Juanita M. Celix

A Trial of Intracranial-Pressure Monitoring in Traumatic Brain Injury

BACKGROUND Intracranial-pressure monitoring is considered the standard of care for severe traumatic brain injury and is used frequently, but the efficacy of treatment based on monitoring in improving the outcome has not been rigorously assessed. METHODS We conducted a multicenter, controlled trial in which 324 patients 13 years of age or older who had severe traumatic brain injury and were being treated in intensive care units (ICUs) in Bolivia or Ecuador were randomly assigned to one of two specific protocols: guidelines-based management in which a protocol for monitoring intraparenchymal intracranial pressure was used (pressure-monitoring group) or a protocol in which treatment was based on imaging and clinical examination (imaging-clinical examination group). The primary outcome was a composite of survival time, impaired consciousness, and functional status at 3 months and 6 months and neuropsychological status at 6 months; neuropsychological status was assessed by an examiner who was unaware of protocol assignment. This composite measure was based on performance across 21 measures of functional and cognitive status and calculated as a percentile (with 0 indicating the worst performance, and 100 the best performance). RESULTS There was no significant between-group difference in the primary outcome, a composite measure based on percentile performance across 21 measures of functional and cognitive status (score, 56 in the pressure-monitoring group vs. 53 in the imaging-clinical examination group; P=0.49). Six-month mortality was 39% in the pressure-monitoring group and 41% in the imaging-clinical examination group (P=0.60). The median length of stay in the ICU was similar in the two groups (12 days in the pressure-monitoring group and 9 days in the imaging-clinical examination group; P=0.25), although the number of days of brain-specific treatments (e.g., administration of hyperosmolar fluids and the use of hyperventilation) in the ICU was higher in the imaging-clinical examination group than in the pressure-monitoring group (4.8 vs. 3.4, P=0.002). The distribution of serious adverse events was similar in the two groups. CONCLUSIONS For patients with severe traumatic brain injury, care focused on maintaining monitored intracranial pressure at 20 mm Hg or less was not shown to be superior to care based on imaging and clinical examination. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01068522.).

Intracranial Pressure Monitoring in Severe Traumatic Brain Injury in Latin America: Process and Methods for a Multi-Center Randomized Controlled Trial

In patients with severe traumatic brain injury (TBI), the influence on important outcomes of the use of information from intracranial pressure (ICP) monitoring to direct treatment has never been tested in a randomized controlled trial (RCT). We are conducting an RCT in six trauma centers in Latin America to test this question. We hypothesize that patients randomized to ICP monitoring will have lower mortality and better outcomes at 6-months post-trauma than patients treated without ICP monitoring. We selected three centers in Bolivia to participate in the trial, based on (1) the absence of ICP monitoring, (2) adequate patient accession and data collection during the pilot phase, (3) preliminary institutional review board approval, and (4) the presence of equipoise about the value of ICP monitoring. We conducted extensive training of site personnel, and initiated the trial on September 1, 2008. Subsequently, we included three additional centers. A total of 176 patients were entered into the trial as of August 31, 2010. Current enrollment is 81% of that expected. The trial is expected to reach its enrollment goal of 324 patients by September of 2011. We are conducting a high-quality RCT to answer a question that is important globally. In addition, we are establishing the capacity to conduct strong research in Latin America, where TBI is a serious epidemic. Finally, we are demonstrating the feasibility and utility of international collaborations that share resources and unique patient populations to conduct strong research about global public health concerns.

Thrombosis and hemorrhage in the acute period following Gamma Knife surgery for arteriovenous malformation

Bleeding of an arteriovenous malformation (AVM) following stereotactic radiosurgery (SRS) is a known risk during the latency interval, but hemorrhage in the 30-day period following radiosurgery rarely has been reported in the literature. The authors present the case of a 57-year-old man who underwent Gamma Knife surgery for a large AVM, and they provide radiographic documentation of a thrombus in the primary draining vein immediately preceding an AVM hemorrhage within 9 days after radiosurgery. They postulate that the pathophysiology of an AVM hemorrhage in the acute period following SRS is related to an association among tissue irradiation, acute inflammatory response, and vessel thrombosis. The authors also review the literature on risk factors for hemorrhage due to untreated and radiosurgically treated AVMs. Recent evidence on the role of inflammation in the pathogenesis of AVMs and the pathophysiology of AVM rupture is presented. Inflammatory markers have been demonstrated in brain AVM tissue, and the association between inflammation and AVM hemorrhage has been established. There is an acute inflammatory response following tissue irradiation, resulting in structural and functional vascular changes that can lead to vessel thrombosis. Early hemorrhage following radiosurgical treatment of AVMs may be related to the acute inflammatory response and associated vascular changes that occur in irradiated tissue. In the first stage of a planned 2-stage Gamma Knife treatment for a large AVM in the featured case, the superior posteromedial portion of the primary draining vein was included in the treatment field. The authors present the planning images and subsequent CT scans demonstrating a new venous thrombus in the primary draining vein. An acute inflammatory response following radiosurgery with resultant acute venous thrombus formation and venous obstruction is proposed as one mechanism of an AVM hemorrhage in this patient. Radiographic evidence of the time course of thrombosis and hemorrhage supports the hypothesis that acute venous obstruction is a cause of intracranial hemorrhage.

Traumatic brain injury in Latin America: lifespan analysis randomized control trial protocol*.

BACKGROUND Although in the developed world the intracranial pressure (ICP) monitor is considered the standard of care for patients with severe traumatic brain injury (TBI), its usefulness to direct treatment decisions has never been tested rigorously. OBJECTIVE The primary focus was to conduct a high-quality, randomized, controlled trial to determine whether ICP monitoring used to direct TBI treatment improves patient outcomes. By providing education, equipment, and structure, the project will enhance the research capacity of the collaborating investigators and will foster the collaborations established during earlier studies. METHODS Study centers were selected that routinely treated ICP based on clinical examination and computed tomography imaging using internal protocols. We randomized patients to either an ICP monitor group or an imaging and clinical examination group. Treatment decisions for the ICP monitor group are guided by ICP monitoring based on established guidelines. Treatment decisions for the imaging and clinical examination group are made using a single protocol derived from those previously being used at those centers. EXPECTED OUTCOMES There are 2 study hypotheses: (1) patients with severe TBI whose acute care treatment is managed using ICP monitors will have improved outcomes and 2) incorporating ICP monitoring in the care of patients with severe TBI will minimize complications and decrease length of intensive care unit stay. DISCUSSION This clinical trial tests the effectiveness of a management protocol based on technology considered pivotal to brain trauma treatment in the developed world: the ICP monitor. A randomized, controlled trial of ICP monitoring has never been performed-a critical gap in the evidence base that supports the role of ICP monitoring in TBI care. As such, the results of this randomized, controlled trial will have global implications regardless of the level of development of the trauma system.

113 Initial Experience With an Image-Guided Robotically Positioned Optical Platform for Aneurysm Surgery.

INTRODUCTION The conventional stereoscopic microscope (CS-m) made safe surgery for intracranial vascular pathology. Recently, an integrated image-guided robotic optical positioning system (ROVOT-m) has been released for clinical use. We undertook a benchside, cadaveric and clinical study to determine its applicability to aneurysm surgery. METHODS Benchside measurements of field of view (FOV) and depth of field (DOF) were obtained for CS-m and ROVOT-m. Two cadavers were operated on to simulate aneurysm surgery using both CS-m and ROVOT-m. Clinical feasibility of ROVOT-m was demonstrated during for surgery for both ruptured and unruptured aneurysms. RESULTS At highest magnification, ROVOT-m has a 25-mm FOV, 40% greater than that of CS-m. At the same FOV of 25 mm and working distance of 250 mm, ROVOT-m has a DOF of 14 mm, more than 3 times greater than CS-m. Cadaveric dissection confirmed that the volume of view (VOV) for the ROVOT-m was substantially larger than for the CS-m. Six aneurysms were clipped using the ROVOT-m: 4 ruptured middle cerebral artery aneurysms, 1 unruptured anterior communicating artery aneurysm, and 1 unruptured superior hypophyseal artery aneurysm. CONCLUSION The ROVOT-m has a substantially larger VOV the volume of surgical anatomy in focus and adequately illuminated. The larger immersive volume of surgical anatomy in focus was especially valuable when temporary clipping in the cases of middle cerebral artery aneurysm as the VOV extended from proximal internal carotid artery to distal M2 branches. The use of preset positions permits multiple relevant optical trajectories to be viewed rapidly and in sequence, which is particularly beneficial for assessing clip placement. Hands-free positioning allows for uninterrupted work flow.

Microsurgical Anatomy of the Vertical Rami of the Superior Longitudinal Fasciculus: An Intraparietal Sulcus Dissection Study

BACKGROUND A number of vertical prolongations of the superior longitudinal fasciculus, which we refer to as the vertical rami (Vr), arise at the level of the supramarginal gyrus, directed vertically toward the parietal lobe. OBJECTIVE To provide the first published complete description of the white matter tracts (WMT) of the Vr, their relationship to the intraparietal and parieto-occipital sulci (IPS-POS complex), and their importance in neurosurgical approaches to the parietal lobe. METHODS Subcortical dissections of the Vr and WMT of the IPS were performed. Findings were correlated with a virtual dissection using high-resolution diffusion tensor imaging (DTI) tractography data derived from the Human Connectome Project. Example planning of a transparietal, transsulcal operative corridor is demonstrated using an integrated neuronavigation and optical platform. RESULTS The Vr were shown to contain component fibers of the superior longitudinal fasciculus (SLF)-II and SLF-III, with contributions from the middle longitudinal fasciculus merging into the medial bank of the IPS. The anatomic findings correlated well with DTI tractography. The line extending from the lateral extent of the POS to the IPS marks an ideal sulcal entry point that we have termed the IPS-POS Kassam-Monroy (KM) Point, which can be used to permit a safe parafascicular surgical trajectory to the trigone. CONCLUSION The Vr are a newly conceptualized group of tracts merging along the banks of the IPS, mediating connectivity between the parietal lobe and dorsal stream/SLF. We suggest a refined surgical trajectory to the ventricular atrium utilizing the posterior third of the IPS, at or posterior to the IPS-POS Point, in order to mitigate risk to the Vr and its considerable potential for postsurgical morbidity.

Intraoperative Cortical Mapping Techniques and Limitations

Cortical mapping is the gold standard for intraoperative localization of eloquent cortex. Stimulation mapping provides a tool to balance the benefits of maximal surgical resection with the risks of damage to eloquent cortex or subcortical fiber tracts. Certain mapping techniques, such as cortical stimulation sensory and language mapping, require an awake cooperative patient, and necessitate specific anesthetic considerations when performing mapping or evoked potential monitoring. Somatosensory-evoked potentials (SSEPs) can be used to quickly and reliably locate Rolandic cortex. SSEPs and motor-evoked potentials (MEPs) can be used for continuous monitoring of sensory and motor cortex and subcortical fiber tracts during surgical resection. Language mapping is performed when there is a surgical lesion in the language-dominant temporal, posterior frontal, or anterior parietal lobe. Wada testing may be needed to lateralize language function preoperatively when language lateralization is in doubt, and is required in certain patient subgroups based on handedness and lesion location. The specific intraoperative techniques of SSEP mapping and monitoring, MEP mapping and monitoring, and cortical stimulation mapping of motor, sensory, and language cortices are presented.

Ethical and methodological considerations on conducting clinical research in poor and low-income countries: Viewpoint of the authors of the BEST TRIP ICP randomized trial in Latin America.

We read with interest the editorial critique of Sahuquillo and Biestro[10] regarding the BEST TRIP trial,[2] and appreciate Hunts editorial response.[6] However, we believe that the several oversights and misinterpretations that flaw the structure of the editorial, although resolvable by careful reading of the paper, will benefit by clarification by us who were directly involved with the study. Our major concerns are regarding the misrepresentation of the studys focus and the sterile analysis of equipoise. As stated in the BEST TRIP report, this was not a study of intracranial pressure (ICP) monitoring per se. It was designed as an investigation of two protocols of aggressive treatment of intracranial hypertension, one driven by monitored ICP and based on recommendations from the Guidelines for the Management of Acute Brain Injury in Adults[1] and the other based on current practices at the study (non-monitoring) institutions, which were guided by serial neurological examination and CT imaging. There was no placebo group in this study; both groups were afforded highly aggressive neurological management. As presented in the BEST TRIP report, there was no difference in the incidence of pre-specified clinical neurological deterioration criteria (one hallmark of inadequate ICP management) between the monitor-driven and the non–monitor-driven protocols. Recognizing the absence of a placebo control group renders specious the suggested parallels between the BEST TRIP trial and ethically questionable studies such as the African zidovudine studies and the Tuskegee and Willowbrook investigations. From a position of academics in high-income countries (HICs), it is argued that ICP monitoring is the standard of care. However, the guidelines themselves note that the weakness of the literature supporting ICP monitoring reflects the lack of randomized control trial (RCT)-level data. There is no doubt that elevated ICP is a bad prognostic indicator; the evidentiary frisson exists because it has not been definitively shown that lowering ICP improves recovery. The correlative nature of the available Class II and III studies cannot differentiate treatment-related selection of patient subgroups with different prognoses versus actually increasing recovery. An objective indication that there is no consensus on ICP monitoring, even in HICs, is the wide variation of its routine use in actual practice (77.4% in the US,[5] 44.5% in Australia and New Zealand,[7] 63% in Canada,[9] and 37% in Europe[12]). Perhaps naively, we believe that these frequencies reflect clinical or global equipoise at HIC centers rather than non-compliance with a true standard of practice. In low- and-middle-income countries (LMICs), although ICP monitoring is generally available (via ventriculostomy), it is rarely used, with availability of neurological surgeons, expense, complications, and labor intensity quoted as reasons. As a result, aggressive treatment of suspected intracranial hypertension is based on serial imaging and neurological examination. The widespread environment of competition for funding and resources in LMICs places the implications of the lack of scientific rigor in a unique context quite different from that in HICs. It is perhaps germane to realize that most, if not all, of the authors of the guidelines have never managed a severe traumatic brain injury (TBI) patient without an ICP monitor. This brings us to our second major area of concern with the Sahuquillo and Biestro critique, which revolves around the sterility of their analysis of equipoise. As noted in the commentary of Hunt, equipoise may be considered to have superficial and deep aspects. Superficially, it is likely true that our Latin American investigators would have been using ICP monitoring before the trial if it were readily available. Of course, cardiac surgeons would have routinely employed internal mammary artery ligation for angina in the 1950s[3] and intensivists would have chosen pulmonary artery catheterization for managing critically ill ICU patients four decades later.[4,8,11] We would all likely benefit from confessing to “medical magpie-ism” and admitting that practice in the high-resource environment of HICs greatly facilitates (and obscures) such a non-scientific proclivity. However, the benefits of living in a high-resource environment also strongly inhibits us from understanding the profoundly different visceral viewpoint that arises from having experienced ones entire medical career in LMICs. Indeed, the BEST TRIP investigators from the US and Argentina were initially taken aback when the site investigators involved in designing a multicenter prospective observational study suggested that they would be interested in performing an RCT involving ICP-monitor-driven care. Not until after much discussion among ourselves and with our site PIs did we realize that their position of equipoise, although difficult for us initially to understand, was internally valid. Without the indispensable experience that we had gained over a decade of working in Latin America, learning and experiencing their reality, it is quite possible that some of the BEST TRIP authors might have co-authored the editorial critique of Sahuquillo and Biestro. It is notable that this trial was evaluated and approved by ethical committees and FWA-approved IRBs in all participating Latin American institutions, as well as by the IRB at the University of Washington in the US. Although there were myriad ethical questions from each entity during these reviews, none found the study unacceptable based on ethical concerns. As far as conflict of interest is concerned, the site PIs who suggested and performed this study had no interest in its implications in HICs, but were very much interested in finding whether the application of our current ICP-monitor-driven protocols in their environment would warrant the required resources. Although the editorial states that “BEST TRIP is a good example of research that has no practical relevance to the health needs of the host country, but it is apparently important to the foreign sponsors and researchers …,” we fail to see how demonstrating inadequacies in our use of an important monitoring device is not relevant to the health needs of both the US and Latin American countries involved in the study. We also take issue with their strong implication that this study was influenced by industry. Given the highly limited funding that comes with Fogarty International Center directed/NIH sponsored research awards, there was no way for us to purchase the required monitors. Integra Life Sciences responded positively to our request that they would supply the necessary hardware, despite explicit prohibitions against their having input into the design, execution, analysis, or publication of the study results. This is collaboration, not collusion, and allegations otherwise would benefit from supporting evidence. In contrast to the implications of the editorial, the BEST TRIP publication explicitly cautions against ready generalization of the results to HIC centers. This is based on the many important differences between these environments and our inability to adequately control for them in our analyses. As the editorial correctly states, the logical next step would be repeating the study at trauma centers in HICs. However, it also posits, “these countries would never allow such a trial to be conducted,” which we believe is incorrect. As noted above, there were sizeable percentages of HIC trauma centers not monitoring prior to the trial, and we perceive an increasing willingness for practitioners who do not routinely monitor to publically admit this following the BEST TRIP publication. A shift in HIC-equipoise balance might not be required to perform such a study. Finally, our site PIs almost to a person took umbrage at the implication in this editorial that the study ICUs were of limited quality due to lack of resources. Anyone who has spent time in these ICUs will immediately recognize the high level of education, diligence, and application represented by the involved intensivists, which is clearly reflected in the data presented in the BEST TRIP publication and the online supplement. We offer a standing invitation to Professor Sahuquillo and Dr. Biestro to visit any or all of the BEST TRIP ICUs toward rectifying their difficulty in differentiating resource limitations and quality of care. We believe that proper response to a careful, thorough reading of the BEST TRIP report is to recognize the critical value of aggressive and attentive management of TBI patients in all settings and to admit that our fields employment of ICP monitoring is under-developed at present, rather than to deny the studys findings. Refinements in threshold setting, TBI subgroup identification, and integration of ICP data with other monitored values and trends appear wanting, but there is no evidence that ICP monitoring should be abandoned. On the larger stage, it is also important to realize that the medical and ethical literature almost exclusively emanates from academic centers in HICs. The only valid method for assessing the generalizability of this literature to LMICs is to make an unbiased, protracted effort to understand their reality, as perceived by them. In this light, it is notable that none of our Latin American colleagues have ever expressed regret that they suggested this study or participated in its execution.

Cerebral metastatic disease: applying what we know to rare brain metastases.

ancer is a leading cause of death worldwide (7). As economies develop, and the world population grows and C ages, the global burden of cancer continues to increase. Although there are regional differences in the prevalence and distribution of cancer risk factors, cancer detection practices, and the availability and use of various treatment modalities, improvements in cancer diagnosis and treatment are far reaching. Advances in the detection of and therapeutic interventions for systemic solid neoplasms have improved median survival times. In turn, longer survival has increased the prevalence of “safe harbor” metastases. For those cancers that have a predilection to metastasize to the central nervous system—breast, lung, melanoma, and renal cancers—improvements in the oncologic armamentaria have greatly increased the likelihood of developing brain metastases. For instance, in the United States, the incidence of brain metastases in patients with known solid tumors was just more than 5% in the 1960s. Now the incidence is approximately 20% (4). In addition, improved mortality patterns for less common cancers, and cancers with historically poor survival, will likely be reflected in the prevalence of cerebral metastatic disease.

Hemorrhage from Arteriovenous Malformation Following Gamma Knife Radiosurgery: Pathophysiology of Rupture Early in the Latency Period

Arteriovenous malformations (AVM) are uncommon congenital abnormalities with a prevalence of 10-18 per 100, 000 adults (Al-Shahi et al. 2002; Berman et al. 2000) and an incidence of 1. 3 per 100, 000 person-years. (Stapf et al. 2003) Arteriovenous malformations typically present with hemorrhage, seizure, or focal neurological deficit. Intracranial hemorrhage is the most common clinical presentation of an AVM, resulting in significant morbidity and mortality. The natural risk of primary hemorrhage in untreated AVMs is 2% to 4% per year. (Barrow and Reisner 1993; Brown et al. 1988; Crawford et al. 1986; Davis and Symon 1985; Forster, Steiner, and Hakanson 1972; Fults and Kelly 1984; Graf, Perret, and Torner 1983; Mast et al. 1997; Ondra et al. 1990; Pollock et al. 1996) The primary goal of AVM treatment is elimination of the risk of hemorrhage by removal of the bleeding potential of the abnormal vasculature. Currently, the therapeutic options for AVM treatment include microsurgical resection, stereotactic radiosurgery (SRS), and endovascular embolization, alone or in combination. Small AVMs or those that are surgically inaccessible in deep brain or eloquent cortex are typically amenable to stereotactic radiosurgery.