Rafael J. Tamargo

Symptomatic vasospasm diagnosis after subarachnoid hemorrhage: Evaluation of transcranial Doppler ultrasound and cerebral angiography as related to compromised vascular distribution

ObjectiveTo evaluate the reliability of transcranial Doppler ultrasound in detecting symptomatic vasospasm in patients after aneurysmal subarachnoid hemorrhage and monitoring response after hypertensive and endovascular treatments. DesignRetrospective chart review. SettingNeurosciences critical care unit in a tertiary-care university hospital. PatientsAll patients admitted to a neurosciences critical care unit with the diagnosis of subarachnoid hemorrhage between January 1990 and June 1997. InterventionsNone Measurements and Main ResultsWe reviewed transcranial Doppler ultrasound data of 199 patients; 55 had symptomatic vasospasm. Clinical symptoms and corresponding vascular distributions were identified, as was angiographic vasospasm (n = 35). The sensitivity and specificity of transcranial Doppler ultrasound for anterior circulation vessels were calculated by using a mean cerebral blood flow velocity criterion of >120 cm/sec. Clinical diagnosis of symptomatic vasospasm was used as the standard to determine sensitivity and specificity of transcranial Doppler ultrasound and cerebral angiography.The sensitivity of transcranial Doppler ultrasound for anterior circulation in patients with symptomatic vasospasm was 73% with a specificity of 80%. The sensitivity of cerebral angiography was 80%. For individual vessels, the sensitivity and specificity of transcranial Doppler ultrasound were middle cerebral artery, 64% and 78%; anterior cerebral artery, 45% and 84%; and internal carotid artery, 80% and 77%, respectively. The mean times for symptomatic and transcranial Doppler ultrasound signs of vasospasm presentation were 6.4 ± 2 and 6.1 ± 3 days, respectively. In patients without symptomatic vasospasm, the mean time for mean cerebral blood flow velocities >120 cm/sec was 7.0 ± 3 days (p < .05). Symptomatic vasospasm also was associated with thickness of clot on head computed tomography scan and rapidly increasing mean cerebral blood flow velocities. Transcranial Doppler ultrasound signs of vasospasm improved after endovascular treatment in 30 patients. ConclusionsThe reliability of transcranial Doppler ultrasound was better at detecting high mean cerebral blood flow velocities in patients with symptomatic vasospasm related to middle cerebral and internal carotid artery distributions than for anterior cerebral artery distribution. Transcranial Doppler ultrasound was as sensitive as cerebral angiography at detecting symptomatic vasospasm. High mean cerebral blood flow velocities can be apparent before the presence of symptomatic vasospasm. Daily transcranial Doppler ultrasound monitoring could provide early identification of patients with aneurysmal subarachnoid hemorrhage who are at high risk for symptomatic vasospasm and may be helpful at following success of endovascular treatment.

Recommendations for the Management of Cerebral and Cerebellar Infarction With Swelling A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association

Background and Purpose— There are uncertainties surrounding the optimal management of patients with brain swelling after an ischemic stroke. Guidelines are needed on how to manage this major complication, how to provide the best comprehensive neurological and medical care, and how to best inform families facing complex decisions on surgical intervention in deteriorating patients. This scientific statement addresses the early approach to the patient with a swollen ischemic stroke in a cerebral or cerebellar hemisphere. Methods— The writing group used systematic literature reviews, references to published clinical and epidemiology studies, morbidity and mortality reports, clinical and public health guidelines, authoritative statements, personal files, and expert opinion to summarize existing evidence and to indicate gaps in current knowledge. The panel reviewed the most relevant articles on adults through computerized searches of the medical literature using MEDLINE, EMBASE, and Web of Science through March 2013. The evidence is organized within the context of the American Heart Association framework and is classified according to the joint American Heart Association/American College of Cardiology Foundation and supplementary American Heart Association Stroke Council methods of classifying the level of certainty and the class and level of evidence. The document underwent extensive American Heart Association internal peer review. Results— Clinical criteria are available for hemispheric (involving the entire middle cerebral artery territory or more) and cerebellar (involving the posterior inferior cerebellar artery or superior cerebellar artery) swelling caused by ischemic infarction. Clinical signs that signify deterioration in swollen supratentorial hemispheric ischemic stroke include new or further impairment of consciousness, cerebral ptosis, and changes in pupillary size. In swollen cerebellar infarction, a decrease in level of consciousness occurs as a result of brainstem compression and therefore may include early loss of corneal reflexes and the development of miosis. Standardized definitions should be established to facilitate multicenter and population-based studies of incidence, prevalence, risk factors, and outcomes. Identification of patients at high risk for brain swelling should include clinical and neuroimaging data. If a full resuscitative status is warranted in a patient with a large territorial stroke, admission to a unit with neurological monitoring capabilities is needed. These patients are best admitted to intensive care or stroke units attended by skilled and experienced physicians such as neurointensivists or vascular neurologists. Complex medical care includes airway management and mechanical ventilation, blood pressure control, fluid management, and glucose and temperature control. In swollen supratentorial hemispheric ischemic stroke, routine intracranial pressure monitoring or cerebrospinal fluid diversion is not indicated, but decompressive craniectomy with dural expansion should be considered in patients who continue to deteriorate neurologically. There is uncertainty about the efficacy of decompressive craniectomy in patients ≥60 years of age. In swollen cerebellar stroke, suboccipital craniectomy with dural expansion should be performed in patients who deteriorate neurologically. Ventriculostomy to relieve obstructive hydrocephalus after a cerebellar infarct should be accompanied by decompressive suboccipital craniectomy to avoid deterioration from upward cerebellar displacement. In swollen hemispheric supratentorial infarcts, outcome can be satisfactory, but one should anticipate that one third of patients will be severely disabled and fully dependent on care even after decompressive craniectomy. Surgery after a cerebellar infarct leads to acceptable functional outcome in most patients. Conclusions— Swollen cerebral and cerebellar infarcts are critical conditions that warrant immediate, specialized neurointensive care and often neurosurgical intervention. Decompressive craniectomy is a necessary option in many patients. Selected patients may benefit greatly from such an approach, and although disabled, they may be functionally independent.

A New Subarachnoid Hemorrhage Grading System Based on the Glasgow Coma Scale: A Comparison with the Hunt and Hess and World Federation of Neurological Surgeons Scales in a Clinical Series

OBJECTIVE Although the Hunt and Hess Scale (HHS) and World Federation of Neurological Surgeons Scale (WFNSS) are the most widely used subarachnoid hemorrhage (SAH) grading systems, neither system has achieved universal acceptance. We propose a simplified grading system based entirely on the Glasgow Coma Scale (GCS), which compresses the 15-point GCS into five grades that are comparable with those of the HHS and WFNSS. We refer to this system as the GCS grading system and present a direct comparison with the HHS and WFNSS for predictive value regarding patient outcome and interrater reliability. METHODS We reviewed 291 consecutive patients with aneurysms treated at our institution between January 1992 and January 1996 and compared the admission grades from the GCS, WFNSS, and HHS with outcome measures at discharge from hospitalization. The Glasgow Outcome score was used as the major outcome measure to evaluate the predictive value of the three scales. Mortality and length of stay (LOS) were also evaluated as outcome measures. The predictive value of each scale was tested with an ordinal logistic regression model for Glasgow Outcome score, a logistic regression model for mortality data, and a linear regression model for LOS. RESULTS Using the logistic regression model, the GCS was the best predictor of discharge Glasgow Outcome score, 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. Using 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. Each of the three scales had a high predictive value for LOS, using a linear model. We discuss, however, the problematic nature of LOS as an outcome measure for SAH. Interrater reliability for each scale was evaluated using kappa statistics, based on 15 additional patients evaluated prospectively, and showed that the GCS grade also had the greatest interrater reliability, with a kappa of 0.46 (P = 0.0002), compared with 0.41 (P = 0.0005) for the HHS and 0.27 (P = 0.027) for the WFNSS. CONCLUSION We conclude that the GCS grade has equal or greater predictive value regarding outcome after SAH than do the currently used grading systems and that it has greater reproducibility across observers. Broader familiarity with the GCS among medical and paramedical personnel may further enhance the usefulness of the GCS grade over the HHS and WFNSS in providing a standardized, universally accepted grading system for SAH.

Risk factors for multiple intracranial aneurysms

OBJECTIVE Risk factors that predispose to the formation of multiple intracranial aneurysms, which are present in up to 34% of patients with intracranial aneurysms, are not well defined. In this study, we examined the association between known risk factors for cerebrovascular disease and presence of multiple intracranial aneurysms. METHODS We reviewed the medical records and results of conventional angiography in all patients with a diagnosis of intracranial aneurysms admitted to the Johns Hopkins University hospital between January 1990 and June 1997. We determined the independent association between various cerebrovascular risk factors and the presence of multiple aneurysms using logistic regression analysis. RESULTS Of 419 patients admitted with intracranial aneurysms (298 ruptured and 121 unruptured), 127 (30%) had multiple intracranial aneurysms. In univariate analysis, female gender (odds ratio [OR] = 1.9; 95% confidence interval [CI], 1.1-3.3) and cigarette smoking at any time (OR = 1.8; 95% CI, 1.1-3.0) were significantly associated with presence of multiple aneurysms. In the multivariate analysis, cigarette smoking at any time (OR = 1.7; 95% CI, 1.1-2.8) and female gender (OR = 2.1; 95% CI 1.2-3.5) remained significantly associated with multiple aneurysms. Hypertension, diabetes mellitus, and alcohol and illicit drug use were not significantly associated with presence of multiple aneurysms. CONCLUSION Cigarette smoking and female gender seem to increase the risk for multiple aneurysms in patients predisposed to intracranial aneurysm formation. Further studies are required to investigate the mechanism underlying the association between cigarette smoking and intracranial aneurysm formation.

Hyperglycemia independently increases the risk of perioperative stroke, myocardial infarction, and death after carotid endarterectomy.

OBJECTIVE:Clinical and experimental evidence suggests that hyperglycemia lowers the neuronal ischemic threshold, potentiates stroke volume in focal ischemia, and is associated with morbidity and mortality in the surgical critical care setting. It remains unknown whether hyperglycemia during carotid endarterectomy (CEA) predisposes patients to perioperative stroke and operative related morbidity and mortality. METHODS:The clinical and radiological records of all patients undergoing CEA and operative day glucose measurement from 1994 to 2004 at an academic institution were reviewed and 30-day outcomes were assessed. The independent association of operative day glucose before CEA and perioperative morbidity and mortality were assessed via multivariate logistic regression analysis. RESULTS:One thousand two hundred and one patients with a mean age of 72 ± 10 years (748 men, 453 women) underwent CEA (676 asymptomatic, 525 symptomatic). Overall, stroke occurred in 46 (3.8%) patients, transient ischemic attack occurred in 19 (1.6%), myocardial infarction occurred in 19 (1.6%), and death occurred in 17 (1.4%). Increasing operative day glucose was independently associated with perioperative stroke or transient ischemic attack (Odds ratio [OR], 1.005; 95% confidence interval [CI], 1.00–1.01; P = 0.03), myocardial infarction (OR, 1.01; 95% CI, 1.004–1.016; P = 0.017), and death (OR, 1.007; 95% CI, 1.00–1.015; P = 0.04). Patients with operative day glucose greater than 200 mg/dl were 2.8-fold, 4.3-fold, and 3.3-fold more likely to experience perioperative stroke or transient ischemic attack (OR, 2.78; 95% CI, 1.37–5.67; P = 0.005), myocardial infarction (OR, 4.29; 95% CI, 1.28–14.4; P = 0.018), or death (OR, 3.29; 95% CI, 1.07–10.1; P = 0.037), respectively. Median and interquartile range length of hospitalization was greater for patients with operative day glucose greater than 200 mg/dl (4 d [interquartile range, 2–15 d] versus 3 d [interquartile range, 2–7 d]; P < 0.05). CONCLUSION:Independent of previous cardiac disease, diabetes, or other comorbidities, hyperglycemia at the time of CEA was associated with an increased risk of perioperative stroke or transient ischemic attack, myocardial infarction, and death. Strict glucose control should be attempted before surgery to minimize the risk of morbidity and mortality after CEA.

Role of inflammation (leukocyte-endothelial cell interactions) in vasospasm after subarachnoid hemorrhage.

BACKGROUND Delayed vasospasm is the leading cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage (aSAH). This phenomenon was first described more than 50 years ago, but only recently has the role of inflammation in this condition become better understood. METHODS The literature was reviewed for studies on delayed vasospasm and inflammation. RESULTS There is increasing evidence that inflammation and, more specifically, leukocyte-endothelial cell interactions play a critical role in the pathogenesis of vasospasm after aSAH, as well as in other conditions including meningitis and traumatic brain injury. Although earlier clinical observations and indirect experimental evidence suggested an association between inflammation and chronic vasospasm, recently direct molecular evidence demonstrates the central role of leukocyte-endothelial cell interactions in the development of chronic vasospasm. This evidence shows in both clinical and experimental studies that cell adhesion molecules (CAMs) are up-regulated in the perivasospasm period. Moreover, the use of monoclonal antibodies against these CAMs, as well as drugs that decrease the expression of CAMs, decreases vasospasm in experimental studies. It also appears that certain individuals are genetically predisposed to a severe inflammatory response after aSAH based on their haptoglobin genotype, which in turn predisposes them to develop clinically symptomatic vasospasm. CONCLUSION Based on this evidence, leukocyte-endothelial cell interactions appear to be the root cause of chronic vasospasm. This hypothesis predicts many surprising features of vasospasm and explains apparently unrelated phenomena observed in aSAH patients. Therapies aimed at preventing inflammation may prevent and/or reverse arterial narrowing in patients with aSAH and result in improved outcomes.

Inhibition of Experimental Vasospasm With Anti–Intercellular Adhesion Molecule-1 Monoclonal Antibody in Rats

BACKGROUND AND PURPOSE Inflammation may play a role in delayed chronic vasospasm after aneurysmal subarachnoid hemorrhage. We investigated the role of intercellular adhesion molecule-1 (ICAM-1) and macrophage/granulocyte infiltration in the rat femoral artery model of vasospasm using systemic administration of a murine anti-ICAM-1 monoclonal antibody (MAb). METHODS The femoral arteries (n = 72) in Sprague-Dawley rats (n = 36) were enclosed in latex pouches bilaterally. Autologous blood was injected into the pouch on one side, and saline was injected on the contralateral side. Chronic vessel narrowing was evaluated with the use of 29 rats, which were randomized into one of three groups for intraperitoneal injections: (1) anti-ICAM-1 MAb (2 mg/kg per dose, n = 10), (2) isotype-matched MAb (2 mg/kg per dose, n = 9), or (3) saline (n = 10), given at 3 hours and 3, 6, and 9 days after blood exposure. These rats were killed 12 days after blood exposure, and femoral artery lumen cross-sectional areas were determined by computerized image analysis. Saturation of ICAM-1 binding sites with this dosing schedule was evaluated by fluorescence-activated cell sorter (FACS) analysis of splenocytes. Immunohistochemical studies with objective cell counts were performed to evaluate macrophage/granulocyte infiltration at 24 hours in 7 rats, comparing anti-ICAM-1 MAb treatment (n = 4) with isotype-matched control MAb (n = 3). RESULTS Animals treated with anti-ICAM-1 MAb showed a significant inhibition of arterial narrowing at 12 days (P = .0081), with lumen patency of 96.5 +/- 5.3% (mean +/- SEM), compared with 77.3 +/- 5.6% for isotype-matched MAb and 72.2 +/- 5.3% for saline-treated controls. FACS analysis of splenocytes from animals treated with anti-ICAM-1 MAb confirmed saturation of ICAM-1 binding sites. Vessels treated with anti-ICAM-1 MAb showed a significant decrease in inflammatory cell infiltrates, with objective macrophage/granulocyte counts of 31.3 +/- 26.6 (mean +/- SEM) per high-powered field, compared with 171.4 +/- 30.7 for isotype-matched control MAb (P = .0027). CONCLUSIONS Anti-ICAM-1 MAb administered systemically starting 3 hours after blood exposure results in significant inhibition of chronic vasospasm in the rat femoral artery model and is correlated with a reduction in the number of infiltrating macrophages and granulocytes in the periadventitial region of blood-exposed arteries. We conclude that inflammatory changes associated with ICAM-1-mediated macrophage and granulocyte migration play an important role in the development of posthemorrhagic chronic vasospasm in this model.

Risk factors for subarachnoid hemorrhage

OBJECTIVECigarette smoking has been demonstrated to increase the risk of subarachnoid hemorrhage (SAH). Whether cessation of smoking decreases this risk remains unclear. We performed a case-control study to examine the effect of smoking and other known risk factors for cerebrovascular disease on the risk of SAH. METHODSWe reviewed the medical records of all patients with a diagnosis of SAH (n = 323) admitted to Johns Hopkins Hospital between January 1990 and June 1997. Controls matched for age, sex, and ethnicity (n = 969) were selected from a nationally representative sample of the Third National Health and Nutrition Examination Survey. We determined the independent association between smoking (current and previous) and various cerebrovascular risk factors and SAH by use of multivariate logistic regression analysis. A separate analysis was performed to determine associated risk factors for aneurysmal SAH. RESULTSOf 323 patients admitted with SAH (mean age, 52.7 ± 14 yr; 93 were men), 173 (54%) were hypertensive, 149 (46%) were currently smoking, and 125 (39%) were previous smokers. In the multivariate analysis, both previous smoking (odds ratio [OR], 4.5; 95% confidence interval [CI], 3.1–6.5) and current smoking (OR, 5.2; 95% CI, 3.6–7.5) were significantly associated with SAH. Hypertension was also significantly associated with SAH (OR, 2.4; 95% CI, 1.8–3.1). The risk factors for 290 patients with aneurysmal SAH were similar and included hypertension (OR, 2.4; 95% CI, 1.8–3.2), previous smoking (OR, 4.1; 95% CI, 2.7–6.0), and current smoking (OR, 5.4; 95% CI, 3.7–7.8). CONCLUSIONHypertension and cigarette smoking increase the risk for development of SAH, as found in previous studies. However, the increased risk persists even after cessation of cigarette smoking, which suggests the importance of early abstinence from smoking.

Administration of hypertonic (3%) sodium chloride/acetate in hyponatremic patients with symptomatic vasospasm following subarachnoid hemorrhage

A retrospective study was carried out to evaluate the effect of hypertonic (3%) saline chloride/acetate on various hemodynamic parameters in mildly hyponatremic patients with symptomatic vasospasm following aneurysmal subarachnoid hemorrhage (SAH). We identified 29 hyponatremic (serum sodium < 135 mEq/L) patients who received hypertonic (3%) sodium chloride/acetate as a continuous infusion. Administration of hypertonic (3%) sodium chloride/acetate resulted in higher central venous pressures and positive fluid balance, with a concomitant increase in serum sodium and chloride concentrations without metabolic acidosis. There were no changes in mean cerebral blood flow velocities after infusion of hypertonic (3%) sodium chloride/acetate. We found no reports of congestive heart failure, pulmonary edema, metabolic acidosis, coagulopathy, intracranial hemorrhages, or central pontine myelinolysis in any of these patients. We conclude that hypertonic (3%) sodium chloride/acetate can be administered to patients with mild hyponatremia in the setting of symptomatic vasospasm following SAH without untoward effects. Sample size and limitations of a retrospective analysis preclude conclusions about safety and efficacy of hypertonic (3%) sodium chloride/acetate administration in this patient population. However, our results support justification for a prospective, randomized, double-blind trial of hypertonic (3%) sodium chloride/acetate versus normal saline in patients with symptomatic vasospasm following SAH.

Non-invasive delivery of stealth, brain-penetrating nanoparticles across the blood - Brain barrier using MRI-guided focused ultrasound

The blood-brain barrier (BBB) presents a significant obstacle for the treatment of many central nervous system (CNS) disorders, including invasive brain tumors, Alzheimers, Parkinsons and stroke. Therapeutics must be capable of bypassing the BBB and also penetrate the brain parenchyma to achieve a desired effect within the brain. In this study, we test the unique combination of a non-invasive approach to BBB permeabilization with a therapeutically relevant polymeric nanoparticle platform capable of rapidly penetrating within the brain microenvironment. MR-guided focused ultrasound (FUS) with intravascular microbubbles (MBs) is able to locally and reversibly disrupt the BBB with submillimeter spatial accuracy. Densely poly(ethylene-co-glycol) (PEG) coated, brain-penetrating nanoparticles (BPNs) are long-circulating and diffuse 10-fold slower in normal rat brain tissue compared to diffusion in water. Following intravenous administration of model and biodegradable BPNs in normal healthy rats, we demonstrate safe, pressure-dependent delivery of 60nm BPNs to the brain parenchyma in regions where the BBB is disrupted by FUS and MBs. Delivery of BPNs with MR-guided FUS has the potential to improve efficacy of treatments for many CNS diseases, while reducing systemic side effects by providing sustained, well-dispersed drug delivery into select regions of the brain.