G. Edward Vates

A Paravascular Pathway Facilitates CSF Flow Through the Brain Parenchyma and the Clearance of Interstitial Solutes, Including Amyloid β

Cerebrospinal fluid flows through channels around brain blood vessels that are bounded by astrocytic endfeet, mediated by water transport through aquaporin-4. A New Footing for Waste Clearance in the Brain Where are the lymph vessels of the brain? The lymphatic system’s complex network of vessels extends throughout most of the body, transporting excess fluid and waste products from the interstitial spaces between cells to the blood. Such vessels are notably absent from the brain, however, leading to long-standing questions about how interstitial fluid in this organ is cleared of waste. Now, Iliff et al. describe an anatomically distinct clearing system in the brain that serves a lymphatic-like function. The researchers first investigated the fate of tracer molecules introduced into the cerebrospinal fluid (CSF) in mice. Produced in ventricular cavities deep within the brain, the CSF fills the subarachnoid space—a gap between two of the membranes that encase the brain and spinal cord. Whereas tracers infused into the ventricle remained near that site, those injected into the subarachnoid space rapidly entered the brain itself. By visualizing fluorescent tracers through a cranial window in live mice, the authors found that CSF enters the brain in specific channels that are defined by features of small blood vessels in the brain. Such vessels are almost entirely ensheathed by astrocytic endfeet (terminal enlargements of long processes that project from astrocytes). The CSF tracers readily flow inward to the brain matter in a compartment between the outside of vessels—in this case small arteries entering the brain—and the astrocytic endfeet. At later time points, the tracer exits the brain in similar channels surrounding veins, having apparently circulated through the brain interstitium. Such CSF flux—and the clearance of tracers injected into the brain itself—were markedly reduced in mice lacking aquaporin-4, a water channel localized to astrocytic endfeet, indicating that these channels mediate this flux. These findings may have relevance for understanding or treating neurodegenerative diseases that involve the mis-accumulation of soluble proteins, such as amyloid β in Alzheimer’s disease. Indeed, Iliff et al. found that normal clearance of amyloid β (previously injected into the brain) requires aquaporin-4. Because it lacks a lymphatic circulation, the brain must clear extracellular proteins by an alternative mechanism. The cerebrospinal fluid (CSF) functions as a sink for brain extracellular solutes, but it is not clear how solutes from the brain interstitium move from the parenchyma to the CSF. We demonstrate that a substantial portion of subarachnoid CSF cycles through the brain interstitial space. On the basis of in vivo two-photon imaging of small fluorescent tracers, we showed that CSF enters the parenchyma along paravascular spaces that surround penetrating arteries and that brain interstitial fluid is cleared along paravenous drainage pathways. Animals lacking the water channel aquaporin-4 (AQP4) in astrocytes exhibit slowed CSF influx through this system and a ~70% reduction in interstitial solute clearance, suggesting that the bulk fluid flow between these anatomical influx and efflux routes is supported by astrocytic water transport. Fluorescent-tagged amyloid β, a peptide thought to be pathogenic in Alzheimer’s disease, was transported along this route, and deletion of the Aqp4 gene suppressed the clearance of soluble amyloid β, suggesting that this pathway may remove amyloid β from the central nervous system. Clearance through paravenous flow may also regulate extracellular levels of proteins involved with neurodegenerative conditions, its impairment perhaps contributing to the mis-accumulation of soluble proteins.

Auditory pathways of caudal telencephalon and their relation to the song system of adult male zebra finches (Taenopygia guttata)

Auditory information is critical for vocal imitation and other elements of social life in songbirds. In zebra finches, neural centers that are necessary for the acquisition and production of learned vocalizations are known, and they all respond to acoustic stimulation. However, the circuits by which conspecific auditory signals are perceived, processed, and stored in long‐term memory have not been well documented. In particular, no evidence exists of direct connections between auditory and vocal motor pathways, and two newly identified centers for auditory processing, caudomedial neostriatum (Ncm) and caudomedial hyperstriatum ventrale (cmHV), have no documented place among known auditory circuits. Our goal was to describe anatomically the auditory pathways in adult zebra finch males and, specifically, to show the projections by which Ncm and vocal motor centers may receive auditory input. By using injections of different kinds of neuroanatomical tracers (biotinylated dextran amines, rhodamine‐linked dextran amines, biocytin, fluorogold, and rhodamine‐linked latex beads), we have shown that, as in other avian groups, the neostriatal field L complex in caudal telencephalon is the primary forebrain relay for pathways originating in the auditory thalamus, i.e., the nucleus ovoidalis complex (Ov). In addition, Ncm and cmHV also receive input from the Ov complex. Ov has been broken down into two parts, the Ov “core” and “shell,” which project in parallel to different targets in the caudal telencephalon. Parts of the field L complex are connected among themselves and to Ncm, cmHV, and caudolateral HV (cIHV) through a complex web of largely reciprocal pathways. In addition, cIHV and parts of the field L complex project strongly to the “shelf” of neostriatum underneath the song control nucleus high vocal center (HVC) and to the “cup” of archistriatum rostrodorsal to another song‐control nucleus, the robust nucleus of the archistriatum (RA). We have documented two points at which the vocal motor pathway may pick up auditory signals: the HVC‐shelf interface and a projection from cIHV to the nucleus interfacialis (NIf), which projects to HVC. These data represent the most complete survey to date of auditory pathways in the adult male zebra finch brain, and of their projections to motor stations of the song system.

Descending auditory pathways in the adult male zebra finch (Taeniopygia guttata).

Here, we examine the connectivity of two previously identified telencephalic stations of the auditory system of adult zebra finches, the neostriatal “shelf” that underlies the high vocal center (HVC) and the archistriatal “cup” adjacent to the robust nucleus of the archistriatum (RA). We used different kinds of neuroanatomical tracers to visualize the projections from the shelf to the HVC. In addition, we show that the shelf projects to the cup and that the cup projects to thalamic, midbrain, and pontine nuclei of the ascending auditory pathway. Our observations extend to songbirds anatomical features that are found in the auditory pathways of a nonoscine bird, the pigeon (Wild et al. [1993] J. Comp. Neurol. 337:32–62), and we suggest that the descending auditory projections found in mammals may also be a general property of the avian brain. Finally, we show that the oscine song control system is closely apposed to auditory pathways at many levels. Our observations may help in understanding the evolution and organization of networks for vocal communication and vocal learning in songbirds. J. Comp. Neurol. 395:137–160, 1998.

Reafferent thalamo-“cortical” loops in the song system of oscine songbirds

Songbirds have a complex vocal repertoire, much of which is learned by imitation. The vocal motor system of songbirds includes a set of telencephalic pathways dedicated to the acquisition and production of learned song. The main vocal motor pathway goes from the high vocal center (HVC) to the robust nucleus of the archistriatum (RA), which in turn innervates mesencephalic and medullary nuclei involved in vocalization. We used neural tract tracers (biotinylated dextran amines, fluorescein‐ and rhodamine‐linked dextran amines, and Fluorogold) to show that RA of adult male canaries (Serinus canaria) and zebra finches (Taeniopygia guttata) sends an ipsilateral projection to the posterior portion of the dorsomedial thalamic nucleus (DMP). DMP projects to the medial portion of the magnocellular nucleus of the anterior neostriatum (mMAN), which is known to project to HVC, forming a feedback circuit. We also observed that the projection from DMP to mMAN is bilateral. Extracellular multi‐unit recordings from awake restrained subjects have demonstrated that mMAN has auditory responses that are selective for the birds own song. These auditory responses are similar to responses recorded simultaneously in HVC, but with a longer latency, suggesting that mMAN receives auditory information from HVC through the circuit we have described. We also saw a weaker projection from RA to the medial part of the dorsolateral nucleus of the thalamus (DLM), which is known to project to the lateral portion of the magnocellular nucleus of the anterior neostriatum (lMAN). lMAN is known to project to RA, completing yet another feedback circuit; lMAN is also part of the anterior forebrain pathway, which plays an essential role in song learning. These thalamo‐telencephalic circuits are similar to thalamo‐cortical circuits found in mammalian motor systems, and we suggest that the signals carried by these loops may be important for song perception, song learning, song production, and/or the bilateral coordination of vocal motor commands. J. Comp. Neurol. 380:275–290, 1997.

Impact of the Accreditation Council for Graduate Medical Education work-hour regulations on neurosurgical resident education and productivity.

OBJECT Recently, the Institute of Medicine examined resident duty hours and their impact on patient safety. Experts have suggested that reducing resident work hours to 56 hours per week would further decrease medical errors. Although some reports have indicated that cutbacks in resident duty hours reduce errors and make resident life safer, few authors have specifically analyzed the effect of the Accreditation Council for Graduate Medical Education (ACGME) duty-hour limits on neurosurgical resident education and the perceived quality of training. The authors have evaluated multiple objective surrogate markers of resident performance and quality of training to determine the impact of the 80-hour workweek. METHODS The United States Medical Licensing Examination (USMLE) Step 1 data on neurosurgical applicants entering ACGME-accredited programs between 1998 and 2007 (before and after the implementation of the work-hour rules) were obtained from the Society of Neurological Surgeons. The American Board of Neurological Surgery (ABNS) written examination scores for this group of residents were also acquired. Resident registration for and presentations at the American Association of Neurological Surgeons (AANS) annual meetings between 2002 and 2007 were examined as a measure of resident academic productivity. As a case example, the authors analyzed the distribution of resident training hours in the University of Virginia (UVA) neurosurgical training program before and after the institution of the 80-hour workweek. Finally, program directors and chief residents in ACGME-accredited programs were surveyed regarding the effects of the 80-hour workweek on patient care, resident training, surgical experience, patient safety, and patient access to quality care. Respondents were also queried about their perceptions of a 56-hour workweek. RESULTS Despite stable mean USMLE Step 1 scores for matched applicants to neurosurgery programs between 2000 and 2008, ABNS written examination scores for residents taking the exam for self-assessment decreased from 310 in 2002 to 259 in 2006 (16% decrease, p < 0.05). The mean scores for applicants completing the written examination for credit also did not change significantly during this period. Although there was an increase in the number of resident registrations to the AANS meetings, the number of abstracts presented by residents decreased from 345 in 2002 to 318 in 2007 (7% decrease, p < 0.05). An analysis of the UVA experience suggested that the 80-hour workweek leads to a notable increase in on-call duty hours with a profound decrease in the number of hours spent in conference and the operating room. Survey responses were obtained from 110 program directors (78% response rate) and 122 chief residents (76% response rate). Most chief residents and program directors believed the 80-hour workweek compromised resident training (96%) and decreased resident surgical experience (98%). Respondents also believed that the 80-hour workweek threatened patient safety (96% of program directors and 78% of chief residents) and access to quality care (82% of program directors and 87% of chief residents). When asked about the effects of a 56-hour workweek, all program directors and 98% of the chief residents indicated that resident training and surgical education would be further compromised. Most respondents (95% of program directors and 84% of chief residents) also believed that additional work-hour restrictions would jeopardize patient care. CONCLUSIONS Neurological surgery continues to attract top-quality resident applicants. Test scores and levels of participation in national conferences, however, indicate that the 80-hour workweek may adversely affect resident training. Subjectively, neurosurgical program directors and chief residents believe that the 80-hour workweek makes neurosurgical training and the care of patients more difficult. Based on experience with the 80-hour workweek, educators think that a 56-hour workweek would further compromise neurosurgical training and patient care in the US.

Grading of Subarachnoid Hemorrhage: Modification of the World Federation of Neurosurgical Societies Scale on the Basis of Data for a Large Series of Patients

OBJECTIVEThe goals of this study were to use a large, prospectively collected, multicenter database for patients with aneurysmal subarachnoid hemorrhage (SAH) who were treated between 1991 and 1997 to determine the prognostic significance of clinical and radiological factors for outcomes and to use those factors to develop a grading scale to predict outcomes. METHODSA total of 3567 patients with SAH who were entered into four randomized clinical trials of tirilazad were studied. Outcomes were assessed 3 months after SAH, with the Glasgow Outcome Scale. Twenty clinical and radiological factors were entered into univariate and multivariate analyses, to determine factors prognostic for outcomes. Grading scales based on the most powerful prognostic parameters were statistically derived and validated and were compared with the World Federation of Neurosurgical Societies (WFNS) grading scale. RESULTSFactors predictive of outcomes included age, WFNS grade, history of hypertension, systolic blood pressure at admission, ruptured aneurysm location and size, blood clot thickness on computed tomographic scans, and angiographic vasospasm at admission. A grading scale using these factors could be derived; it predicted outcomes more accurately than did the WFNS scale, although it would be more complex to use. CONCLUSIONOutcome prediction after SAH can be improved by adding additional clinical and radiological factors to the WFNS scale, albeit with added complexity.

Gliomatosis Cerebri: A Review of 22 Cases

OBJECTIVEGliomatosis cerebri is an enigmatic diffuse brain neoplasm whose prognosis is grim. We reviewed data for patients with gliomatosis who were treated at the University of California, San Francisco, during a 10-year period. Our focus was on presentation, radiological and pathological features, and outcomes. METHODSWe reviewed hospital and clinic records and magnetic resonance imaging scans for 22 patients with gliomatosis. The diagnosis was based on magnetic resonance imaging findings and tissue confirmation for all patients. Seven patients also underwent magnetic resonance spectroscopy. Eleven patients were male (50%), and the median age at presentation was 49 years (range, 7–79 yr). RESULTSKaplan-Meier analysis demonstrated median lengths of survival as follows: no treatment, 1 month (n = 4); radiotherapy alone, 28 months (95% confidence interval, 5–51 mo; n = 13); radiotherapy followed by chemotherapy, two patients, alive at 28 and 104 months; radiotherapy and chemotherapy simultaneously, three patients, one alive at 18 months and the others dead at 7 and 9 months. There was no significant difference between radiotherapy alone and radiotherapy combined with chemotherapy (P = 0.69). Karnofsky Performance Scale scores of ≥70 and grade were both significantly related to length of survival in univariate analyses (P < 0.05); these correlations were confirmed in the multivariate analysis, although the small numbers of patients and deaths precluded reliable interpretation. CONCLUSIONAlthough the small number of patients in our study and its retrospective nature preclude definitive conclusions regarding the utility of treatment, our findings suggest that biopsies are useful not only for diagnosis but also for prediction of the length of survival.

Stereotactic radiosurgery for glioblastoma: retrospective analysis

PurposeThis retrospective study was done to better understand the conditions for which stereotactic radiosurgery (SRS) for glioblastoma may be efficacious.MethodsBetween 2000 and 2007, 33 patients with a pathological diagnosis of glioblastoma received SRS with the Novalis® Shaped Beam Radiosurgery system. Eighteen patients (54%) underwent salvage SRS for recurrence while 15 (45%) patients received upfront SRS following standard fractionated RT for newly diagnosed glioblastoma.ResultsThere were no RTOG grade >2 acute side effects. The median survival after SRS was 6.7 months (range 1.4 – 74.7). There was no significant difference in overall survival (from the time of initial diagnosis) with respect to the timing of SRS (p = 0.2). There was significantly better progression free survival in patients treated with SRS as consolidation versus at the time of recurrence (p = 0.04). The majority of patients failed within or at the margin of the SRS treatment volume (21/26 evaluable for recurrence).ConclusionSRS is well tolerated in the treatment of glioblastoma. As there was no difference in survival whether SRS is delivered upfront or at recurrence, the treatment for each patient should be individualized. Future studies are needed to identify patients most likely to respond to SRS.

A neurocytoma and an associated lenticulostriate artery aneurysm presenting with intraventricular hemorrhage: case report.

OBJECTIVE AND IMPORTANCE Hemorrhage associated with central neurocytoma has been described previously, but never in association with an aneurysm originating from a feeding artery. We present the first reported case of a central neurocytoma in a patient with intraventricular hemorrhage caused by rupture of an aneurysm on a lenticulostriate artery that supplied the tumor. CLINICAL PRESENTATION A 35-year-old man who presented with an intraventricular hemorrhage underwent magnetic resonance imaging and cerebral angiography that disclosed a right lateral intraventricular mass and a 7-mm fusiform aneurysm from a lateral lenticulostriate branch of the right middle cerebral artery. INTERVENTIONThe patient underwent a contralateral transcallosal exploration and resection of the tumor, with excision of the adjacent lenticulostriate artery aneurysm. Pathological review demonstrated that the tumor was a neurocytoma. The aneurysm was discrete from the tumor but occurred on a vessel that supplied the tumor. CONCLUSIONPrevious reports have demonstrated that intraventricular neurocytoma may present with tumor hemorrhage. In this case, an aneurysm separate and distinct from the tumor was the bleeding culprit, and the aneurysm was on an artery that fed into the tumor. Any such aneurysm must be identified and treated appropriately for therapy to be complete.

Methods and Design Considerations for Randomized Clinical Trials Evaluating Surgical or Endovascular Treatments for Cerebrovascular Diseases

OBJECTIVEThe results of clinical trials affect the practice of surgery and endovascular therapy for cerebrovascular diseases. The purpose of this report is to review the basic components of the designs and methods for randomized clinical trials and to describe the influence of those components on the interpretation of trial results. METHODSThe goal of an optimal clinical trial of a new procedure is to provide the most objective and rigorous evaluation of the safety and effectiveness of that procedure. Anything in the design, performance, or analysis that impairs such an assessment decreases the ability of the trial to achieve its goal and answer the research question. To highlight the components of a clinical trial, this report uses examples of Phase III clinical trials that have influenced the practice of cerebrovascular surgery and endovascular therapy in the past three decades, including the International Cooperative Study of Extracranial/Intracranial Arterial Anastomosis, the North American Symptomatic Carotid Endarterectomy Trial, the Asymptomatic Carotid Atherosclerosis Study, the Prolyse in Acute Cerebral Thromboembolism II study, and the International Subarachnoid Aneurysm Trial. RESULTSThe research question (objective) of the trial must be clearly defined, with an objective measure of efficacy and a specified quantitative difference to define the superiority of one intervention over another, in a relatively homogeneous patient population. Allocation concealment, randomization with or without stratification, and blinding (or masking) are important strategies to prevent differences in the study populations that could adversely affect the conclusions of the study. The primary end point must correspond to the specific aims of the trial. It should be objectively defined, quantifiable, reliable, and reproducible. Commonly defined end points in surgical trials include changes from baseline illness or disease severity scores, morbidity and mortality rates, and relative risks of reaching an end point with time. The statistical methods used for interim and final analyses are important. The effects of dropouts, crossovers, and missing data should be understood in the context of the final analysis. Additional concepts, such as intention-to-treat analysis and use of actual versus predicted outcomes, are important with respect to interpretation of the final results of the study. CONCLUSIONThe neurosurgical and neuroendovascular communities are currently planning or conducting several clinical trials to evaluate new procedures for the treatment of cerebrovascular diseases. It is hoped that a better understanding of the components of clinical trials will facilitate the design and implementation of effective studies.