✓In an effort to help clarify the current state of medical therapy for cerebral vasospasm, the authors reviewed the relevant literature on the established medical therapies used for cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH), and they discuss burgeoning areas of investigation. Despite advances in the treatment of aneurysmal SAH, cerebral vasospasm remains a common complication and has been correlated with a 1.5- to threefold increase in death during the first 2 weeks after hemorrhage. A number of medical, pharmacological, and surgical therapies are currently in use or being investigated in an attempt to reverse cerebral vasospasm, but only a few have proven to be useful. Although much has been elucidated regarding its pathophysiology, the treatment of cerebral vasospasm remains a dilemma. Although a poor understanding of SAH-induced cerebral vasospasm pathophysiology has, to date, hampered the development of therapeutic interventions, current research efforts promise the eventual production of new medical therapies.
J Mocco, Brad E. Zacharia, Ricardo J. Komotar and E. Sander Connolly Jr.
Ricardo J. Komotar, J Mocco, David A. Wilson, E. Sander Connolly Jr., Sean D. Lavine and Philip M. Meyers
A substantial number of strokes are caused by intracranial atherosclerosis, a disease that traditionally has been treated medically. Recent technological advancements, however, have revolutionized the treatment of this condition by enabling the use of endovascular methods. In this paper the authors focus on the internal carotid artery, and review relevant studies concerning angioplasty with stent placement for the management of intracranial atherosclerosis in this vessel. With continued experience and a multidisciplinary approach in the evaluation of these patients, favorable outcomes may be achieved.
Ricardo J. Komotar, J Mocco, David A. Wilson, E. Sander Connolly Jr., Sean D. Lavine and Philip M. Meyers
Intracranial atherosclerosis is the cause of a significant number of strokes. Despite maximal medical therapy, this disease continues to carry a poor prognosis. The authors reviewed studies in which the outcomes after conservative management in patients with intracranial carotid artery atherosclerosis were reported. Analysis of the literature demonstrates that maximal medical therapy frequently fails with this disease, leaving patients at high risk for cerebral infarction and death. A better understanding of the pathophysiological aspects and natural history of this condition may serve to guide clinical decision making and the choice of therapeutic options in this patient population.
William J. Mack, Ryan G. King, Andrew F. Ducruet, Kurt Kreiter, J Mocco, Ahmed Maghoub, Stephan Mayer and E. Sander Connolly Jr.
Elevated intracranial pressure (ICP) is an important consequence of aneurysmal subarachnoid hemorrhage (SAH) that often results in decreased cerebral perfusion and secondary clinical decline. No definitive guidelines exist regarding methods and techniques for ICP management following aneurysm rupture. The authors describe monitoring practices and outcome data in 621 patients with aneurysmal SAH admitted to their neurological intensive care unit during an 8-year period (1996–2003).
A fiberoptic catheter tip probe or external ventricular drain (EVD) was used to record ICP values. The percentage of monitored patients varied, as expected, according to admission Hunt and Hess grade (p < 0.0001). Intracranial pressure monitoring devices were used in 27 (10%) of 264 Grade I to II patients, 72 (38%) of 189 Grade III patients, and 134 (80%) of 168 Grade IV to V patients. There was a strong propensity to favor transduced ventricular drains over parenchymal fiberoptic bolts, with the former used in 221 (95%) of 233 cases. This tendency was particularly strong in the poor-grade cohort, in which EVDs were placed in 99% of monitored individuals. The rates of cerebrospinal fluid infection in patients in whom ICP probes (0%) and ventricular drains (12%) were placed accorded with those in the literature.
Following aneurysmal SAH, ICP monitoring prevalence and techniques differ with respect to admission Hunt and Hess grade and are associated with the patient's functional status at discharge.
J Mocco, William J. Mack, Grace H. Kim, Alan P. Lozier, Ilya Laufer, Kurt T. Kreiter, Robert R. Sciacca, Robert A. Solomon, Stephan A. Mayer and E. Sander Connolly Jr.
Object. Proinflammatory adhesion molecule expression has been demonstrated to be elevated in patients with aneurysmal subarachnoid hemorrhage (SAH). Recent studies have shown that elevations in soluble intercellular adhesion molecule—1 (ICAM-1) may be predictive of poor outcome in patients with good grade (Hunt and Hess Grades 1–2) aneurysmal SAH at delayed time points that correspond with the risk period for cerebral vasospasm. In addition, ICAM-1 is upregulated in experimental models of vasospasm. Unfortunately, the relationship of adhesion molecule expression to human vasospasm remains unclear. The authors hypothesized that the delayed elevation of soluble ICAM-1 in patients with aneurysmal SAH is associated with the development of cerebral vasospasm.
Methods. Eighty-nine patients with aneurysmal SAH were prospectively enrolled in a study and stratified according to the presence or absence of vasospasm, as evidenced by daily monitoring of transcranial Doppler (TCD) velocities (presence, > 200 cm/second; absence, ≤ 120 cm/second). Levels of soluble ICAM-1 were determined using enzyme-linked immunosorbent assay every other day for 12 days post-SAH. An analysis of covariance model was used to evaluate trends in soluble ICAM-1 levels from 2 days prior to 6 days after the occurrence of documented vasospasm. Two groups of patients, matched for admission admission Hunt and Hess grade, were compared: nine patients with TCD velocities greater than 200 cm/second and nine patients with TCD velocities less than 120 cm/second. From among the patients with TCD velocities greater than 200 cm/second six patients with angiographically documented vasospasm were selected. Patients with TCD velocities less than 120 cm/second and matched admission Hunt and Hess grades but without angiographically documented vasospasm were selected. Patients with TCD-demonstrated vasospasm showed a significant mean rate of rise (p < 0.01) in soluble ICAM-1 levels during the perivasospasm period, but admission Hunt and Hess grade—matched control patients did not (p = not significant [NS]). There was a significant difference between these groups' rates of soluble ICAM increase (p < 0.01). Patients with both TCD- and angiographically demonstrated vasospasm likewise showed a highly significant mean rate of increase in soluble ICAM-1 levels during the perivasospasm period (p < 0.01), whereas admission Hunt and Hess grade—matched controls did not (p = NS). The difference beween these groups' rates of increase was highly significant (p < 0.001).
Conclusions. These data suggest a role for ICAM-1 in the pathophysiology of cerebral vasospasm or its ischemic sequelae. As this relationship is further elucidated, adhesion molecules such as ICAM-1 may provide novel therapeutic targets in the prevention of vasospasm or its ischemic consequences.
William J. Mack, J Mocco, Daniel J. Hoh, Judy Huang, Tanvir F. Choudhri, Kurt T. Kreiter, Alan Lozier, Marcello Opperman, Alexander Poisik, Joshua Yorgason, Robert A. Solomon, Stephan A. Mayer and E. Sander Connolly Jr.
Object. Although upregulated adhesion molecule expression has been demonstrated in experimental models of subarachnoid hemorrhage (SAH) and in the cerebrospinal fluid of patients with aneurysmal SAH, the clinical significance of these proinflammatory findings remains unclear. The authors hypothesize that 1) serum levels of soluble intercellular adhesion molecule-1 (ICAM-1) are increased in all patients with aneurysmal SAH shortly after the hemorrhagic event, and 2) elevated soluble ICAM-1 values are associated with poor patient outcome, even when controlling for the severity of the initial hemorrhagic insult.
Methods. One hundred one patients were prospectively enrolled and stratified according to their admission Hunt and Hess grade and functional status at discharge (modified Rankin Scale [mRS] score). Soluble ICAM-1 levels were determined every other day for 12 days post-SAH by using the enzyme-linked immunosorbent assay. Early soluble ICAM-1 levels (post-SAH Days 2–4) were increased compared with levels in control patients without SAH (p < 0.05). Patients with aneurysmal SAH who had a poor outcome (mRS Grades 4–6) had significantly higher soluble ICAM-1 levels over the first 2 weeks post-SAH compared with patients who had a good outcome (mRS Grades 0–3, p < 0.01). 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 = not significant) and was best seen in patients with Hunt and Hess Grades I and II, in whom only those with poor outcomes demonstrated delayed ICAM-1 elevations (p < 0.05).
Conclusions. These data demonstrate a correlation between soluble ICAM-1 levels and functional outcome following aneurysmal SAH that appears to be, at least in part, independent of the initial hemorrhage.
J Mocco, William J. Mack, Andrew F. Ducruet, Ryan G. King, Michael E. Sughrue, Alexander L. Coon, Sergei A. Sosunov, Robert R. Sciacca, Yuan Zhang, Henry C. Marsh Jr., David J. Pinsky and E. Sander Connolly Jr.
Postischemic cerebral inflammatory injury has been extensively investigated in an effort to develop effective neuroprotective agents. The complement cascade has emerged as an important contributor to postischemic neuronal injury. Soluble complement receptor Type 1 (sCR1), a potent inhibitor of complement activation, has been shown to reduce infarct volume and improve functional outcome after murine stroke. Given numerous high-profile failures to translate promising antiinflammatory strategies from the laboratory to the clinic and given the known species-specificity of the complement cascade, the authors sought to evaluate the neuroprotective effect of sCR1 in a nonhuman primate model of stroke.
A total of 48 adult male baboons (Papio anubis) were randomly assigned to receive 15 mg/kg of sCR1 or vehicle. The animals were subjected to 75 minutes of middle cerebral artery occlusion/reperfusion. Perioperative blood samples were analyzed for total complement activity by using a CH50 assay. Infarct volume and neurological scores were assessed at the time the animals were killed, and immunohistochemistry was used to determine cerebral drug penetration and C1q deposition. An interim futility analysis led to termination of the trial after study of 12 animals. Total serum complement activity was significantly depressed in the sCR1-treated animals compared with the controls. Immunostaining also demonstrated sCR1 deposition in the ischemic hemispheres of treated animals. Despite these findings, there were no significant differences in infarct volume or neurological score between the sCR1- and vehicle-treated cohorts.
A preischemic bolus infusion of sCR1, the most effective means of administration in mice, was not neuroprotective in a primate model. This study illustrates the utility of a translational primate model of stroke in the assessment of promising antiischemic agents prior to implementation of large-scale clinical trials.
William J. Mack, Christopher P. Kellner, Daniel H. Sahlein, Andrew F. Ducruet, Grace H. Kim, J Mocco, Joseph Zurica, Ricardo J. Komotar, Raqeeb Haque, Robert Sciacca, Donald O. Quest, Robert A. Solomon, E. Sander Connolly Jr. and Eric J. Heyer
Recent data from both experimental and clinical studies have supported the use of intravenous magnesium as a potential therapy in the setting of cerebral ischemia. This study assessed whether intraoperative magnesium therapy improves neuropsychometric testing (NPT) following carotid endarterectomy (CEA).
One hundred eight patients undergoing CEA were randomly assigned to receive placebo infusion or 1 of 3 magnesium-dosing protocols. Neuropsychometric testing was performed 1 day after surgery and compared with baseline performance. Assessment was also performed on a set of 35 patients concurrently undergoing lumbar laminectomy to serve as a control group for NPT. A forward stepwise logistic regression analysis was performed to evaluate the impact of magnesium therapy on NPT. A subgroup analysis was then performed, analyzing the impact of each intraoperative dose on NPT.
Patients treated with intravenous magnesium infusion demonstrated less postoperative neurocognitive impairment than those treated with placebo (OR 0.27, 95% CI 0.10–0.74, p = 0.01). When stratified according to dosing bolus and intraoperative magnesium level, those who were treated with low-dose magnesium had less cognitive decline than those treated with placebo (OR 0.09, 95% CI 0.02–0.50, p < 0.01). Those in the high-dose magnesium group demonstrated no difference from the placebo-treated group.
Low-dose intraoperative magnesium therapy protects against neurocognitive decline following CEA.