Faculty Bibliography

The neurovascular unit is composed of endothelial cells, vascular smooth muscle cells, pericytes, astrocytes and neurons. Through tightly regulated multi-directional cell signaling, the neurovascular unit is responsible for the numerous functionalities of the cerebrovasculature - including the regulation of molecular and cellular transport across the blood-brain barrier, angiogenesis, blood flow responses to brain activation and neuroinflammation. Historically, the study of the brain vasculature focused on endothelial cells; however, recent work has demonstrated that pericytes and vascular smooth muscle cells - collectively known as mural cells - play critical roles in many of these functions. Given this emerging data, a more complete mechanistic understanding of the cellular basis of brain vascular malformations is needed. In this review, we examine the integrated functions and signaling within the neurovascular unit necessary for normal cerebrovascular structure and function. We then describe the role of aberrant cell signaling within the neurovascular unit in brain arteriovenous malformations and identify how these pathways may be targeted therapeutically to eradicate or stabilize these lesions.

Dural arteriovenous fistulas (DAVFs) represent 10%-15% of all intracranial arteriovenous malformations.¹ DAVFs located in the posterior cranial fossa are rare and often present with intracranial hemorrhage and myelopathy.² Arterial supply could be provided by the meningeal branches of the vertebral artery and external and internal carotid arteries.³ A 68-year-old man presented with progressive lower-extremity weakness (Video 1). Magnetic resonance imaging revealed a patchy longitudinal cord signal abnormality extending from the cervicomedullary junction to C7. A tentorial DAVF supplied by the right posterior meningeal artery with drainage via dorsal and ventral perimedullary veins was identified on angiography. According to the Cognard classification, the patient's DAVF was determined to be high risk as a type V lesion with spinal venous drainage and progressive myelopathy.⁴ The fistula was embolized with 50% ethanol resulting in near-complete occlusion. However, follow-up angiography revealed a persistent arteriovenous shunt and slightly worsening symptoms for the patient. He underwent a sitting supracerebellar approach with a torcular craniotomy for successful clip ligation of the dural arteriovenous fistula. The patient was discharged with improvements in lower-extremity strength and no residual arteriovenous shunting in postoperative imaging.

A hyperplastic anterior choroidal artery is a vascular anomaly where the anterior choroidal artery supplies the posterior cerebral artery territory. We report a case of subarachnoid hemorrhage from a hyperplastic anterior choroidal artery with tandem fusiform aneurysms. The patient underwent a temporal craniotomy and transcortical transventricular transchoroidal-fissure approach for clip reconstruction. This case illustrates an unusual cerebrovascular pathology and approach to the ambient cistern.

OBJECTIVE:During the microsurgical clipping of known aneurysms, angiographically occult (AO) aneurysms are sometimes found and treated simultaneously to prevent their growth and protect the patient from future rupture or reoperation. The authors analyzed the incidence, treatment, and outcomes associated with AO aneurysms to determine whether limited surgical exploration around the known aneurysm was safe and justified given the known limitations of diagnostic angiography. METHODS:An AO aneurysm was defined as a saccular aneurysm detected using the operative microscope during dissection of a known aneurysm, and not detected on preoperative catheter angiography. A prospective database was retrospectively reviewed to identify patients with AO aneurysms treated microsurgically over a 20-year period. RESULTS:One hundred fifteen AO aneurysms (4.0%) were identified during 2867 distinct craniotomies for aneurysm clipping. The most common locations for AO aneurysms were the middle cerebral artery (60 aneurysms, 54.1%) and the anterior cerebral artery (20 aneurysms, 18.0%). Fifty-six AO aneurysms (50.5%) were located on the same artery as the known saccular aneurysm. Most AO aneurysms (95.5%) were clipped and there was no attributed morbidity. The most common causes of failed angiographic detection were superimposition of a large aneurysm (type 1, 30.6%), a small aneurysm (type 2, 18.9%), or an adjacent normal artery (type 3, 36.9%). Multivariate analysis identified multiple known aneurysms (odds ratio [OR] 3.45, 95% confidence interval [CI] 2.16-5.49, p < 0.0001) and young age (OR 0.981, 95% CI 0.965-0.997, p = 0.0226) as independent predictors of AO aneurysms. CONCLUSIONS:Meticulous inspection of common aneurysm sites within the surgical field will identify AO aneurysms during microsurgical dissection of another known aneurysm. Simultaneous identification and treatment of these additional undiagnosed aneurysms can spare patients later rupture or reoperation, particularly in those with multiple known aneurysms and a history of subarachnoid hemorrhage. Limited microsurgical exploration around a known aneurysm can be performed safely without additional morbidity.

OBJECTIVECerebral bypass procedures are microsurgical techniques to augment or restore cerebral blood flow when treating a number of brain vascular diseases including moyamoya disease, occlusive vascular disease, and cerebral aneurysms. With advances in endovascular therapy and evolving evidence-based guidelines, it has been suggested that cerebral bypass procedures are in a state of decline. Here, the authors characterize the national trends in cerebral bypass surgery in the United States from 2002 to 2014.METHODSUsing the National (Nationwide) Inpatient Sample, the authors extracted for analysis the data on all adult patients who had undergone cerebral bypass as indicated by ICD-9-CM procedure code 34.28. Indications for bypass procedures, patient demographics, healthcare costs, and regional variations are described. Results were stratified by indication for cerebral bypass including moyamoya disease, occlusive vascular disease, and cerebral aneurysms. Predictors of inpatient complications and death were evaluated using multivariable logistic regression analysis.RESULTSFrom 2002 to 2014, there was an increase in the annual number of cerebral bypass surgeries performed in the United States. This increase reflected a growth in the number of cerebral bypass procedures performed for adult moyamoya disease, whereas cases performed for occlusive vascular disease or cerebral aneurysms declined. Inpatient complication rates for cerebral bypass performed for moyamoya disease, vascular occlusive disease, and cerebral aneurysm were 13.2%, 25.1%, and 56.3%, respectively. Rates of iatrogenic stroke ranged from 3.8% to 20.4%, and mortality rates were 0.3%, 1.4%, and 7.8% for moyamoya disease, occlusive vascular disease, and cerebral aneurysms, respectively. Multivariate logistic regression confirmed that cerebral bypass for vascular occlusive disease or cerebral aneurysm is a statistically significant predictor of inpatient complications and death. Mean healthcare costs of cerebral bypass remained unchanged from 2002 to 20014 and varied with treatment indication: moyamoya disease $38,406 ± $483, vascular occlusive disease $46,618 ± $774, and aneurysm $111,753 ± $2381.CONCLUSIONSThe number of cerebral bypass surgeries performed for adult revascularization has increased in the United States from 2002 to 2014. Rising rates of surgical bypass reflect a greater proportion of surgeries performed for moyamoya disease, whereas bypasses performed for vascular occlusive disease and aneurysms are decreasing. Despite evolving indications, cerebral bypass remains an important surgical tool in the modern endovascular era and may be increasing in use. Stagnant complication rates highlight the need for continued interest in advancing available bypass techniques or technologies to improve patient outcomes.

OBJECTIVEBrain arteriovenous malformations (bAVMs) are rupture-prone tangles of blood vessels with direct shunting of blood flow between arterial and venous circulations. The molecular and/or cellular mechanisms contributing to bAVM pathogenesis and/or destabilization in sporadic lesions have remained elusive. Initial insights into AVM formation have been gained through models of genetic AVM syndromes. And while many studies have focused on endothelial cells, the contributions of other vascular cell types have yet to be systematically studied. Pericytes are multifunctional mural cells that regulate brain angiogenesis, blood-brain barrier integrity, and vascular stability. Here, the authors analyze the abundance of brain pericytes and their association with vascular changes in sporadic human AVMs.METHODSTissues from bAVMs and from temporal lobe specimens from patients with medically intractable epilepsy (nonvascular lesion controls [NVLCs]) were resected. Immunofluorescent staining with confocal microscopy was performed to quantify pericytes (platelet-derived growth factor receptor-beta [PDGFRβ] and aminopeptidase N [CD13]) and extravascular hemoglobin. Iron-positive hemosiderin deposits were quantified with Prussian blue staining. Syngo iFlow post-image processing was used to measure nidal blood flow on preintervention angiograms.RESULTSQuantitative immunofluorescent analysis demonstrated a 68% reduction in the vascular pericyte number in bAVMs compared with the number in NVLCs (p < 0.01). Additional analysis demonstrated 52% and 50% reductions in the vascular surface area covered by CD13- and PDGFRβ-positive pericyte cell processes, respectively, in bAVMs (p < 0.01). Reductions in pericyte coverage were statistically significantly greater in bAVMs with prior rupture (p < 0.05). Unruptured bAVMs had increased microhemorrhage, as evidenced by a 15.5-fold increase in extravascular hemoglobin compared with levels in NVLCs (p < 0.01). Within unruptured bAVM specimens, extravascular hemoglobin correlated negatively with pericyte coverage (CD13: r = -0.93, p < 0.01; PDGFRβ: r = -0.87, p < 0.01). A similar negative correlation was observed with pericyte coverage and Prussian blue-positive hemosiderin deposits (CD13: r = -0.90, p < 0.01; PDGFRβ: r = -0.86, p < 0.01). Pericyte coverage positively correlated with the mean transit time of blood flow or the time that circulating blood spends within the bAVM nidus (CD13: r = 0.60, p < 0.05; PDGFRβ: r = 0.63, p < 0.05). A greater reduction in pericyte coverage is therefore associated with a reduced mean transit time or faster rate of blood flow through the bAVM nidus. No correlations were observed with time to peak flow within feeding arteries or draining veins.CONCLUSIONSBrain pericyte number and coverage are reduced in sporadic bAVMs and are lowest in cases with prior rupture. In unruptured bAVMs, pericyte reductions correlate with the severity of microhemorrhage. A loss of pericytes also correlates with a faster rate of blood flow through the bAVM nidus. This suggests that pericytes are associated with and may contribute to vascular fragility and hemodynamic changes in bAVMs. Future studies in animal models are needed to better characterize the role of pericytes in AVM pathogenesis.

BACKGROUND AND IMPORTANCE/BACKGROUND:Advances in minimally invasive (MIS) and mini-open surgical approaches have led to reductions in perioperative morbidity without compromising rates of resection of non-degenerative intradural spinal pathologies. Whether these approaches may be adapted for the surgical resection for intramedullary vascular malformations - such as cavernous malformations (CMs) - has yet to be reported. The authors describe a mini-open transspinous approach to resect a ruptured intramedullary CM of the conus medullaris. CLINICAL PRESENTATION/METHODS:A 28-year-old man presented with sudden onset of bilateral lower extremity weakness, urinary retention and saddle anesthesia. Magnetic resonance imaging demonstrated a ruptured CM within the conus medullaris with pronounced extralesional hemorrhage. A mini-open transspinous approach with an expandable tubular retractor was successfully applied to facilitate microsurgical resection of the CM and evacuation of the associated hematoma. The patient made a good neurologic recovery, and postoperative imaging confirmed a gross total resection of the CM. CONCLUSION/CONCLUSIONS:A mini-open transspinous approach utilizing an expandable tubular retractor offers feasible less invasive alternative to provide dorsal midline access for the microsurgical resection of intramedullary spinal CMs. Larger case series or future randomized prospective trials are warranted to fully explore suitability of MIS techniques for the surgical management of intradural spinal cord vascular pathologies - such as CMs.

OBJECTIVEShunt-dependent hydrocephalus is an important cause of morbidity following aneurysmal subarachnoid hemorrhage (aSAH) in excess of 20% of cases. Hydrocephalus leads to prolonged hospital and ICU stays, well as to repeated surgical interventions, readmissions, and complications associated with ventriculoperitoneal (VP) shunts, including shunt failure and infection. Whether variations in surgical technique at the time of aneurysm treatment may modify rates of shunt dependency remains a matter of debate. Here, the authors report on their experience with tandem fenestration of the lamina terminalis (LT) and membrane of Liliequist (MoL) at the time of open microsurgical repair of the ruptured aneurysm.METHODSThe authors conducted a retrospective review of 663 consecutive patients with aSAH treated from 2005 to 2015 by open microsurgery via a pterional or orbitozygomatic craniotomy by the senior author (M.T.L.). Data collected from review of the electronic medical record included age, Hunt and Hess grade, Fisher grade, need for an external ventricular drain, and opening pressure. Patients were stratified into those undergoing no fenestration and those undergoing tandem fenestration of the LT and MoL at the time of surgical repair. Outcome variables, including VP shunt placement and timing of shunt placement, were recorded and statistically analyzed.RESULTSIn total, shunt-dependent hydrocephalus was observed in 15.8% of patients undergoing open surgical repair following aSAH. Tandem microsurgical fenestration of the LT and MoL was associated with a statistically significant reduction in shunt dependency (17.9% vs 3.2%, p < 0.01). This effect was confirmed with multivariate analysis of collected variables (multivariate OR 0.09, 95% CI 0.03-0.30). Number-needed-to-treat analysis demonstrated that tandem fenestration was required in approximately 6.8 patients to prevent a single VP shunt placement. A statistically significant prolongation in days to VP shunt surgery was also observed in patients treated with tandem fenestration (26.6 ± 19.4 days vs 54.0 ± 36.5 days, p < 0.05).CONCLUSIONSTandem fenestration of the LT and MoL at the time of open microsurgical clipping and/or bypass to secure ruptured anterior and posterior circulation aneurysms is associated with reductions in shunt-dependent hydrocephalus following aSAH. Future prospective randomized multicenter studies are needed to confirm this result.

BACKGROUND AND PURPOSE:Inflammatory cells play a significant role in secondary injury after ischemic stroke. Recent studies have suggested that a lack of autophagy in myeloid cells causes augmented proinflammatory cytokine release and prolonged inflammation after tissue injury. In this study, we investigated the roles of myeloid cell autophagy in ischemic brain injury. METHODS:Focal cerebral ischemia was induced via transient middle cerebral artery occlusion in mice with autophagy-deficient myeloid lineage cells (Atg5flox/flox LysMCre+) and in their littermate controls (Atg5flox/flox). Infarct volume, neurological function, inflammatory cell infiltration, and proinflammatory cytokine expression levels were evaluated. RESULTS:<0.05). Although there was no difference in infarct volume at 12 hours between the 2 groups, mice lacking autophagy in myeloid lineage cells had larger infarct volumes at later time points (3 and 7 days after reperfusion) with worse neurological deficit scores and lower grip test scores. There were a higher number of ionized calcium binding adaptor molecule 1-positive cells and cells expressing M1 marker CD16/32 in mice lacking autophagy in myeloid cells at the later time points. Moreover, these mice had higher expression levels of proinflammatory cytokines at later time points; however, there was no difference in ionized calcium binding adaptor molecule 1-positive cells or mRNA levels of proinflammatory cytokines at the earlier time point (12 hours after reperfusion). CONCLUSIONS:These data suggest that the lack of myeloid cell autophagy aggravates secondary injury by augmenting and prolonging inflammation after ischemic stroke without affecting the initial injury.