Cerebral vasospasm is a devastating medical complication of aneurysmal subarachnoid hemorrhage (SAH). It is associated with high morbidity and mortality rates, even after the aneurysm has been treated. A substantial amount of experimental and clinical research has been conducted in an effort to predict and prevent its occurrence. This research has contributed to significant advances in the understanding of the mechanisms leading to cerebral vasospasm. The ability to accurately and consistently predict the onset of cerebral vasospasm, however, has been challenging. This topic review describes the various methodologies and approaches that have been studied in an effort to predict the occurrence of cerebral vasospasm in patients presenting with SAH.
The English-language literature on the prediction of cerebral vasospasm after aneurysmal SAH was reviewed using the MEDLINE PubMed (1966–present) database.
The risk factors, diagnostic imaging, bedside monitoring approaches, and pathological markers that have been evaluated to predict the occurrence of cerebral vasospasm after SAH are presented.
To date, a large blood burden is the only consistently demonstrated risk factor for the prediction of cerebral vasospasm after SAH. Because vasospasm is such a multifactorial problem, attempts to predict its occurrence will probably require several different approaches and methodologies, as is done at present. Future improvements in the prevention of cerebral vasospasm from aneurysmal SAH will most likely require advances in our understanding of its pathophysiology and our ability to predict its onset.
Subarachnoid hemorrhage (SAH) is a significant healthcare problem (9). It is estimated that 30,000 Americans are stricken with aneurysmal SAH each year (180). Delayed neurological deterioration from vasospasm remains the greatest cause of morbidity and mortality after SAH (9,105). There are two definitions of cerebral vasospasm: angiographic and symptomatic. Angiographic vasospasm is a narrowing of the contrast medium column in the major cerebral arteries first described by Ecker and Riemenschneider in 1951 (37). Angiographic vasospasm usually starts on Days 3 to 5 of SAH, exhibits maximal narrowing of the arterial lumen during Days 5 to 14, and slowly resolves over 2 to 4 weeks (105). Angiographic vasospasm is identified in 30 to 70% of arteriograms performed at approximately the seventh day after SAH (75). Symptomatic vasospasm is the syndrome of the ischemic consequences of cerebral arterial narrowing and is characterized by an insidious onset of confusion and decreased level of consciousness, followed by focal motor and/or speech impairment. The time course for symptomatic vasospasm parallels that of angiographic vasospasm, but whereas up to 70% of aneurysm patients may develop arterial narrowing, only 20 to 30% will manifest neurological deficits or die despite maximal contemporary therapy (59). Although significant advances in the treatment of SAH and vasospasm have occurred over the past three decades, outcomes still remain poor. In the control arm of a recent multicenter randomized trial that examined the effect of tirilazad mesylate on vasospasm, 33% of patients experienced symptomatic vasospasm (58). Twenty-four percent of these patients experienced delayed neurological deterioration as a result of vasospasm. In a recent critical analysis, symptomatic vasospasm was associated with increased cost because of lengthened intensive care unit and hospital stays (24). Symptomatic vasospasm has also been associated with poor 3-month outcomes on the modified Rankin Scale (24). Thus, epidemiological findings support the need to prevent or reduce the incidence of vasospasm and its associated morbidity and mortality.
The diagnosis of vasospasm occurs primarily during the onset of neurological deterioration, precluding timely application of the neuroprotective treatment necessary for the prevention of clinical deficits (179). Given that current diagnostic modalities possess poor predictive values, observation of vasospasm before clinical deficits have been established remains a principal clinical challenge for physicians. To date, a large blood burden in the subarachnoid space is the only consistently demonstrated risk factor for vasospasm (47). Furthermore, despite efforts to identify predictors of vasospasm, transcranial Doppler (TCD) ultrasonography remains the only noninvasive diagnostic technique with high sensitivity and specificity in clinical use (93,163,185). The interval between TCD velocity changes and subsequent ischemia, however, is insufficient for optimization of the benefits of early intervention for many patients (96,129,185). In addition, TCD velocity changes occur after the onset of vessel narrowing, potentially limiting the efficacy of medical management instituted at that time (179).
Future improvements in the prevention of cerebral vasospasm from aneurysmal SAH will probably result from advances in our understanding of its pathophysiology and our ability to predict its onset. The ongoing discovery of risk factors and markers for vasospasm may strengthen a clinical diagnosis, thereby improving application of prophylactic therapy and revealing new insights concerning causes of the disease and its prevention. The aims of this topic review are to 1) describe the current theories proposed for the pathophysiology of cerebral vasospasm that have aided efforts to predict and prevent its occurrence and 2) review the risk factors and markers that have been explored and proposed for predicting the onset of cerebral vasospasm after aneurysmal SAH.
PATHOPHYSIOLOGY OF CEREBRAL VASOSPASM
The pathophysiology of vasospasm after SAH is still not definitively understood. It is widely accepted, however, that blood products contribute to vasospasm, because the time period during which erythrocytes break down and blood disappears from the cerebrospinal fluid (CSF) closely mirrors the onset and resolution of clinical vasospasm (164). The agents thought to be responsible for SAH-induced vasospasm, “spasmogens,” have yet to be clearly identified, however. For the purposes of this review, the current theories of the pathophysiology of cerebral vasospasm are summarized below. These include prolonged arterial contraction, breakdown of blood products, structural changes in the arterial wall, and induced inflammatory response (see Weir et al.  for a detailed review).
Prolonged Arterial Contraction
Cerebral vasospasm may result from prolonged smooth muscle contraction mediated or triggered by oxyhemoglobin (97). Oxyhemoglobin may have a direct effect on the smooth muscle cells or may function through indirect mechanisms, such as the local release of vasoactive substances from the arterial wall or the production of free radicals and lipid peroxides (33). The production of superoxide free radicals has been postulated to inactivate nitric oxide, a potent vasodilator, and to increase the activity of lipid peroxidases (33). In turn, inactivation of nitric oxide may result in an increase in lipid protein kinase C activity, with subsequent release of intracellular calcium (Ca2+) stores (33). Oxyhemoglobin may cause depletion of intracellular Ca2+ and suppression of protein synthesis, which subsequently causes the influx of extracellular Ca2+ through voltage-independent Ca2+ channels. This may explain the intracellular Ca2+ increase observed after SAH (33). Massive influx of calcium ions into mitochondria has been shown to produce free radicals, such as nitric oxide, superoxide anion, hydroxyl free radical, and peroxynitrite, from the mitochondrial respiratory chain (135). Free radical formation may alter the balance of circulating prostaglandins in favor of the vasoconstricting prostaglandin E2 over the vasodilating prostaglandin I2 through a Ca2+- and/or calmodulin-dependent mechanism (179). It has been shown that Ca2+ activates calmodulin, which in turn activates the myosin light chain kinase (7). This leads to phosphorylation of the myosin light chain, which interacts with and degrades thin filament-associated proteins to cause vascular smooth muscle contraction and luminal narrowing. Phosphorylation of myosin light chain by Ca2+-dependent activation of myosin light chain kinase is widely accepted as the key pathway for vascular contraction (86).
Structural Changes in the Arterial Wall
Ultimately, prolonged contraction of the smooth musculature of the arteries may lead to secondary morphological changes that can take the form of intimal hyperplasia or subendothelial fibrosis of the vessel wall (33). Intraluminally, white blood cells and platelets aggregate and are also believed to lead to structural vessel wall abnormalities such as an increase in wall thickness (33). Once regarded as a major cause of luminal narrowing, these alterations are now considered secondary responses to cerebral vasospasm (33). Luminal narrowing is now believed to result from sustained arterial contraction rather than structural thickening of the vessel wall with lumen encroachment (44). The structural changes resulting from arterial hyperplasia, platelet aggregation, and edema lead to increased cerebrovascular resistance and eventually, decreased cerebral blood flow (CBF). Findlay et al. (45), in 1989, quantified arterial wall changes in monkeys with an experimentally created unilateral SAH. At the time that the monkeys were killed, the middle cerebral arteries (MCAs) were harvested and were studied with scanning and transmission electron microscopy. A mean 57% reduction in vessel caliber and a five-fold increase in vessel wall thickness were observed compared with normal, nonvasoconstricted MCAs, as well as degenerative changes in the tunica intima and media. These findings suggested that the arterial narrowing and vessel wall thickening seen within several weeks of SAH was a result of medial contraction, but unlike simple vasoconstriction, was associated with degenerative ultrastructural changes in the endothelium and vascular smooth muscle cells.
Breakdown of Blood Products
Another theory suggests that vasospasm is caused by the breakdown products (spasmogens) of platelets and erythrocytes in extravasated blood. Some known spasmogenic substances released in the breakdown process are serotonin, prostaglandins, catecholamines, histamine, angiotensin, and oxyhemoglobin (188). Although each of these is a known spasmogen, none have consistently caused or sustained vasospasm in laboratory experiments. Furthermore, when individually neutralized, none have prevented or improved vasospasm. It is unlikely, therefore, that any of these spasmogenic substances is the single causative factor in the development of vasospasm.
After SAH, erythrocyte hemolysis begins almost immediately and continues until all the red blood cells are phagocytized or lysed. Red cells incubated in CSF in vitro at body temperature release large amounts of hemoglobin over hours to days (188). Lumbar puncture shows that the CSF is clear of red blood cells within a few days to a month (188). Several clot fractionation experiments have also demonstrated that erythrocytes are the blood component that causes vasospasm in vivo, and not white blood cells, platelets, or plasma alone (98). These findings point toward hemoglobin as a key suspect as the main spasmogen (98). However, it has been suspected that hemoglobin is not the sole factor, because hemolysate of red blood cells, which contains numerous substances in addition to hemoglobin, usually is a more potent vasoconstrictor than hemoglobin alone in many model systems (5). Moreover, Weir et al. (188) noted that many experiments that used hemoglobin had unknown proportions of oxyhemoglobin and deoxyhemoglobin and other substantial impurities and that ultrapure hemoglobin in some of their experiments was not a very potent constrictor in vivo. Taken together, these findings suggest that hemoglobin alone may not be the cause of vasospasm.
A final theory suggests that the pathogenesis of cerebral vasospasm is linked to an inflammatory response occurring after SAH. Two types of inflammation have been suggested to occur in response to SAH. The first consists of classic inflammatory phenomena resulting from infection, trauma, or immune disease; the second consists of neurogenic inflammation caused by excessive release of peptides such as substance P and calcitonin gene-related peptide from the terminals of the trigeminal sensory nerves (159). Both of these types of inflammation and their potential roles in the pathogenesis of cerebral vasospasm are discussed below.
The antidromic release of substance P and calcitonin gene-related peptide has been demonstrated by measurements showing rapidly increased concentrations in the CSF after SAH (178). The release of substance P and calcitonin gene-related peptide, as well as other substances such as histamine, 5-hydroxytryptamine, endothelin-1 (ET-1), and bradykinin, after SAH has been proposed to dislocate proteins forming the blood-brain barrier, a mechanical barrier to the movement of most molecules circulating in the blood. The dislocation of these proteins may cause vascular permeability and allow numerous substances to enter the vessel and potentially cause blood-brain barrier rupture (159). The neurogenic inflammatory response lasts as long as the neuropeptides and other neuromodulators are released from the perivascular nerve endings. Complete exhaustion roughly coincides with the occurrence of vasospasm and has been suggested to contribute to it (38). The end of the neurogenic inflammation does terminate the other inflammatory phenomena that are described below.
The extravasated blood from SAH is responsible for a cascade of reactions involving the release of various vasoactive and proinflammatory factors from blood and vascular components of the subarachnoid space. These factors have been linked to the development of inflammatory lesions of the cerebral vasculature and include 1) hemoglobin from lysed erythrocytes; 2) the activity, expression, and metabolites of lipoxygenases, cyclooxygenases, and nitric oxide synthases; 3) ET-1; 4) prothrombotic and proinflammatory action of complement and thrombin toward endothelium; 5) multiple actions of activated platelets, including platelet-derived growth factor production; 6) perivascular and intramural macrophages and granulocytes and their interaction with adhesion molecules; and 7) proinflammatory cytokines (159).
Although substantial evidence supports the role of inflammatory responses in the pathogenesis of cerebral vasospasm, it is possible that inflammation is an important but not necessarily sufficient factor. A number of anti-inflammatory agents have been shown to be effective in preventing vasospasm in animal models, but angiographic vasospasm has usually been regarded as the end point, which does not always reflect the human condition. Moreover, the efficacy of these agents in animal studies has not been reproduced in human trials (see Sercombe et al.  for a detailed review of cerebrovascular inflammation after SAH].
Identifying markers and risk factors may improve clinical prediction and allow for more effective prevention of vasospasm after SAH. Considerable research effort has been directed toward identifying potential predictors of cerebral vasospasm after aneurysmal SAH (192). These predictors have included, but have not been limited to, patient-related risk factors, diagnostic neurological imaging parameters, bedside monitoring data, and pathological markers. A brief discussion of each of these approaches is presented below.
All patients who have sustained SAH secondary to a ruptured intracranial aneurysm are at risk for development of vasospasm. Although advanced age, size of aneurysm, female sex, preexisting hypertension, smoking, etc., may be risk factors for SAH, they may not necessarily be risk factors for cerebral vasospasm. There are, however, some specific clinical findings positively correlated with frequency of occurrence of cerebral vasospasm. Thus, the scope of this review is limited to a discussion of identified factors and markers that may serve as predictors of cerebral vasospasm. Each of these risk factors is described below.
An important clinical predictor of vasospasm is the clinical grade of SAH of the patient on admission to the hospital (23,65). It is generally agreed that the surgical risk is closely related to the patient's condition at the time of surgery. In a study of 274 patients with SAH, Graf and Nibbelink (54) found a clear correlation between angiographic evidence of vasospasm and worsening clinical grade. That is, the frequency and severity of vasospasm increase with severity of initial clinical grade. Clinical grade is generally based on level of consciousness and neurological dysfunction. Many criteria have been proposed for the determination of surgical risk; some are based on whether or not the patient is “conscious,” others on the number of days that have passed since the last hemorrhage, and still others on the patient's age (15,60). The most commonly used grading scales for predicting and evaluating outcome in patients with SAH are the Hunt and Hess Scale (HHS), shown in Table 1; the World Federation of Neurological Surgeons Scale (WFNSS), shown in Table 2; the Fisher Scale, shown in Table 3; and the Glasgow Coma Scale (GCS), shown in Table 4. Although these scales have been proposed as good predictors of outcome in patients with SAH, the accurate prediction of disability remains quite imprecise, in part because of the timing of application of the scale used as a predictor. A multivariate analysis comparing different scales applied during different clinical moments has suggested that the best predictor is the WFNSS at the clinical worst before treatment (22). The HHS was solely correlated to outcome when assessed at clinical worst (22). However, with the GCS and the WFNSS, grading at all pretreatment times was significantly correlated with outcome, although outcome was best predicted before treatment, regardless of the scale used, if grading was performed at the patient's clinical worst (22). Unfortunately, many centers now report the post-resuscitation or post-ventricular drainage grade as the grade on record. Clearly, the timing of grading is an important factor in outcome prediction that needs to be standardized. Oshiro et al. (132) reviewed 291 consecutive patients with aneurysms treated at their institution and compared the admission grades from the GCS, WFNSS, and HHS with outcome measures at discharge from hospitalization. The Glasgow Outcome Scale score was used as the major outcome measure to evaluate the predictive value of the three scales. The predictive value of each scale was tested with an ordinal logistic regression model for Glasgow Outcome Scale score, a logistic regression model for mortality data, and a linear regression model for length of stay. Using the logistic regression model, the investigators found that the GCS was the best predictor, with an odds ratio of 2.585 (P = 0.0001), compared with 2.311 (P = 0.0001) for the WFNSS and 2.262 (P = 0.0001) for the HHS (132). By use of mortality data in the logistic model, the HHS was the best predictor, with an odds ratio of 3.391 (P = 0.0001), compared with 2.859 (P = 0.0001) for the GCS and 2.560 (P = 0.0001) for the WFNSS (132). Each of the three scales had a high predictive value for length of stay by use of a linear model. Furthermore, the GCS grade also had the greatest interrater reliability (P = 0.0002), compared with the HHS (P = 0.0005) and the WFNSS (P = 0.027) (132). Crossman et al. (30), however, found that there is often a disparity between the quoted and actual GCS of patients referred to their unit. They also found that only 51% of the patients had a correct GCS on referral.
The use of grading scales to predict outcomes after aneurysmal SAH is commonplace. However, none of the grading scales mentioned above have achieved universal acceptance. No grading scale has been found to consistently outperform any other across age or severity, and contradictory findings have been reported. Cavanagh and Gordon (20) noted that difficulties are encountered when comparing grading scales because of administration, scoring schemes, timing of assessment, and psychometric properties such as interrater reliability. The timing of measurements and the use of serial measures have emerged as important factors in the prediction of clinical outcomes. Assessments made close to the time of surgical intervention have been found to have superior predictive abilities. Clearly, the timing of grading is an important factor in outcome prediction that needs to be standardized.
Blood Volume and Frequency of SAH
A second clinical predictor of the occurrence, severity, and distribution of vasospasm is the extent of subarachnoid blood or large clots in the subarachnoid cisterns as evidenced by computed tomographic (CT) scan. A high correlation exists between the development of severe vasospasm and the presence of a large volume of blood or clots (47). For example, Fisher et al. (47) found that 23 of 24 patients who had subarachnoid blood clots larger than 5 × 3 mm, as measured by CT scan, developed serious symptomatic vasospasm in the corresponding arterial territory. Conversely, if no blood or diffusely distributed blood is evident in the subarachnoid space, symptomatic vasospasm occurred in only 1 of 18 patients (47). A later prospective study of 41 aneurysm patients conducted by these investigators confirmed their initial results (82). In that study, however, severe vasospasm occurred unpredictably in 5 of 19 patients presenting with no or only diffuse subarachnoid blood (82). Such a finding supports the hypothesis that other factors in addition to blood volume may be of importance in the development of vasospasm in patients with SAH. Interestingly, cerebral blood volume is elevated in regions supplied by severely spastic vessels, a finding that suggests that distal small penetrating arterioles may dilate and lose their capacity for autoregulation in an effort to decrease intracranial arterial resistance (138). Recently, Claassen et al. (24) proposed a modified Fisher SAH grading system. This scale was proposed as a result of a study of 276 consecutively admitted patients with an available CT scan performed within 72 hours of onset. Demographic, clinical, laboratory, and neuroimaging data were recorded, and the amount and location of SAH, intraventricular hemorrhage, and intracerebral hemorrhage on admission CT scans were quantified (24). The results of the study found that among SAH variables, thick clot completely filling any cistern or fissure was the best predictor of delayed cerebral ischemia (DCI) (P = 0.008), and among intraventricular hemorrhage variables, blood in both lateral ventricles was most predictive (P = 0.001) (24). These variables had independent predictive value for DCI in a multivariate analysis of CT findings, and both were included in a final multivariate model when evaluated in conjunction with other clinical risk factors (24). Thus, a new SAH rating scale was proposed that accounts for the independent predictive value of subarachnoid and ventricular blood for DCI.
In addition to blood volume, the number and severity of bleeding episodes has been correlated with the incidence of vasospasm. In the laboratory, several groups have noted that repeated injections of subarachnoid blood resulted in a rapid onset of more intense vasospasm (40,136). Zabramski et al. (194) further studied the effect of altering the volume and timing of hemorrhage and found that the severity of spasm associated with delayed rebleeding (3 wk) was out of proportion to the total volume of hemorrhage. They suggested that once exposed to subarachnoid blood, the cerebral vessels become sensitized to its vasospastic effects. In an angiographic study of cerebral vasospasm in humans, it has been shown that a rebleeding episode induces vasospasm earlier than does the primary hemorrhage (83). Moreover, it is well documented that patients with known rebleeding episodes are more severely affected and have a higher mortality rate than patients with a single hemorrhage, both when the rebleeding complicates the initial hospital course (36,177) and when it occurs several years later (125,190). Although there was no established correlation with severity of vasospasm in these studies, the findings partially support the observation that the development of vasospasm is related both to the volume of subarachnoid blood and to the timing and number of hemorrhages (66).
Size and Location of Aneurysm(s)
A third potential factor influencing the occurrence of vasospasm is the size and location of the aneurysm. Clinical evidence of a correlation between ruptured aneurysm location and incidence of cerebral vasospasm is inconclusive. Although several reports have suggested that the frequency of vasospasm may vary with the location of the aneurysm, those sites identified as being associated with a high frequency of vasospasm differ from study to study (23). For example, Fisher et al. (47) found a higher incidence of vasospasm of the anterior cerebral artery compared with the MCA. Graf and Nibbelink (54), conversely, found that 50% of patients with an internal carotid aneurysm, 44.7% of patients with a middle cerebral aneurysm, and 35.2% of patients with an anterior carotid aneurysm had localized or diffuse vasospasm. Furthermore, other studies have shown that the incidence of vasospasm is higher in patients with aneurysms of the medial circle of Willis, such as those in the internal carotid artery, than in patients having aneurysms located more peripherally, such as those in the MCA (192,194). McGirt et al. (108) found that patients with ruptured posterior cerebral artery aneurysms were 20-fold (P < 0.005) less likely to develop symptomatic vasospasm. In contrast, several reports suggest that the frequency of vasospasm does not vary with anatomic position (15,123,152). For example, in a study of 100 consecutive patients with aneurysmal SAH, Bonilha et al. (13) demonstrated no difference in the incidence of vasospasm as a function of aneurysm size or location.
In addition to location, the effect of aneurysm size on the incidence of vasospasm is also inconclusive. Macdonald et al. (99) analyzed data obtained from 3567 patients with SAH by use of univariate and multivariate logistic regression to determine factors that predict the development of symptomatic vasospasm. They found that larger aneurysm size was associated with an increase in the incidence of vasospasm (99). A number of other studies, however, reported no association (4,13,48,189).
Cocaine and its metabolites have been shown to potently induce cerebral artery vasoconstriction and cause chronic cerebral hypoperfusion in both animal models and human clinical studies (29,69,79,101,102,168,183). Cocaine may directly predispose patients who have sustained an aneurysmal SAH to symptomatic vasospasm by increasing the reactivity of cerebral vessels to vasoconstrictive factors present in the SAH clot and indirectly by decreasing CBF reserves through chronic hypoperfusion (29). Conway and Tamargo (29) conducted a retrospective study to determine the prevalence of vasospasm and outcome of 440 patients who presented with aneurysmal SAH associated with cocaine exposure. Univariate and multivariate statistical models were evaluated to determine whether recent cocaine exposure was independently associated with cerebral vasospasm and clinical outcome (29). The results of the study showed that cocaine users were more likely to experience cerebral vasospasm, defined as a delayed clinical deficit (3–16 d after SAH), than control subjects (P = 0.001) (29). A significant difference was not observed, however, in the Glasgow Outcome Scale scores between the two groups (P = 0.73) (29). In a recent retrospective study conducted by Howington et al. (68), cocaine use was associated with a 2.8-fold greater risk of developing vasospasm in SAH patients compared with controls. In that study, however, cocaine use was associated with a 3.3-fold greater risk of poor outcome in SAH patients, as assessed by Glasgow Outcome Scale score, compared with controls (68). Thus, although cocaine use in patients seems to be associated with an increased risk of developing vasospasm after SAH, its association with outcome in SAH patients is unclear.
Although women seem to be more susceptible to aneurysm formation than men, there is no indication that women are at increased risk of aneurysm rupture compared with men (133). This observation seems to be supported by the majority of studies that have shown no correlation between sex differences and increased risk or incident of vasospasm (4,13,48,54,152,189). For example, in a cooperative study of intracranial aneurysms and SAH, Graf and Nibbelink (54) found that the incidence of vasospasm among men (39.2%) was virtually identical to that in women (39.4%).
Age of Patient
Torbey et al. (176) conducted a retrospective study on the effects of age on the incidence of vasospasm after aneurysmal SAH. A total of 81 patients with complete medical records and TCD examinations of the vessels of interest were included in the study. Patients were subdivided into two groups by age: younger, less than 68 years of age (n = 47), and older, greater than or equal to 68 years of age. The mean flow velocity, maximum mean flow velocity, and incidence of symptomatic vasospasm were reported (176). The results of this study showed that 1) older SAH patients have a lower mean flow velocity (P < 0.003), 2) older patients have a lower incidence of symptomatic vasospasm (P < 0.05), 3) older patients develop symptomatic vasospasm at a lower mean flow velocity (P = 0.04 in the MCA; P = 0.02 in the internal carotid artery), 4) maximum mean flow velocity preceded diagnosis of symptomatic vasospasm by 2 days in older and 1 day in younger patients (P = 0.7), and 5) the median time to symptomatic vasospasm is less in older patients (P = 0.06) (176). The investigators concluded that older patients have a lower incidence of symptomatic vasospasm and that such vasospasm develops at lower CBF velocity than younger patients (176). Rabb et al. (145) performed a statistical analysis of risk factors related to symptomatic cerebral vasospasm and identified younger age (<35 yr) as a predictive parameter. Moreover, Charpentier et al. (21) demonstrated through multivariate analysis that the probability of occurrence of symptomatic vasospasm decreased with age greater than 50 years. The lower incidence of vasospasm in older patients may be secondary to the age-related increase in atherosclerosis, which results in impairment of contractility and elasticity of the muscle wall of small arteries and arterioles (25,111). Postmortem histological studies have demonstrated that aging is accompanied by the appearance of collagen fibers in major intracranial arteries, which is usually associated with the loss of elasticity of the vessel wall (64). Dewey et al. (32) described a collapse of downstream vasculature as diastolic pressure falls below the critical closing pressure of cerebral blood vessels. They reported that younger patients, because of having more compliant and collapsible vessels, may have a greater decrease in CBF as cerebral perfusion pressure reaches a critical closing pressure (32). Hence, elderly subjects with more rigid vessels may be able to maintain small-vessel patency at similar pressures.
The effect of age on the occurrence of vasospasm, however, is controversial. Lanzino et al. (87) reported that symptomatic vasospasm but not angiographic vasospasm was more frequent in elderly patients. Others have not found a relationship between age and risk of symptomatic vasospasm (32,71,87). The discrepancy in these results may be attributed to differences in the characteristics of the population under study, definitions of vasospasm, and management strategies among various studies.
Lasner et al. (88) performed a prospective analysis of 75 consecutively admitted patients to identify risk factors for symptomatic vasospasm other than the thickness of blood within the basal cisterns. Demographic and clinical parameters were evaluated by use of multivariate logistic regression to determine factors independently associated with cerebral vasospasm. Multivariate analysis demonstrated that cigarette smoking increases the risk of symptomatic vasospasm after aneurysmal SAH, independent of Fisher grade (P = 0.033) (88). Weir et al. (187) performed a prospective study of nearly 3500 patients from North America and Europe who were enrolled in five different multicenter controlled studies coordinated at the Neuroclinical Trials Center of the Virginia Neurological Institute at the University of Virginia. Among the prospective data gathered were whether the patients smoked at the time of their most recent SAH and the evolution of angiographic vasospasm. The results of the study showed that cigarette smoking was associated with an increased incidence of clinically confirmed vasospasm (P < 0.005) (187).
Hypertension has been shown to increase, independently of other factors, the risk of cerebral infarction after SAH (88). In a clinical study conducted by Ohman et al. (128), a follow-up CT scan was performed on 47 patients with a previous history of hypertension on admission and 176 patients with no previous history of hypertension. Of the hypertensive patient group, a total of 63.8% had an infarct on CT scan, compared with 45.5% of the nonhypertensive group. The use of nimodipine did not have an effect on the frequency of infarcts in the hypertensive patient group. The pathophysiology of why patients have more infarcts after aneurysmal SAH remains unclear. It has been suggested that the brain of a hypertensive patient may be less tolerant of ischemia than that of a normotensive patient (128).
The stroke-prone spontaneously hypertensive rat (SPSHR) has been used to investigate the mechanisms predisposing to stroke in hypertension. Similar to the human disease, stroke in the SPSHR seems to be a complex, polygenic, and multifactorial trait. Expression of the morbid phenotype depends on both the presence of hypertension and the interaction with environmental variables, such as exposure to a diet higher in sodium and lower in potassium and protein. If these conditions are met, SPSHRs show an extremely high rate of stroke that occurs rapidly within a few weeks to months (184). Lowering of blood pressure to normal levels greatly reduces or eliminates the occurrence of stroke in both SPSHRs and humans.
DIAGNOSTIC NEUROLOGICAL IMAGING
Early prediction of the risk of vasospasm is important in the management of patients after SAH. In the International Cooperative Study on the Timing of Aneurysm Surgery, the worst outcomes occurred among patients whose surgery was performed between Days 7 and 10 after bleeding (76). This period corresponds to the peak incidence of vasospasm and to the maximum reduction in CBF. A number of diagnostic methods have been developed to predict the occurrence of vasospasm and its associated neurological deficits. Attempts have been made from time to time to improve prediction, largely without success. In a recent example, 283 control subjects from a drug trial were analyzed (91). An index based on four significant variables (thickness of subarachnoid clot, early increase in TCD velocity, initial Glasgow Coma Scale score less than 14, and carotid or anterior cerebral artery aneurysms) was still only 68% sensitive in identifying those who would develop delayed ischemic deficit, limiting the usefulness of this index (35). Nevertheless, neurological imaging methods used to predict cerebral vasospasm include but are not limited to conventional angiography, CT imaging, CT perfusion, TCD sonography, single-photon emission computed tomography (SPECT), and magnetic resonance perfusion and diffusion imaging. The usefulness, advantages, and pitfalls of each method are discussed below.
Although CT angiography and magnetic resonance angiography can identify vasospastic vessels, conventional angiography is the “gold standard” method for the definitive diagnosis of vasospasm. Conventional angiography performed after aneurysm surgery can identify causes of morbidity and mortality that may be correctable (184). The angiographic diagnosis of cerebral vasospasm is usually based on a subjective reduction of the arterial lumen compared with images without vasospasm (7). Le Roux et al. (91) performed a retrospective analysis of 597 diagnostic angiograms obtained after aneurysm surgery for 494 patients to determine the risks and benefits of angiography. The results of the study showed that catheter-induced spasm and dissection occurred most frequently in the internal carotid artery and were observed in approximately 1% of the patients. No angiography-associated strokes were identified. Aneurysm remnants were identified in 5.7% of the 637 aneurysms that were treated and were significantly associated with atherosclerosis (P < 0.01) or multiple clip applications (P < 0.01). Angiographic vessel occlusion was observed in 5.7% of the patients and resulted in stroke in 2.8% of these patients. Vessel occlusion was associated with increasing aneurysm size (P < 0.001), atherosclerosis (P < 0.001), temporary clips (P < 0.001), multiple clips (P = 0.03), multiple clip applications (P = 0.001), and a new postoperative neurological deficit (P = 0.002). The authors concluded that angiography after aneurysm surgery is safe and can be performed routinely (91). Despite these claims, conventional angiography is an invasive procedure with occasional complications. Although it is accepted as the most accurate diagnostic standard, conventional angiography can miss vasospasm altogether if the spasm is restricted to small vessels that are not seen angiographically (35). In addition, conventional angiography does not distinguish between angiographic and symptomatic vasospasm.
Computed Tomography/CT Perfusion Imaging
Computed tomography has been used as an initial screening tool for the prediction of cerebral vasospasm after SAH. The total amount of subarachnoid blood seen on an initial CT scan is a well-established predictor of infarction caused by vasospasm (17,57,114). In a study of 47 patients, Fisher et al. (47) divided them into four groups with predictable outcomes, as presented in Table 4. When subarachnoid blood was not seen on the CT scan or was faintly and diffusely distributed, symptomatic vasospasm was uncommon, occurring in only 1 of 18 patients (47). Furthermore, describing a group of almost 1000 patients, an international cooperative study on the timing of aneurysm surgery found that the best prognostic indicator of vasospasm-related ischemia was initial CT appearance: focal or thick collections of clot in the basilar cisternae put the patient at high risk for developing vasospasm and delayed ischemic deficit (56).
In addition to the total amount of blood loss after initial SAH, Hirashima et al. (67) have proposed that the clearance rate of SAH by surgery be considered as an additional index for the indirect effect of SAH. They noted that extensive surgical removal of subarachnoid blood during the acute stage is known to be effective in preventing the occurrence of vasospasm and suggested that the initial amount of SAH is therefore not enough to indicate the indirect lesional effects after the removal of blood surgically (67). Other imaging methods such as magnetic resonance imaging and SPECT are more sensitive in detecting areas of vasospasm-related ischemia and decreased blood flow and perfusion, respectively (164). However, although these techniques are more sensitive than CT imaging, they are not as widely available and cannot be as easily obtained compared with CT imaging. In addition, virtually all available data are based on CT scans (164).
CT perfusion is a method that has been shown to overcome many of the limitations of other CBF technologies. It provides direct anatomic correlation, directly calculates the partition coefficient, and provides relatively high-resolution, quantitative, and reproducible CBF information (80,110,166). In addition, CT perfusion can provide early, highly accurate delineation of ischemic tissue, allowing the underlying hemodynamic disturbances of vasospasm to be further analyzed. Because CT perfusion imaging can assess physiological parameters such as CBF, cerebral blood volume, and mean transit time, it offers additional data that can be useful in detecting and characterizing tumors, infection, inflammation, and infarction, which can all have similar appearances on both contrast-enhanced and non–contrast-enhanced conventional CT images.
Xenon-enhanced CT (Xe/CT) perfusion imaging has been used as an alternative approach to contrast-enhanced CT perfusion imaging. The performance of Xe/CT involves repeated scanning of the same brain slices during the administration of xenon (193). Flow values near zero have been recorded by the Xe/CT method in experimental studies of focal cerebral ischemia that have consistently predicted infarction (144). Such sensitivity allows the clinician to distinguish between reversible ischemia and irreversible infarction and to detect a fall in CBF far in advance of ischemic neurological deficit. Disadvantages of Xe/CT include significant irradiation to the head, mental status effects of xenon, and complex effects of xenon on cerebral perfusion, quantification reliability questions, and technical limitations inhibiting the patient's tolerance. This may lead to a high failure rate in obtaining an accurate examination (1). Nevertheless, CT perfusion imaging is a rapidly evolving noninvasive technique that, unlike conventional magnetic resonance and CT angiographic methods, can be used to evaluate capillary level tissue perfusion.
Transcranial Doppler Sonography
TCD sonography is a well-established technique for investigating changes in cerebral hemodynamics. The TCD technique can detect increased velocities in the proximal segments of the internal carotid, middle cerebral, anterior cerebral, posterior cerebral, vertebral, and basilar arteries, which are presumably caused by vessel lumen reduction. Indeed, a rise in TCD velocity in the basal cerebral vessels occurs in nearly all patients after SAH, and a rapid rise to high levels is frequently associated with clinical deterioration caused by vasospasm and subsequent delayed ischemia (28,157,158). Flow velocities greater than 120 cm/s are associated with mild to moderate angiographic vasospasm, and flow velocities greater than 200 cm/s are associated with severe vasospasm. Some patients, however, may remain asymptomatic for vasospasm despite velocities greater than 200 cm/s, thus accounting for false-positive results for symptomatic vasospasm (89). Vora et al. (185) suggested that only very low or very high MCA velocities (<120 or >200 cm/s) negatively (94%) or positively (87%) predict angiographic and symptomatic vasospasm in a reliable manner, and they suggested that intermediate velocities had a lower predictive value and were poorly discriminative. In addition, this study showed that hypertensive hypervolemic therapy is associated with higher velocities even in the absence of vasospasm. In a retrospective study comparing blood velocity as measured by TCD ultrasonography and CBF as measured by Xe/CT and using a CBF cutoff point of 31 ml/100 g/min, greater velocities were recorded at greater local CBF (27). These data suggest that increased blood velocity in proximal cerebral arteries is associated with increased downstream flow in the presence of vessels with reduced vasoactive response. Therefore, increased velocity may represent a compensatory blood flow increase and not necessarily a critically compromised flow. In situations of both proximal and distal vasospasm, no compensatory velocity increase is observed, thus accounting for false-negative results. Okada et al. (129) compared TCD velocity with angiographic features and cerebral circulation time. Overall, TCD had a sensitivity of 84% and a specificity of 89% for detecting vasospasm of the MCA compared with angiography. Although TCD sonography may warn of spasm development, TCD sonography itself is not entirely accurate. The technique is quite operator dependent, and the results may be misleading because of false-negative findings attributed to vasospasm of peripheral sites.
Single-Photon Emission Computed Tomography
SPECT imaging of the brain has been well established in the assessment of regional CBF (rCBF). Unlike TCD, SPECT can assess cerebral perfusion at the cellular level (72). SPECT uses single-pass radiopharmaceutical agents able to cross the blood-brain barrier and distribute to neurons in direct relationship to regional CBF (85,130). SPECT scanning is particularly valuable in poor-grade patients who cannot be evaluated reliably for clinical deterioration (92). SPECT may be normal and patients remain asymptomatic at the same time that TCD velocities are extremely elevated in individual vessels because of preserved autoregulation and collateral flow (92). SPECT may be persistently abnormal in patients with technically successful angioplasty of spastic vessels and normalization of TCD velocities after treatment, corresponding to tissue death (92). SPECT enables images to be acquired within 24 hours that reflect the flow that existed at the time of injection. Additional advantages include lack of patient discomfort, which leads to rare failure to obtain images, and multiplanar image display. The drawbacks of SPECT imaging include its semiquantitative analysis (except with 133Xe), operator error in generating region of interest, and normalization to the cerebellum (which can be affected by vasospasm) for semiquantification (116). Naderi et al. (116) conducted a study to evaluate the value of SPECT for the early diagnosis and monitoring of vasospasm and compared it with other diagnostic methods, such as CT imaging, digital subtraction angiography (DSA), and somatosensory evoked potentials (SEP). They applied SPECT, DSA, CT imaging, and SEP to 25 patients who were susceptible to vasospasm secondary to SAH and evaluated their values in the early diagnosis of vasospasm. Patients were graded by Botterel's system for clinical status, Sano's system for CT results, and, according to the distribution of vasospasm, compared with the contralateral vascular diameters for DSA results. In SEP, central conduction time was measured in each patient by stimulating the nervus medianus and recording from the contralateral cerebral cortex. The results were compared with those of a control group (116). Prolonged central conduction time values were obtained in vasospasm parallel to the level of ischemia in SEP. However, the sensitivity of the test was low compared with SPECT and DSA (116). In the study, CT imaging and SEP seemed less valuable in the early diagnosis of vasospasm but could be acceptable for patients with high-grade clinical conditions. SPECT was found to be more sensitive than DSA for providing functional information but was less specific for the detection of borderline areas of ischemia at risk for vasospasm: 88% of patients had SPECT abnormalities and 68% had angiopositive vasospasm (116). In a retrospective review of 16 patients, Powsner et al. (143) found good sensitivity (89%) and acceptable specificity (75%) for the detection of vasospasm by use of SPECT. They noted that a rigorous comparison of SPECT and CT findings is essential to avoid misinterpretation of SPECT abnormalities resulting from other pathological conditions (such as atrophy, mass lesions, etc.) from those resulting from a reduction in perfusion (116). Rosen et al. (149) emphasized the importance of correlation with anatomic imaging in postoperative studies, because the majority of patients in their study demonstrated perfusion abnormalities that could be explained by postoperative changes.
Diffusion-weighted and Perfusion-weighted Magnetic Resonance Imaging
In patients with SAH, there may be multiple causes for neurological impairment. It is often difficult to be certain whether ischemia caused by vasospasm is in fact a contribution or whether “ischemic” injury relates to direct effects of the hemorrhage, surgical retraction, temporary arterial occlusion, or embolism from endovascular devices. Better measures of cerebral tissue perfusion and earlier detection of vasospasm-related ischemic injury are needed to prevent its occurrence or to guide therapy in SAH patients with vasospasm. Rordorf et al. (148) sought to identify vasospasm-related tissue ischemia and early ischemic injury with combined diffusion-weighted and hemodynamically weighted magnetic resonance imaging (DWI and HWI, respectively), in six patients with clinical and angiographic vasospasm. Analysis of the passage of an intravenous contrast bolus through brain was used to construct multislice maps of relative cerebral blood volume, relative CBF (rCBF), and tissue mean transit time. The results of the study showed that small, sometimes multiple, ischemic lesions on DWI were seen encircled by a large area of decreased rCBF and increased tissue mean transit time in all patients with symptomatic vasospasm. Decreases in relative cerebral blood volume were not prominent. HWI abnormalities occurred in regions supplied by vessels with angiographic vasospasm. All patients with neurological deficit showed an area of abnormal tissue mean transit time much larger than the area of DWI abnormality (148). The investigators concluded that DWI/HWI in symptomatic vasospasm can detect widespread changes in tissue hemodynamics that encircle early foci of vasospasm-induced ischemic injury (148). The specificity of the observed patterns for vasospasm in patients after SAH, however, will require study of a larger patient cohort. Moreover, serial HWI in patients with SAH should be studied for its ability to detect a particular hemodynamic pattern that precedes and reliably predicts the occurrence of clinically significant vasospasm.
Unlike DWI, which shows diffusibility of water, perfusion-weighted magnetic resonance imaging (PWI) requires rapid intravenous injection of contrast medium to permit measurement of rCBF, relative cerebral blood volume, and tissue mean transit time. Leclerc et al. (90) assessed the usefulness of DWI and PWI for the detection of brain damage in 11 patients with suspected vasospasm after rupture of an aneurysm of the anterior circulation. All patients were evaluated by DWI, PWI, and SPECT within 2 weeks of their SAH. PWI revealed an area of slowed flow in seven patients, including four with major and three with minor hypoperfusion on SPECT. DWI showed a high signal in two patients who had severe vasospasm on TCD, a marked slowing on the time-to-peak map, and major hypoperfusion on SPECT. The extent of the abnormal signal was less than that of slowed flow on PWI. In most patients with suspected vasospasm on TCD, PWI and SPECT were abnormal. A high signal on the initial DWI within a region that appeared hypoperfused on PWI was associated with a permanent neurological deficit (90). On the basis of these preliminary studies, DWI and PWI may be used to show brain damage in patients with vasospasm. The usefulness of these techniques will probably depend on the timing of the examination and the severity of vasospasm, as demonstrated by Domingo et al. (34) in an animal model and Rowe et al. (150) in a clinical study. Further clinical studies in larger groups of patients are required, however, before definitive conclusions about these techniques can be drawn.
BEDSIDE INTRACEREBRAL MICRODIALYSIS MONITORING
Because arterial vasospasm is more often a focal rather than a diffuse phenomenon, CBF velocities, which are usually measured with TCD from the large cerebral arteries, may not always reflect microcirculatory alterations and are insensitive to regional hemodynamic changes. Intracerebral microdialysis is a sensitive technique to monitor metabolic changes in cerebral areas that are considered at risk for secondary ischemic injury. Intracerebral microdialysis has been demonstrated to be a useful and safe method for the detection of brain ischemia in neurointensive care patients with SAH (41,137,155). The technique involves the insertion of a small microdialysis catheter into the brain parenchyma. The catheter is perfused with a physiological solution, which passes through a semipermeable membrane at the tip, across which endogenous substances from the extracellular fluid of the brain can diffuse into the catheter. Samples are collected continuously and can later be analyzed for various energy metabolites, neurotransmitters, and other substances (124). Microdialysis allows a bedside comparison of changes in neurochemistry with the neurological status of the patient. For example, many investigators have reported increased CSF lactate concentration after SAH (31,43,115,124,154,169). Lactate was chosen for evaluation because it has been shown to be a marker of cellular oxygen deficiency. The data from these studies were all obtained during a relatively short interval (within 12 hours) after SAH, and the increase of CSF lactate reflected not only glycolysis by blood cells in the hematoma but also brain tissue hypoxia caused by the SAH. Shimoda et al. (161) reported a longer time course of CSF lactate concentrations in SAH and emphasized a significant increase in them on the fifth through seventh days after SAH. They also demonstrated that this delayed increase of CSF lactate occurs concurrently with the onset of cerebral vasospasm and attributed it to brain hypoxia caused by the vasospasm (161). In addition to lactate, a number of other metabolites have been investigated by microdialysis for their potential to predict the onset of vasospasm. De Micheli et al. (31) conducted a study to test the sensitivity of microdialysis to detect the neurochemical changes caused by vasospasm in patients with nonsevere SAH and to identify patterns of neurochemical markers that may assist in predicting the development of cerebral ischemia. Dialysate was collected from patients every 6 hours and then analyzed for energy metabolism markers, including glucose, glycerol, lactate, glutamate, aspartate, γ-aminobutyric acid, and taurine by high-performance liquid chromatography. Analysis of the microdialysis data demonstrated that lactate is the most sensitive marker of cellular energy imbalance in patients presenting with a mild-to-moderate hypoxic condition. Increased lactate levels correlated positively with glutamate (P < 0.0001), aspartate (P < 0.0001), γ-aminobutyric acid (P < 0.0001), and taurine (P < 0.0001) concentrations (31). The results of the study suggested that sustained high levels of glutamate and taurine, when associated with increased lactate production, might represent a pattern predicting an impending condition of cellular ischemia (31). The study also demonstrated the sensitivity of intracerebral microdialysis in revealing subtle metabolic abnormalities in patients with nonsevere SAH (31). Nevertheless, a few pitfalls must be overcome before the technique can be recommended for widespread use. First, the microdialysis probe must be placed in the tissue that may become ischemic to observe changes in the metabolic parameters (137). Second, it is not clear that this technology, which is costly and time-consuming, is an earlier or more sensitive indicator of impending vasospasm than other existing methods of detection (137). Third, microdialysis does not allow the clinician to evaluate more than one region of the brain at a time. The microdialysis data must be systematic and comparable to standard clinical monitoring, which includes TCD and perhaps also brain tissue PO2. Still, the ability to monitor the metabolism of the human brain at the bedside in “real time” may be of immense value in understanding a number of disorders affecting the brain and in evaluating therapeutic interventions.
Cerebral blood vessels affected by vasospasm exhibit structural changes that are consistent with the actions of vascular mitogens. Smooth muscle and myofibroblast proliferation, as well as cellular necrosis and remodeling, are common features of vasospastic segments (165). Intimal hyperplasia, as well as collagen deposition and fibrosis, have also been described extensively (106). These changes may contribute to arterial wall thickening and decreased vessel wall compliance after SAH. Cellular proliferation and increased vessel wall thickness may, in turn, cause vascular stiffening that contributes to cerebral vasospasm (14). Underlying these changes in endothelial function are complex cascades of biochemical reactions that are triggered in response to the SAH. The identification of growth factors, extracellular matrix molecules, vasoconstrictors, immunomodulators, and other mediators released in response to the initial hemorrhage may serve as identifying markers for the impending occurrence of vasospasm. Indeed, a number of potential markers have been identified and are discussed below.
Endothelial cells play a key role in the local regulation of vascular smooth muscle tone by producing and releasing relaxing and contracting factors. Although the physiological role of endothelium-dependent contractions in the regulation of the cerebrovascular system is unclear, existing evidence supports the concept that vasoconstrictor substances may become more prominent under pathological conditions (95). Endothelial cells produce ET-1, one of the most potent endogenous vasoconstrictor substances known (191). Its long-lasting vasoconstrictor and hypertensive action has been well documented, and it is generally accepted that increased production of ET-1 may contribute to the pathogenesis of a number of vascular diseases (119). Several lines of evidence implicate ET-1 in the pathophysiology of cerebral vasospasm after SAH. First, levels of ET-1 are generally increased in the CSF and plasma of SAH patients (104,172) in close correlation with development of vasospasm (39,73,156,171,196). Second, delayed vasospasm can be evoked experimentally by the administration of ET-1 (6,175,197). Third, antagonists of ET-1 attenuate vasospasm in experimental models of SAH (26,126,198). Until recently, the mechanisms and cellular origins of ET-1 synthesis and release have been unknown. Fabender et al. (42) demonstrated that ET-1 is subarachnoidally produced by CSF mononuclear leukocytes in the context of a compartmentalized inflammatory host response, and that blood-CSF contact acts as a trigger for such leukocytic ET-1 synthesis. Furthermore, they demonstrated that in vitro coincubation of CSF and blood could trigger leukocytic release of ET-1 in parallel with release of inflammatory mediators (42). They observed that subjects with evidence of severe vasospasm exhibit higher ET-1 concentrations in CSF. It should be noted, however, that not all studies have demonstrated a correlation between increased levels of ET-1 in CSF and plasma and the occurrence of vasospasm (51,139,160). It has been suggested that an increase in CSF ET-1 levels may be the result of cerebral ischemia rather than the cause of vasospasm (139). Nevertheless, the possibility that increased levels of ET-1 play an important role in the development of neuronal cell death after SAH and acute cerebral ischemia deserves further investigation. Indeed, ET-1 may cause constriction of collateral vessels and contribute to a vicious circle, with further reduction in regional blood flow, enhancement of the severity and size of the infarcted tissue, and worsening of the neurological outcome. The demonstration that ET-1 is produced by activated CSF mononuclear leukocytes suggests that subarachnoid inflammation may represent a therapeutic target to prevent vasospasm and DCI after SAH (42).
Leukocytosis results from a transient increase in leukocytes in the blood that occurs in response to hemorrhage and/or inflammation. Leukocytosis occurs through a process referred to as transmigration and involves three steps: rolling, activation, and migration across the endothelium and into the perturbed tissue (18). Rolling consists of adhesive interactions that are sufficient to slow the leukocyte but not sufficient to overcome blood flow and stop the leukocyte. In response to a stimulus such as hemorrhage or inflammation, large numbers of leukocytes will become adherent to the side of the vessel by the aid of cellular adhesion molecules such as selectin and integrin. In contrast to rolling, firm adhesion or activation is associated with flattening and spreading of the leukocyte. With progression of an inflammatory response from the initial SAH, the vessel may become occluded by adherent leukocytes, and blood flow may essentially stop. Firm adhesion is usually followed by migration across the endothelial monolayer (160).
Daily monitoring of the serum leukocyte count is typically included as postoperative management in patients with SAH and therefore represents a potentially convenient marker for assessing the risk of vasospasm (70). Neil-Dwyer and Cruickshank (120) first demonstrated the prognostic significance of leukocytosis in the outcome of patients with SAH. Parkinson and Stephensen (134) described increased rates of death in patients with leukocytosis after SAH. They found that a white blood cell count exceeding 20,000 was associated with poor clinical grade on admission and a 50% mortality rate. Maiuri et al. (103) observed a similar association and hypothesized that arterial spasm may account for this association. In contrast, Spallone et al. (167) found no association between admission leukocyte count and risk of subsequent ischemic complications. More recently, increased serum leukocyte counts have been reported in patients who developed vasospasm after aneurysmal SAH (122,186); however, investigators in these studies did not adjust for confounding variables and therefore cannot assess an independent association between leukocyte count and cerebral vasospasm. In the most recent study, however, McGirt et al. (108) revealed that leukocytosis is a risk factor for the subsequent onset of vasospasm (P < 0.01), which is independent of blood clot load or location, clinical status, or patient age.
From these studies, it can be concluded that leukocytosis may represent a convenient marker of increased risk of cerebral vasospasm after SAH, which could potentially influence treatment of these patients. Significant leukocytosis may identify patients who should undergo more frequent imaging studies and may signify those who could benefit from more aggressive hypertension, hypervolemia, hemodilution therapy, novel anti-inflammatory therapies, or early angioplasty.
Soluble Adhesion Molecules
Adhesion molecules consist of an evolving set of macromolecules the interplay of which helps mediate the white cell response to injury through transmigration (142). Although the appearance or up-regulation of adhesion molecules occurs in response to hemorrhagic shock (147), there is no recognized association between adhesion molecule up-regulation and SAH. However, given the massive release of blood and blood breakdown products into CSF and the observation that inflammatory changes in smooth muscle of large cerebral vessels occur in vasospasm after SAH (151), a role for adhesion molecules in the pathogenesis of cerebral vasospasm can be postulated. A number of adhesion molecules have been implicated in the pathogenesis of cerebral vasospasm. These include intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1, E-selectin, and L-selectin. Each of these molecules has been shown to be present in a soluble form in human serum obtained from normal volunteers and to decrease with increasing age (118). The E-selectin is an inducible molecule localized primarily to endothelial cells that binds a ligand present on neutrophils, monocytes, and lymphocytes (12,46). The L-selectin is expressed constitutively on peripheral leukocytes and may interact with P-selectin to permit “rolling” of leukocytes along vascular endothelium (2,63). Vascular cell adhesion molecule-1 appears on vascular endothelial cells in response to cytokine activation and binds to very late antigen-4, a β1 integrin expressed on lymphocytes and monocytes (61). ICAM-1 is expressed by vascular endothelium and binds to members of the β2 integrin family of ligands, present on circulating leukocytes (61).
Recent studies in animals have implicated ICAM-1 in the cause of vasospasm after SAH. Sills et al. (162) demonstrated an association between ICAM-1 up-regulation and femoral artery vasospasm after vascular exposure to blood in a rat femoral artery model. In a rabbit model of SAH, Bavbek et al. (8) demonstrated that antibodies to ICAM-1 and its ligand CD18 attenuate basilar artery vasospasm. The relevance of these experimental findings to human vasospasm, however, is not yet known. Polin et al. (141) demonstrated elevation of soluble E-selectin (P = 0.0013), ICAM-1 (P = 0.0001), and vascular cell adhesion molecule-1 (P = 0.048) levels in the CSF of patients after aneurysmal SAH. Mack et al. (100) found a correlation between serum soluble ICAM-1 levels and outcome in patients with aneurysmal SAH, even with control for initial presentation. This association with outcome was predicted by late increases (Day 6, P = 0.07; Days 8–12, P < 0.05) rather than early increases (P = NS) in ICAM-1 levels and was best seen in poor-outcome patients with Hunt and Hess Grades I and II (P < 0.05). To further investigate the relationship between vasospasm and ICAM-1 up-regulation, Mocco et al. (113) examined soluble ICAM-1 levels at various time points after aneurysmal SAH and analyzed them with respect to changes in vessel flow dynamics and morphology by use of TCD and cerebral angiography. They found a significant rise in soluble ICAM-1 from 2 days before to 6 days after TCD-documented cerebral vasospasm (P < 0.01) that was not observed in Hunt and Hess grade-matched controls (113). Their results provide further support for a role for ICAM-1 in the development of cerebral vasospasm. The role of ICAM-1 and other adhesion molecules in the pathogenesis of vasospasm, however, remains unclear. It is possible that they may play a causative role in the pathogenesis of vasospasm; alternatively, their up-regulation may be a consequence of the occurrence of vasospasm. As the pathophysiological mechanisms involved become better elucidated, adhesion molecules such as ICAM-1 may provide a novel therapeutic target in designing antivasospasm therapies.
Free radical reaction and oxidative challenge after blood lysis in the subarachnoid space has been implicated in the development of cerebral vasospasm (16,170). As mentioned earlier in this review, oxyhemoglobin has been suggested as a key substance that evokes free radical reactions, such as lipid peroxide production (153). Unlike other parts of the body, CSF is almost completely lacking in defense mechanisms against free radicals. When such free radical reactions are provoked in the subarachnoid space after SAH, it is suspected that this cascade may cause functional or structural damage in the arterial wall, resulting in cerebral vasospasm (74). These chain reactions cause both an augmentation of contraction and suppression of vessel dilation (192). Phosphatidylcholine and cholesteryl ester are very important functional components of biological membranes and are also major structural constituents in tissue lipids (112). Lipid peroxides, such as phosphatidylcholine hydroperoxide (PCOOH) and cholesteryl ester hydroperoxide (CEOOH), are both products of free radical oxidation of such fatty acids and major substances for starting the chain-reaction production of free radicals (94). Suzuki et al. (170) measured PCOOH levels in the cerebral arteries and tissues obtained from a primate model of SAH. They found that PCOOH levels in cerebral arteries that display vasospasm are significantly higher (P < 0.025) than those measured in arteries in which no contraction is evident. The levels of PCOOH in the brain tissue in contact with the subarachnoid clot were five times higher than those measured in other regions (170). Polidori et al. (140) measured plasma levels of CEOOH in patients with SAH. They found that plasma CEOOH levels paralleled the persistence of vasospasm but were not predictive of symptomatic vasospasm. Kamezaki et al. (74) investigated the relationship between the patients’ clinical profiles and the levels of lipid peroxides in the CSF rather than in plasma, where free radical reactions and vasospasm are known to occur. The objectives of the study were to determine whether lipid peroxides, including PCOOH and CEOOH, are detectable in the CSF as biochemical markers of free radical damage in patients with SAH and to correlate their levels in the CSF with the occurrence of symptomatic vasospasm and clinical outcome (74). The results of the study found that increased levels of both PCOOH and CEOOH measured in the CSF during the acute stage of SAH (i.e., within 7 d after onset of SAH) were predictive of both symptomatic vasospasm (P = 0.002) and poor outcome (P = 0.043) (74). They concluded that measurements of lipid peroxides in the CSF could be prognostically useful for patient outcomes as well as for predicting symptomatic vasospasm (74).
Although the use of free radical scavengers in preventing vasospasm in clinical practice has been disappointing, Kodama et al. (84) successfully prevented vasospasm by cisternal irrigation therapy with ascorbic acid in a study of 217 patients. It is possible, therefore, that a maximal protective effect could be achieved by the intrathecal administration of water-soluble free radical scavengers. Clearly, further studies in larger patient cohorts are needed to determine the role of lipid peroxides in the pathogenesis of cerebral vasospasm.
Cellular Proliferation and Growth Factors
Endothelial damage and intimal proliferation occur in vasospastic cerebral arteries after SAH. Coagulation of subarachnoid blood activates platelets, which release potent growth factors for cells in the vascular wall. Previous studies have shown that growth factors from platelets are increased in the CSF of patients with SAH (52,81). Among these growth factors are platelet-derived growth factor-AB (PDGF-AB), transforming growth factor-β1 (TGF-β1), vascular endothelial growth factor (VEGF), serum von Willebrand factor (vWF), fibronectin containing extra type III domain (ED1-fn), and matrix metalloproteinase-9 (MMP-9).
Both PDGF-AB and TGF-β1 are important mitogens for smooth muscle cells in the vascular media and fibroblasts in the adventitia (146). PDGF-AB concentrations in CSF from SAH patients have been shown to be significantly higher than those from non-SAH patients and normal controls (P < 0.003) both during the first week after SAH and for all time points measured (14). Smooth muscle and fibroblast proliferation has been observed after SAH in a mouse model of endovascular injury and SAH, and this cellular replication was observed in conjunction with PDGF protein at the sites of thrombus (14). In human pial arteries, localized thrombus has been shown to stimulate vessel wall proliferation. This proliferation was blocked by neutralizing antibodies directed against PDGF (14). TGF-β1 is a multifunctional fibrogenic cytokine that controls the production of extracellular matrix protein and actions of other cytokines (81). It has also been found to play an important role in generating communicating hydrocephalus after SAH (81). Platelets store a large quantity of TGF-β1, which is released during SAH (81). In a recent study in humans, Flood et al. (49) measured TGF-β1 levels in sequential samples of CSF in 11 patients with hydrocephalus after SAH. They found that mean total TGF-β1 levels were elevated to 4400 ± 3435 pg/ml in these patients, compared with control patients, whose levels were 97 ± 4 pg/ml at 1 to 2 days after hemorrhage (49). Thereafter, levels fell to 714 ± 401 by 5 to 6 days after hemorrhage, and then rose to a second peak of 1667 ± 774 at 9 to 10 days after hemorrhage, remaining significantly increased until 19 days after hemorrhage (P = 0.007) (94). The authors concluded that the elevated levels of TGF-β1 in CSF after SAH are derived initially from extravasated platelets and later from endogenous sources, such as the choroid plexus (49).
In the peripheral vasculature, endothelial damage increases MMP-9 and VEGF levels, causing neointimal proliferation (19). VEGF stimulates endothelial cell proliferation and permeability, increases intercellular adhesion molecule expression and leukocyte infiltration, and facilitates vascular smooth muscle cell migration and intimal proliferation, as observed in vasospastic cerebral arteries (55,109). MMP-9 alone can initiate VEGF activity by increasing VEGF availability within the vascular media (10). After endothelial cell damage, MMP-9 expression is increased by smooth muscle cells and infiltrating leukocytes, contributing to the initiation of myointimal proliferation (195). In a prospective study conducted by McGirt et al. (107), venous serum levels of vWF, MMP-9, and VEGF were measured daily for 12 days or until the onset of vasospasm. To establish whether these markers were specific for vasospasm versus ischemia, blood samples were obtained from a group of 42 patients within 24 hours after stroke onset unrelated to SAH (107). The results of this study showed that the development of cerebral vasospasm after SAH was preceded by increases in serum vWF (P = 0.01), MMP-9 (P = 0.006), and VEGF (P = 0.023) levels in the SAH prevasospasm cohort compared with the SAH nonvasospasm cohort and that these levels accurately predicted the onset of cerebral vasospasm after SAH (107). These factors were not elevated by SAH alone or in a separate cohort of patients with ischemic stroke, suggesting that these factors might play a role in the pathogenesis of human cerebral vasospasm (107).
Endothelial cell activation plays an important pathogenetic role in the development of cerebral ischemia after SAH. Both vWF and ED1-fn are known markers of endothelial cell activation. vWF, a large adhesive glycoprotein that is stored in endothelial Weibel-Palade bodies, plays an important role in the coagulation system by increasing platelet aggregation at the site of vessel endothelium damage (11). It seems to be a suitable circulating marker of endothelial cell activation because of its sensitivity, its long plasma half-life, and its relative specificity for endothelial cells (182). ED1-fn, conversely, has been thought to promote angiogenesis by migratory recruitment of endothelial cells (121). ED1-fn, an adhesive glycoprotein, is a fibronectin synthesized in endothelial cells. It contains an extra Type III domain as a result of alternative messenger ribonucleic acid splicing (50). Endothelial cells do not express the ED1 domain under normal circumstances, but the ED1 domain is included in fibronectin molecules in pathological conditions (53,173). Frijns et al. (50) measured plasma concentrations of ED1-fn and vWF among 27 patients with aneurysmal SAH. They found that both ED1-fn (P < 0.04) and vWF (P = 0.02) levels were higher among patients in poor clinical condition at admission compared with patients in good clinical condition (50). They also observed a significant increase in concentrations of both markers after surgery (ED1-fn, P = 0.01; vWF, P = 0.05) and after ischemic episodes (ED1-fn, P = 0.02; vWF, P = 0.04) (50). Whether endothelial cell activation is a causal or indirectly related factor in the pathogenesis of vasospasm after SAH is still uncertain. A larger study is needed to confirm the prognostic value of vWF and ED1-fn levels before these markers are used to guide aggressive diagnostic or therapeutic interventions.
Endogenous electrolyte levels have been shown to be important modulators of cerebrovascular smooth muscle tone. For example, a low level of serum magnesium, i.e., hypomagnesemia, is frequently present after SAH and is associated with severity of SAH (53). In a study conducted by van den Bergh et al. (181), the frequency and time distribution of hypomagnesemia after SAH was assessed by measuring serum magnesium levels in 107 consecutive patients admitted within 48 hours after SAH. Hypomagnesemia at admission and during the DCI onset period (Days 2 – 12) was related to the occurrence of DCI, and hypomagnesemia at admission and hypomagnesemia that occurred any time during the first 3 weeks after SAH was related to outcome (181). Hypomagnesemia at admission was found in 41 patients (38%) and was associated with more cisternal (P = 0.006) and ventricular (P = 0.005) blood, a longer duration of unconsciousness (P = 0.007), and a worse World Federation of Neurosurgical Societies scale score at admission (P = 0.001) (181). The investigators concluded that hypomagnesemia is frequently present after SAH and is associated with the severity of SAH (181). Hypomagnesemia occurring between Days 2 and 12 after SAH predicts DCI (181).
The average cell expresses 15,000 to 40,000 genes out of a total genome containing 60,000 to 100,000 genes (97), of which several hundred are thought to play some tissue-specific roles in the cell. However, because most of them are unknown and have not been characterized, it is important to identify the unknown genes that could be involved in the pathogenesis of cerebral vasospasm. Recently, a number of molecular biological techniques have been applied in the studies of cerebral vasospasm. Technology such as the complementary deoxyribonucleic acid array is now available to determine the relative levels of expression of possibly every gene expressed in a cell in response to a given stimulus. In essence, analysis of a vasospastic artery is the analysis of multiple cell types at different stages of response to numerous stimuli. For example, Onda et al. (131) applied complementary deoxyribonucleic acid expression array and messenger ribonucleic acid differential display to examine changes in gene expression at different times after SAH in dogs. They identified 18 genes that were up-regulated and 2 that were down-regulated after SAH. Of these, 12 represented known genes or homologs of genes characterized previously, and the other 8 genes were not related to any sequences in the nucleotide databases (131). These genes were classified into three groups according to their function: genes for molecules associated with inflammation, genes the expression of which can be induced by stress conditions such as hypoxia and hypoglycemia, and genes apparently not related to cerebral vasospasm (131). Nam et al. (117) examined the relationship between immune activation and cerebral vasospasm after SAH. They hypothesized that risk factors related to individual variation in cytokine production may predict the risk of vasospasm after SAH (117). Northern hybridization was used to evaluate the expression of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in cultured monocytes after lipopolysaccharide stimulation in 24 SAH patients who had angiographically proven cerebral aneurysms. The results of the study showed that the activation index of IL-1β, but not TNF-α, was higher in patients with symptomatic vasospasm than in patients without (P = 0.039) (117). Furthermore, the IL-1β activation index was correlated with the degree of postoperative angiographic vasospasm (P = 0.007) (117). The investigators concluded that individual variation in systemic immune activation, measured by monocyte-derived IL-1β expression levels after stimulation, might be associated with the development of vasospasm after SAH (117). The monocyte-derived IL-1β expression, therefore, may be useful in the prediction of the severity of vasospasm in aneurysmal SAH. In addition to the aforementioned studies, a number of other studies have identified candidate genes that have been positively correlated with the onset of cerebral vasospasm (3,52,62,77,78,127,174). Taken together, these and several other studies have shown that inflammatory and stress-related reactions are closely related to the development of cerebral vasospasm.
Cerebral vasospasm is associated with high rates of morbidity and mortality, even after an aneurysm has been secured surgically or endovascularly. Clearly, early detection and rapid treatment of cerebral vasospasm are needed before ischemic damage occurs. However, despite numerous attempts to identify reliable risk factors and markers to predict the occurrence of vasospasm in patients presenting with SAH, a large blood burden is the only consistently demonstrated risk factor for vasospasm.
Much research continues to be devoted to elucidating the complex pathophysiology of vasospasm itself and of the consequent, but less common, ischemia. The mechanism of vasospasm after SAH remains to be fully delineated, but there are probably contributions by multiple factors. Indeed, a number of theories have been proposed to explain the causes; however, no one theory is fully accepted. One theory suggests that biochemically mediated contractions and relaxations of cerebral arterial smooth muscle cells are altered after SAH. Among them are free radical reactions triggered by oxyhemoglobin released from the subarachnoid clot and subsequent lipid peroxidation, which may participate in the pathogenesis of cerebral vasospasm. These chain reactions cause both an augmentation of contraction and suppression of vessel dilation. A second theory suggests that vasospasm is caused by the breakdown of blood products of platelets and erythrocytes in extravasated blood. Although a number of spasmogens have been identified, none have consistently caused or sustained vasospasm in laboratory experiments. A third theory is based on the development of structural changes within the vessel after aneurysmal rupture and SAH. This theory suggests that a mitogenic substance released from the platelets causes arterial hyperplasia. The structural changes resulting from arterial hyperplasia result in increased cerebrovascular resistance and, eventually, decreased CBF. A final theory suggests that vasospasm is caused by an inflammatory reaction occurring after SAH. The time course of vasospasm after the onset of SAH seems to be consistent with an immune-mediated response, and the suggestion that immunological processes may be involved deserves further evaluation.
Our understanding of why certain patients become symptomatic and others do not is still a challenge. Regardless of who develops vasospasm, it would be most effective if medical therapy could be easily administered and targeted at prevention rather than controlling symptoms or reversing existing spasm. Because vasospasm is such a multifactorial problem, it is probable that prevention will continue to require a combination of approaches, as is used at present with diagnostic imaging, patient monitoring, clearance of blood, hypervolemia, calcium antagonists, and if necessary, intensive triple-H therapy (hypertensive, hypervolemic, hemodilution) and balloon or chemical angioplasty. Future improvements in the prediction of cerebral vasospasm after aneurysmal SAH will probably result from improvement in patient evaluation and diagnostic methodologies. Recent advances in molecular biology have allowed the identification of genes and their transcription products that may be up-regulated in response to aneurysmal SAH. We speculate that changes in gene expression in the arterial wall contribute to the onset and resolution of vasospasm. Therefore, future research efforts will probably focus on the identification of such genes and their function in cerebral vasospasm.
Cerebral vasospasm after aneurysmal subarachnoid hemorrhage persists as the major contributor to morbidity and mortality in survivors of the initial event. However, the clinician's ability to accurately predict which patients will develop vasospasm remains imperfect. Harrod et al. present an excellent review of the advances in the field of neurosurgery over the past 3 decades in the prediction of cerebral vasospasm. Their review appropriately outlines the complex pathophysiological mechanisms proposed in the cascade of events that may lead to cerebral vasospasm, specifically discussing the roles of oxyhemoglobin, free radical formation, lipid peroxidases, calcium influx, prostaglandins, and phosphorylation of myosin light chain. Furthermore, the effects of structural changes in the arterial wall, “spasmogens” in the perivascular space, and the role of inflammation are also well presented.
The crucial issue, of course, is deciding what factors should enter a predictive model for cerebral vasospasm, and Harrod et al. discuss the numerous clinical factors that have been explored, as well as such classic radiographic features as outlined in the Fisher Scale. Perhaps more discussion would have been interesting regarding the impact of age and hypertension with the development of cerebral vasospasm, because the concept of impaired cerebral autoregulation in these populations is only briefly touched on, and yet this may provide an important clue regarding vessel reactivity. In addition, the timing of therapies to treat cerebral vasospasm is often unclear, and the importance of monitoring for clinically significant examination changes should be emphasized.
Harrod et al. provide an excellent overview of the diagnostic neuroimaging that is being applied to assessing cerebral vasospasm, from “gold standard” conventional angiography, which is relatively invasive, to bedside transcranial Doppler measurements, which often lack both sensitivity and specificity. Magnetic resonance imaging with diffusion- and perfusion-weighted sequences are discussed, but aside from the fact that their use has yet to be validated in a study with sufficient numbers, the use of magnetic resonance imaging is difficult in subarachnoid hemorrhage patients with multiple intensive care unit issues. The same can be said for single-photon emission computed tomography, which is also limited by its lack of availability in most centers. Computed tomographic (CT) angiography with CT perfusion imaging may be the most promising technique. All patients at our center who arrive with subarachnoid hemorrhage undergo CT angiography at admission, and this not only serves to delineate the anatomy of the aneurysm but also can serve as a baseline for the vessel lumen diameters. Thus, once the possibility of vasospasm is entertained, either clinically or by transcranial Doppler measurement, a second CT angiogram can provide more definitive evidence of true vasospasm, short of performing the more invasive conventional angiogram.
Other techniques that are discussed include microdialysis monitoring and biochemical markers of vasospasm. Intracerebral microdialysis has gathered steam in the past several years but remains limited by its ability to monitor only one small region of the brain, which may not reflect ischemic injury caused by vasospasm in other areas. The numerous biochemical markers that Harrod et al. discuss include endothelin 1, leukocytosis, soluble adhesion molecules, lipid peroxidases, growth factors, magnesium, and genetic markers. The complexity of the issue of predicting vasospasm in subarachnoid hemorrhage patients is well presented, and it is clear that the ultimate prediction model probably should depend on a number of factors: clinical, radiographic, and biochemical.
David M. Greer
Christopher S. Ogilvy
Harrod et al. have exhaustively reviewed the contemporary literature on vasospasm, its causes, and predictors of its occurrence. This thorough review analyzes the pathophysiology, epidemiology, and predictive factors of vasospasm. The extensive body of literature referenced in this article points to the single most confounding aspect of this clinical entity, namely, that we still do not know how to prevent it or understand its mechanism of action completely. This work serves as a valuable review for neurosurgeons and students of neurosurgery alike.
Felipe C. Albuquerque
This article reviews the pathophysiology of vasospasm after aneurysmal subarachnoid hemorrhage, as well as risk factors, diagnostic measures, and pathological markers that might predict vasospasm. After a comprehensive analysis, the authors found that a large blood burden is the only consistent predictor of vasospasm. It is discouraging that after decades of research and technological advances, this factor is the only one with predictive value. However, this article highlights important advances that will most likely lead to other predictors and preventive therapies in the near future.
Michael T. Lawton
San Francisco, California
Cerebral vasospasm continues to defy our best attempts to understand the pathophysiology of this disease. Although we have advanced significantly in our ability to manage the ischemic complications that often develop because of vasospasm, our ability to predict which patients are likely to develop delayed cerebral ischemia continues to be fairly primitive. The Fisher grading scale serves only to predict a high- and a low-risk population, but this dichotomous division is not particularly useful in clinical practice. Similarly, the presence of high velocity on transcranial Doppler ultrasonography can identify individuals at a particularly high risk for vasospasm, but there are a very significant number of false-negative and false-positive determinations. Newer technologies, such as CT perfusion scans, hold the promise of being able to identify specific areas in the brain that are becoming ischemic before clinical symptoms arise. It is likely that these types of technologies might give us the ability to aggressively treat a targeted subset of patients before the onset of symptoms.
Harrod et al. have exhaustively reviewed the literature on cerebral vasospasm, with special focus on methodologies to predict the onset of delayed cerebral ischemia. The various theories regarding the pathophysiology of vasospasm are nicely summarized. However, the reader will appreciate that despite nearly 50 years of an extensive research effort by the neurosurgical community, the underlying mechanism of developing cerebral vasospasm and subsequently delayed cerebral ischemia remains unknown. This review challenges researchers in this field to define the underlying pathophysiology, the critical step in developing the cure.
Robert A. Solomon
New York, New York
Despite remarkable advances in the surgical and endovascular treatment of intracranial aneurysms, cerebral vasospasm remains a major source of morbidity and mortality in patients experiencing aneurysmal subarachnoid hemorrhage. The authors have provided an exhaustive yet concise review of the pertinent literature related to cerebral vasospasm after aneurysmal subarachnoid hemorrhage. In doing so, they have outlined the prevailing theories regarding the pathophysiology of cerebral vasospasm and the various clinical and laboratory findings that predict the development of this potentially devastating complication. Although a number of novel diagnostic modalities have shown promise in providing earlier recognition of the development of symptomatic vasospasm, no single protocol is available to prevent or eliminate cerebral vasospasm. In view of the innovative research and enormous body of literature dealing with cerebral vasospasm, it is fascinating that the relatively simple but important observation of Fisher et al. (1) in correlating the likelihood of subsequent cerebral vasospasm to the amount of blood deposited at the time of the initial subarachnoid hemorrhage remains the single most important factor predicting the development of subsequent cerebral vasospasm.
Daniel L. Barrow