Nicholas J. Szerlip

Real-time imaging of convection-enhanced delivery of viruses and virus-sized particles

OBJECT Despite recent evidence showing that convection-enhanced delivery (CED) of viruses and virus-sized particles to the central nervous system (CNS) is possible, little is known about the factors influencing distribution of these vectors with convection. To better define the delivery of viruses and virus-sized particles in the CNS, and to determine optimal parameters for infusion, the authors coinfused adeno-associated virus ([AAV], 24-nm diameter) and/or ferumoxtran-10 (24 nm) by using CED during real-time magnetic resonance (MR) imaging. METHODS Sixteen rats underwent intrastriatal convective coinfusion with 4 microl of 35S-AAV capsids (0.5-1.0 x 10(14) viral particles/ml) and increasing concentrations (0.1, 0.5, 1, and 5 mg/ml) of a similar sized iron oxide MR imaging agent (ferumoxtran-10). Five nonhuman primates underwent either convective coinfusion of 35S-AAV capsids and 1 mg/ml ferumoxtran-10 (striatum, one animal) or infusion of 1 mg/ml ferumoxtran-10 alone (striatum in two animals; frontal white matter in two). Clinical effects, MR imaging studies, quantitative autoradiography, and histological data were analyzed. RESULTS Real-time, T2-weighted MR imaging of ferumoxtran-10 during infusion revealed a clearly defined hypointense region of perfusion. Quantitative autoradiography confirmed that MR imaging of ferumoxtran-10 at a concentration of 1 mg/ml accurately tracked viral capsid distribution in the rat and primate brain (the mean difference in volume of distribution [Vd] was 7 and 15% in rats and primates, respectively). The Vd increased linearly with increasing volume of infusion (Vi) (R2 = 0.98). The mean Vd/Vi ratio was 4.1 +/- 0.2 (mean +/- standard error of the mean) in gray and 2.3 +/- 0.1 in white matter (p < 0.01). The distribution of infusate was homogeneous. Postinfusion MR imaging revealed leakback along the cannula track at infusion rates greater than 1.5 microl/minute in primate gray and white matter. No animal had clinical or histological evidence of toxicity. CONCLUSIONS The CED method can be used to deliver AAV capsids and similar sized particles to the CNS safely and effectively over clinically relevant volumes. Moreover, real-time MR imaging of ferumoxtran-10 during infusion reveals that AAV capsids and similar sized particles have different convective delivery properties than smaller proteins and other compounds.

Extracorporeal life support as a treatment for neurogenic pulmonary edema and cardiac failure secondary to intractable intracranial hypertension: A case report and review of the literature

Neurogenic pulmonary edema (NPE) and cardiac dysfunction have been reported with subarachnoid hemorrhage (SAH) and with isolated traumatic brain injury (TBI).1–3 The pathophysiology is poorly understood4; nevertheless, the consequences of these conditions: hypoxia, hypotension, or hypercapnia, may increase intracranial pressures (ICPs) and worsen outcome.5 It is now recognized that patients with TBI develop nonneurologic organ dysfunction and that this organ failure is associated with a worse neurologic outcome.6 We present a case in which extracorporeal life support (ECLS) was used to treat severe TBI and subsequent multiorgan failure (MOF), allowing maintenance of normal blood oxygen and carbon dioxide (CO2) levels, and subsequently leading to successful treatment of increased ICPs. This case represents the extreme severity of multiple organ dysfunction that can follow isolated TBI, and highlights the need for multispecialty involvement in the treatment of TBI to maximize functional outcome.

The impact of blood pressure management after spinal cord injury: A systematic review of the literature

OBJECTIVE Spinal cord injury (SCI) results in significant morbidity and mortality. Improving neurological recovery by reducing secondary injury is a major principle in the management of SCI. To minimize secondary injury, blood pressure (BP) augmentation has been advocated. The objective of this study was to review the evidence behind BP management after SCI. METHODS This systematic review was conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Using the PubMed database, the authors identified studies that investigated BP management after acute SCI. Information on BP goals, duration of BP management, vasopressor selection, and neurological outcomes were analyzed. RESULTS Eleven studies that met inclusion criteria were identified. Nine studies were retrospective, and 2 were single-cohort prospective investigations. Of the 9 retrospective studies, 7 reported a goal mean arterial pressure (MAP) of higher than 85 mm Hg. For the 2 prospective studies, the MAP goals were higher than 85 mm Hg and higher than 90 mm Hg. The duration of BP management varied from more than 24 hours to 7 days in 6 of the retrospective studies that reported the duration of treatment. In both prospective studies, the duration of treatment was 7 days. In the 2 prospective studies, neurological outcomes were stable to improved with BP management. The retrospective studies, however, were contradictory with regard to the correlation of BP management and outcomes. Dopamine, norepinephrine, and phenylephrine were the agents that were frequently used to augment BP. However, more complications have been associated with dopamine use than with the other vasopressors. CONCLUSIONS There are no high-quality data regarding optimal BP goals and duration in the management of acute SCI. Based on the highest level of evidence available from the 2 prospective studies, MAP goals of 85-90 mm Hg for a duration of 5-7 days should be considered. Norepinephrine for cervical and upper thoracic injuries and phenylephrine or norepinephrine for mid- to lower thoracic injuries should be considered.

Dural Cells Release Factors Which Promote Cancer Cell Malignancy and Induce Immunosuppressive Markers in Bone Marrow Myeloid Cells

BACKGROUND Thirty per cent of cancer patients develop spine metastases with a substantial number leading to spinal cord compression and neurological deficits. Many demonstrate a propensity toward metastasis to the posterior third of the vertebral body. The dura, the outer layer of the meninges, lies in intimate contact with the posterior border of the vertebral body and has been shown to influence adjacent bone. The effects of the dura on bone marrow and cancer cells have not been examined. Understanding the biology of spinal metastasis will provide insights into mechanisms of cancer growth and allow for new treatment strategies. OBJECTIVE To examine the extent to which dura influences bone marrow/tumor cell metastatic characteristics. METHODS Dura conditioned media (DCM) from primary dura was examined for the ability to stimulate tumor cell proliferation/invasion and to alter bone marrow cell populations. RNA sequencing of dural fibroblasts was performed to examine expression of cytokines and growth factors. RESULTS DCM induced a significant increase in invasion and proliferation of multiple tumor cell lines, and of patient-derived primary spinal metastatic cells. DCM also increased the proliferation of bone marrow myeloid cells, inducing expression of immunosuppressive markers. RNA sequencing of dural fibroblasts demonstrated abundant expression of cytokines and growth factors involved in cancer/immune pathways. CONCLUSION Factors released by primary dural cells induce proliferation of tumor cells and alter bone marrow to create a fertile environment for tumor growth. The dura therefore may play an important role in the increased incidence of metastases to adjacent bone.

Online postconcussion return-to-play instructions

OBJECTIVE The authors of recent concussion guidelines have sought to form a consensus on injury management, but it is unclear if they have been effective in conveying this information to the public. Many parents and athletes obtain medical recommendations via the Internet. This review is aimed at evaluating consistency between online resources and published guideline statements in postconcussion return-to-play (RTP) decisions. METHODS Five websites were selected through a Google search for RTP after concussion, including a federal government institution (Centers for Disease Control and Prevention) website, a national high school association (National Federation of State High School Associations) website, a popular nationally recognized medical website for patients (WebMD), a popular parent-driven website for parents of children who participate in sports (MomsTeam), and the website of a private concussion clinic (Sports Concussion Institute), along with a university hospital website (University of Michigan Medicine). Eight specific items from the Zurich Sport Concussion Consensus Statement 2012 were used as the gold standard for RTP recommendations. Three independent reviewers graded each website for each of the 8 recommendations (A = states guideline recommendations appropriately; B = mentions guideline recommendation; C = does not mention guideline recommendation; F = makes inappropriate recommendation). RESULTS A grade of A was assigned for 45.8% of the recommendations, B for 25.0%, C for 25.0%, and F for 4.2%. All the websites were assigned an A grade for the recommendation of no RTP on the day of injury. Only 1 website (WebMD) mentioned medication usage in conjunction with the Zurich statement, and only 2 websites (Sports Concussion Institute and University of Michigan Medicine) mentioned appropriate management of persistent symptoms. None of these websites commented correctly on all 8 guideline recommendations. CONCLUSIONS Online resources are inconsistent in relaying guideline recommendations for RTP and provide a potential source of confusion in the management of concussion for athletes and their parents, which can result in inappropriate RTP decisions.

Anatomic and functional imaging in the diagnosis of spine metastases and response assessment after spine radiosurgery

Spine stereotactic radiosurgery (SSRS) has recently emerged as an increasingly effective treatment for spinal metastases. Studies performed over the past decade have examined the role of imaging in the diagnosis of metastases, as well as treatment response following SSRS. In this paper, the authors describe and review the utility of several imaging modalities in the diagnosis of spinal metastases and monitoring of their response to SSRS. Specifically, we review the role of CT, MRI, and positron emission tomography (PET) in their ability to differentiate between osteoblastic and osteolytic lesions, delineation of initial bony pathology, detection of treatment-related changes in bone density and vertebral compression fracture after SSRS, and tumor response to therapy. Validated consensus guidelines defining the imaging approach to SSRS are needed to standardize the diagnosis and treatment response assessment after SSRS. Future directions of spinal imaging, including advances in targeted tumor-specific molecular imaging markers demonstrate early promise for advancing the role of imaging in SSRS.