of vasospasm [ 1 , 8789 ] .
et-1 itself is a potent vasoconstrictor whose upregulation peaks 3 - 4 days after injury .
it is thought to be increased due to cerebral ischemia and other stressors with possible augmentation by the aforementioned antecedent inflammatory cascade .
its effect on vasoconstriction is multifaceted [ 91 , 92 ] . through a negative feedback loop
no plays a significant role in vascular tone through the inhibition of calcium production and subsequent reduction in contractile forces ; thus , its inhibition leads to vessel narrowing . additionally , et-1 is also integral to fibrosis , tissue growth , and inflammation [ 26 , 92 , 95 ] . in summary , through several distinct mechanisms , the inflammatory changes surrounding sah lead to global stenosis of cerebral vasculature [ 26 , 9699 ] .
several clinical trials have either corroborated or refuted the clinical efficacy of the suggested treatments .
anti - inflammatory agents such as dexamethasone and cyclosporine a ( cys - a ) have shown favorable improvements in experimental models [ 100 , 101 ] . however , other known agents , such as tacrolimus , an inhibitor of t - cell maturation similar to cys - a , have not shown similar results .
there are also studies implicating the complement system , the 3-hydroxy-3-methyl - glutaryl coenzyme a ( hmg - coa ) reductase pathway , and multiple other systems ; however , results even in the experimental stages have been varied [ 103106 ] .
there have been experimental reports documenting improvement in cvs using various pharmaceutical agents , however , the variety of these treatments is sparse ( table 3 ) . in 2011 ,
velat and colleagues reviewed 44 randomized control trials ( rct ) and 9 meta - analyses on vasospasm after sah .
their studies suggested that only oral nimodipine was efficacious in stymieing cvs with improvement in neurological decline after sah . in an experimental murine model of cerebral vasospasm , bowman and colleagues demonstrated a statistically significant dose dependent reduction in vasospasm after administration of a polyclonal antibody targeted against il-6 ( p < 0.05 ) .
such findings indicate that cytokine upregulation is antecedent to radiographic vasospasm , and their attenuation may minimize vessel narrowing .
the propensity for magnesium supplementation to mitigate cvs has also been widely studied [ 108113 ] .
in fact , a small swiss study in 2012 suggested that high dose magnesium administration compared to low dosage suppressed post - sah increases in il-6 ( p = 0.021 ) and il-1 ( p < 0.001 ) , respectively .  
agents such as organic stress reducers including trehalose modulate the effect of the cyclooxygenase-2 ( cox-2 ) catalytic pathway . in experimental murine models ,
the polysaccharide reduced concentrations of pro - inflammatory markers leading to a reversal of sah induced vasospasm .
of the multiple markers that trehalose modulates is endothelin-1 , which modulates vasoconstriction [ 91 , 92 ] , via its effects on nitric oxide , fibrosis , tissue growth , and inflammation .
consequently , it has been the target of major studies on the treatment of vasospasm .
these evidences along with other recent experimental findings suggest a multifactorial process that precedes cvs and clinical neurological dysfunction , which may or may not be directly related .  
myeloperoxidase ( mpo ) , a marker of inflammation in coronary artery disease , is thought to be implicated in the inflammatory process of cvs .
mpo is a lysosomal enzyme that is a component of the respiratory burst in leukocyte antibacterial function .
the enzyme catalyzes the production of hypohalous acids like hypoclorous acid ( hocl ) , which modify cellular membranes . in reports by lim and colleagues ,
the biomarker demonstrated elevations in csf concentrations that mirror the onset of cbf abnormalities in cvs , supporting mpo as a surrogate predictor of cvs after sah .
because of to its role in inflammation , its upregulation is most likely related to antecedent leukocyte recruitment .
the mortality that ensues after cvs is often due to delayed cerebral ischemia ( dci ) .
dci is defined as new focal neurological deficits ( symptomatic vasospasm ) or ischemic focus in the setting of radiographic vasospasm .
while the relationship between inflammation and cvs is irrefutable , it is unlikely to be the single perpetrator behind delayed cerebral ischemia ( dci ) and subsequent neurologic decline .
results from the conscious trials assessed the effects of the endothelin-1 receptor antagonist clazosentan after sah , and while there was significant improvement in angiographic cvs , neurological dysfunction was only minimally affected .
hansen - schwartz and colleagues concluded that these results point to a more extensive implication of inflammation in the pathophysiology of post - sah neurological dysfunction .
hansen - schwartz also argued that the lack of temporal alignment between angiographic cvs and dci symptoms suggest the need for further studies .
cortical spreading depolarization ( csd ) , intravascular microthrombosis , and early brain injury have all received traction in the field as alternate theories of cvs [ 120124 ] . in the immediate posthemorrhage period ,
rapid increases in cerebral edema , icp [ 126 , 127 ] , and changes in cerebral autoregulation   are all thought to disrupt the homeostatic milieu resulting in early brain injury .
transient and sporadic neuroelectrical disruptions also occur in the injured brain after acute injury . through experimental murine models
, researchers have demonstrated that these brief episodes of electrical dampening differentially affect cerebral perfusion resulting in either hyperperfusion or hypoperfusion . this hemodynamic imbalance propagates damage created during early brain injury .
finally , correlations between elevated procoagulant factors and dci occurrence have strongly suggested a role for microthrombosis in the pathophysiology .
the detection of microthrombi in postmortem analysis   and a 70% prevalence of microthrombi in sah patients   also point to the involvement of the coagulation cascade in the development of dci .
it is now more likely that cvs is one of many factors that play some part in the neurological decline consistent with dci .  
most notably , the earlydrain and lumas trials evaluate early evacuation of csf through a lumbar drain [ 134 , 135 ] .
the lumas trial evaluated 210 patients with asah and randomized 105 to receive standard therapy and a lumbar drain , with the remaining 105 randomized to the control group receiving only standard management .
the authors found that lumbar drainage of csf after asah was associated with reduced dind and improved early clinical outcome but had no difference in outcomes at 6 months .
preliminary studies have also shown efficacy using a kinetic treatment , intrathecal thrombolytic therapy in conjunction with head shaking . in this small study ,
after 14 days of observation , there was decreased dind and vasospasm related infarct in the intrathecal thrombolytic therapy group compared to the control .
lastly , the depolarizations in ischaemia after aneurysmal subarachnoid haemorrhage ( discharge-1 ) trial are an ongoing multicenter diagnostic phase iii study that assesses electrical depression of the cerebral cortex after asah .
the aim is to calculate the sensitivity and specificity of the duration of cortical spreading depression as a proxy for dci after asah .
as we look to future research , it is hoped that these theories may become incorporated in to standard therapies for the treatment of cvs .
from all indications , one of the major limiting factors in the management of cvs is an understanding of the extent of early brain injury secondary to sah .
we are currently limited by the difficulty in consistently and accurately diagnosing and treating affected patients .
the role of inflammation in cvs represents a possible mechanism behind the development of dci after sah , and targeting the inflammatory process has potential to significantly reduce cvs , though further studies are necessary .
cerebral vasospasm continues to be regarded as an important factor in the progression to dci in patients following sah .
it can not be however regarded as the single factor behind the neurological decline in this patient cohort .
 cerebral vasospasm ( cvs ) is a potentially lethal complication of aneurysmal subarachnoid hemorrhage ( asah ) . 
 recently , the symptomatic presentation of cvs has been termed delayed cerebral ischemia ( dci ) , occurring as early as 3 - 4 days after the sentinel bleed . for the past 5 - 6 decades 
 , scientific research has promulgated the theory that cerebral vasospasm plays a primary role in the pathology of dci and subsequently delayed ischemic neurological decline ( dind ) . 
 approximately 70% of patients develop cvs after asah with 50% long - term morbidity rates . 
 the exact etiology of cvs is unknown ; however , a well - described theory involves an antecedent inflammatory cascade with alterations of intracellular calcium dynamics and nitric oxide fluxes , though the intricacies of this inflammatory theory are currently unknown . 
 consequently , there have been few advances in the clinical treatment of this patient cohort , and morbidity remains high . 
 identification of intermediaries in the inflammatory cascade can provide insight into newer clinical interventions in the prevention and management of cerebral vasospasm and will hopefully prevent neurological decline . in this review , 
 we discuss current theories implicating the inflammatory cascade in the development of cvs and potential treatment targets . 