Faculty Bibliography

BACKGROUND AND PURPOSE/OBJECTIVE:Bone marrow-derived cells (BMDCs) home to vascular endothelial growth factor (VEGF)-induced brain angiogenic foci, and VEGF induces cerebrovascular dysplasia in adult endoglin heterozygous (Eng(+/-)) mice. We hypothesized that Eng(+/-) BMDCs cause cerebrovascular dysplasia in the adult mouse after VEGF stimulation. METHODS:BM transplantation was performed using adult wild-type (WT) and Eng(+/-) mice as donors/recipients. An adeno-associated viral vector expressing VEGF was injected into the basal ganglia 4 weeks after transplantation. Vascular density, dysplasia index (vessels >15 µm/100 vessels), and BMDCs in the angiogenic foci were analyzed. RESULTS:The dysplasia index of WT/Eng(+/-) BM mice was higher than WT/WT BM mice (P<0.001) and was similar to Eng(+/-)/Eng(+/-) BM mice (P=0.2). Dysplasia in Eng(+/-) mice was partially rescued by WT BM (P<0.001). WT/WT BM and WT/Eng(+/-) BM mice had similar numbers of BMDCs in the angiogenic foci (P=0.4), most of which were CD68(+). Eng(+/-) monocytes/macrophages expressed less matrix metalloproteinase-9 and Notch1. CONCLUSIONS:Endoglin-deficient BMDCs are sufficient for VEGF to induce vascular dysplasia in the adult mouse brain. Our data support a previously unrecognized role of BM in the development of cerebrovascular malformations.

OBJECTIVE:Vessels in brain arteriovenous malformations are prone to rupture. The underlying pathogenesis is not clear. Hereditary hemorrhagic telangiectasia type 2 patients with activin receptor-like kinase 1 (Alk1) mutation have a higher incidence of brain arteriovenous malformation than the general population. We tested the hypothesis that vascular endothelial growth factor impairs vascular integrity in the Alk1-deficient brain through reduction of mural cell coverage. METHODS AND RESULTS/RESULTS:Adult Alk1(1f/2f) mice (loxP sites flanking exons 4-6) and wild-type mice were injected with 2×10(7) PFU adenovious-cre recombinase and 2×10(9) genome copies of adeno-associated virus-vascular endothelial growth factor to induce focal homozygous Alk1 deletion (in Alk1(1f/2f) mice) and angiogenesis. Brain vessels were analyzed 8 weeks later. Compared with wild-type mice, the Alk1-deficient brain had more fibrin (99±30×10(3) pixels/mm(2) versus 40±13×10(3); P=0.001), iron deposition (508±506 pixels/mm(2) versus 6±49; P=0.04), and Iba1(+) microglia/macrophage infiltration (888±420 Iba1(+) cells/mm(2) versus 240±104 Iba1(+); P=0.001) after vascular endothelial growth factor stimulation. In the angiogenic foci, the Alk1-deficient brain had more α-smooth muscle actin negative vessels (52±9% versus 12±7%, P<0.001), fewer vascular-associated pericytes (503±179/mm(2) versus 931±115, P<0.001), and reduced platelet-derived growth factor receptor-β expression. CONCLUSIONS:Reduction of mural cell coverage in response to vascular endothelial growth factor stimulation is a potential mechanism for the impairment of vessel wall integrity in hereditary hemorrhagic telangiectasia type 2-associated brain arteriovenous malformation.

BACKGROUND AND IMPORTANCE/BACKGROUND:Contrast extravasation on computed tomography angiography (CTA) is becoming more common, with increasing use of CTA for myriad intracranial vascular pathologies. This article describes the first 2 documented cases of contrast extravasation from a nonaneurysmal basilar artery source seen on CTA and discusses possible pathophysiologic mechanisms. CLINICAL PRESENTATION/METHODS:We present 2 cases of diffuse atraumatic subarachnoid hemorrhage in which the CTA showed an abnormality in association with the basilar artery highly suggestive of a ruptured aneurysm. Follow-up digital subtraction angiography, however, was completely negative. Subsequent repeat digital subtraction angiography failed to reveal a vascular lesion. Both patients were treated for complications associated with SAH, but given the negative digital subtraction angiography, no intervention was performed. CONCLUSION/CONCLUSIONS:Because of the frequent use of CTA, contrast extravasation is an increasingly common observation. Physicians should be aware that basilar artery extravasation can mimic the appearance of an aneurysm.

BACKGROUND:The late 1990s/early 2000s was a time of change in both the prevention and acute care of ischemic stroke, with primary prevention driven by increased utilization of antihypertensive, antiplatelet, anticoagulation, and lipid-lowering agents. AIM/OBJECTIVE:To examine whether ischemic stroke hospitalization rates and outcomes in the United States have changed. METHOD/METHODS:We retrospectively identified 894 169 hospitalizations with a primary diagnosis of ischemic stroke from 1 January 1998 through to 31 December 2007 in the Nationwide Inpatient Sample, the largest all-payer healthcare database in the United States. Annual, national case estimates were combined with US Census data to derive age-adjusted and age-specific population hospitalization rates. Temporal trends were tested using linear regression. RESULTS:From 1998 through 2007, there were an estimated 4 382 336 ischemic stroke hospitalizations in the United States. Overall, the age-adjusted rate of ischemic stroke hospitalization decreased from 184 to 128 per 100 000 (P < 0·0001). Age-specific rates decreased among those 55+ years old (P < 0·0001), but increased among those 25-34 and 35-44 years old (P < 0·001 and P < 0·0001, respectively). Rates among those <25 and 45-54 years old were unchanged. In-hospital mortality decreased from 7·0% (standard error 0·1) to 5·4% (standard error 0·1) (P < 0·0001). Case proportion at the highest quintile of hospitals by annual caseload increased from 54·0% (standard error 2·1) to 61·8% (standard error 2·0) (P < 0·0001). Mean adjusted hospitalization costs increased from $9273 (standard deviation 199) to $10 524 (standard deviation 77) (P < 0·0001). CONCLUSION/CONCLUSIONS:In 1998 through to 2007, the overall rate of ischemic stroke hospitalization in the United States decreased. However, rates among young adults increased. In-hospital mortality rates decreased over the study period.

BACKGROUND:Quantitative MRA (qMRA) is a relatively new technique that uses traditional time-of-flight and phase-contrast MRI to visualize extracranial and intracranial vascular anatomy and measure volumetric blood flow. We aimed to assess the clinical utility of qMRA in assessing the hypothesized pathophysiology (HP) in a range of cerebrovascular diseases. Moreover, we postulated that evaluation of the arterial waveforms, can improve the evaluation of the hypothesized pathophysiology by qMRA. METHODS:We reviewed studies from 10 patients who underwent qMRA examinations before and after their treatments. Two reviewers assessed the anatomy, volumetric flow rates and arterial waveforms for each vessel sampled and reached a consensus as to whether the above parameters supported the clinical diagnosis/hypothesized pathophysiology and the subsequent management. FINDINGS/RESULTS:All 20 qMRA studies were technically adequate. qMRA supported the HP in all 10 patients as determined by abnormal volumetric flow values in the affected vessels before treatment and by the correction of these abnormal values in the patients whose treatment was successful. Each of our five patients with occlusive disease/vasoconstriction demonstrated evidence of dampening of the arterial waveforms distally to the narrowed artery (parvus-tardus phenomenon). The parvus-tardus effect disappeared after treatment. CONCLUSION/CONCLUSIONS:qMRA is unique in combining time-of-flight MRA in a complementary manner with phase-contrast MRA to obtain volumetric flow values and potentially important physiologic information from arterial waveform analysis in patients with a range of cerebrovascular diseases during the course of a single MR examination.

Objective. To assess prevalence, clinical characteristics, trends in treatment pattern, and outcome in patients with intracranial vascular malformations (IVMs). Methods. Nationwide inpatient sample. Patients with the diagnosis of an IVM admitted to US hospitals from 2000 to 2007. Results. In 58,051 IVM-related admissions (detection rate 2.4/100,000 person-years; mean age 49 ± 17 years; 52% women) major diagnoses were intracranial hemorrhage (ICrH) in 15%, seizure 32%, ischemia 5%, and headache 9%. Procedures included surgery (13%), embolization (13%), radiation therapy (2%), aneurysm clipping (1%), and mechanical ventilation (6%). Ventilation and ICrH were associated with death (2%), whereas ventilation, ICrH, surgery, seizure, and ischemia were associated with unfavorable outcome (20%). IVM detection rate and hospital outcome remained stable over time, whereas mean age and comorbid diagnosis of cerebral ischemia increased (ICrH and seizure decreased). Conclusion. IVMs are infrequent and present in 1/6 patients with some form of ICrH. Overall, seizure is the dominant comorbid diagnosis (1/3 patients). IVMs are equally prevalent among race-ethnic groups and are increasingly detected later in life. The inpatient care of IVM patients results in death or discharge into specialized care in 1/5 patients.

PURPOSE/OBJECTIVE:To characterize patterns in incidence, management, and costs of malignant spinal cord compression (MSCC) hospitalizations in the United States, using population-based data. METHODS AND MATERIALS/METHODS:Using the Nationwide Inpatient Sample, an all-payer healthcare database representative of all U.S. hospitalizations, MSCC-related hospitalizations were identified for the period 1998-2006. Cases were combined with age-adjusted Surveillance, Epidemiology and End Results cancer death data to estimate annual incidence. Linear regression characterized trends in patient, treatment, and hospital characteristics, costs, and outcomes. Logistic regression was used to examine inpatient treatment (radiotherapy [RT], surgery, or neither) by hospital characteristics and year, adjusting for confounding. RESULTS:We identified 15,367 MSCC-related cases, representing 75,876 hospitalizations. Lung cancer (24.9%), prostate cancer (16.2%), and multiple myeloma (11.1%) were the most prevalent underlying cancer diagnoses. The annual incidence of MSCC hospitalization among patients dying of cancer was 3.4%; multiple myeloma (15.0%), Hodgkin and non-Hodgkin lymphomas (13.9%), and prostate cancer (5.5%) exhibited the highest cancer-specific incidence. Over the study period, inpatient RT for MSCC decreased (odds ratio [OR] 0.68, 95% confidence interval [CI] 0.61-0.81), whereas surgery increased (OR 1.48, 95% CI 1.17-1.84). Hospitalization costs for MSCC increased (5.3% per year, p < 0.001). Odds of inpatient RT were greater at teaching hospitals (OR 1.41, 95% CI 1.19-1.67), whereas odds of surgery were greater at urban institutions (OR 1.82, 95% CI 1.29-2.58). CONCLUSIONS:In the United States, patients dying of cancer have an estimated 3.4% annual incidence of MSCC requiring hospitalization. Inpatient management of MSCC varied over time and by hospital characteristics, with hospitalization costs increasing. Future studies are required to determine the impact of treatment patterns on MSCC outcomes and strategies for reducing MSCC-related costs.

BACKGROUND:The understanding of stroke has been greatly enhanced by studies employing nonhuman primate models of focal ischemia. However, devastating neurological disability in previously described stroke models has led to ethical concerns and difficulty achieving prolonged survival for the evaluation of long-term outcome. We determined if reversible occlusion of the anterior cerebral artery in baboons would produce a small infarct with minimal neurological impairment. METHODS:In six baboons, anesthetized with isoflurane, Guglielmi coils were placed by endovascular technique in the anterior cerebral artery. In two baboons coils were placed for 3 h at the proximal A2 segment. In four baboons coils were placed at the junction of the A2 and A3 segments of the anterior cerebral artery for 1.5 h (n = 2) or 3 h (n = 2). The coils were removed and reperfusion confirmed by angiography. Thereafter, the animals were awakened from anesthesia and brain MRI studies were performed at 1 week. RESULTS:Baboons awakened with minimal neurological impairment. Animals subject to occlusion at the proximal A2 segment and animals subject to 1.5 h of occlusion at the junction of A2 and A3 had no infarct. Animals with 3-h occlusion at the junction of A2 and A3 showed infarcts of 3.5% and 2.8% of cerebral hemispheres. CONCLUSIONS:This study indicates that reversible anterior cerebral artery occlusion may provide a new humane animal model for small stroke and limited neurological deficit.

BACKGROUND AND PURPOSE/OBJECTIVE:Report on the status of an on-going National Institutes of Neurological Disorders and Stroke (NINDS)-supported clinical trial of management of unbled brain arteriovenous malformations. SUMMARY OF REVIEW/RESULTS:Begun in April 2007 with 3 centers, the trial has grown to 65 centers, and has randomized 124 patients through mid-June 2010 en route to the planned 400. The current literature continues to support the rationale for the trial. CONCLUSIONS:ARUBA is steadily approaching its monthly randomization goals and has already reached the number needed to test the maximum published interventional complication rates against the minimum hemorrhage rates for natural history.

PURPOSE/OBJECTIVE:Catheter cerebral angiography and noninvasive cerebral imaging have steadily improved in the past several decades. Now, catheter angiography is frequently reserved for treatment planning. To remain relevant as a diagnostic modality, catheter angiography must be safe, even in critically ill patients. The present report describes the complication rate of catheter cerebral angiography performed by neurointerventional specialists at an academic medical center. MATERIALS AND METHODS/METHODS:From July 2001 through June 2007, 3,636 diagnostic catheter cerebral angiograms were obtained at a large academic institution. Complication data were prospectively acquired according to institutional policy and New York Patient Occurrence Reporting and Tracking System criteria. Data collected included patient age, sex, indication for the procedure, operator, and nature of adverse event, including need for treatment. Clinical predictors of complications were evaluated with logistic regression. RESULTS:Among 3,636 diagnostic cerebral angiograms obtained in 6 years, there were 11 clinical complications (0.30%). One patient (0.03%) had magnetic resonance imaging-detected stroke with no apparent clinical deterioration. Iatrogenic dissections were seen in five arteries (0.14%). No patient developed neurologic symptoms. Nonneurologic complications occurred in five patients (0.14%) who had arteriotomy site-related complications: one femoral abscess, two occlusions of the femoral artery with leg ischemia requiring surgical revascularization, one dissection with pseudoaneurysm formation requiring percutaneous thrombin injection, and one retroperitoneal hemorrhage requiring transfusion. Three of these patients were treated with an arterial closure device. Age greater than 65 years was associated with development of complications (P = .03). CONCLUSIONS:Modern catheter cerebral angiography performed by neurointerventionalists is associated with a low complication rate of 0.30%, even in a highly complex patient population.