David S. Hersh

Evolving Drug Delivery Strategies to Overcome the Blood Brain Barrier.

The blood-brain barrier (BBB) poses a unique challenge for drug delivery to the central nervous system (CNS). The BBB consists of a continuous layer of specialized endothelial cells linked together by tight junctions, pericytes, nonfenestrated basal lamina, and astrocytic foot processes. This complex barrier controls and limits the systemic delivery of therapeutics to the CNS. Several innovative strategies have been explored to enhance the transport of therapeutics across the BBB, each with individual advantages and disadvantages. Ongoing advances in delivery approaches that overcome the BBB are enabling more effective therapies for CNS diseases. In this review, we discuss: (1) the physiological properties of the BBB, (2) conventional strategies to enhance paracellular and transcellular transport through the BBB, (3) emerging concepts to overcome the BBB, and (4) alternative CNS drug delivery strategies that bypass the BBB entirely. Based on these exciting advances, we anticipate that in the near future, drug delivery research efforts will lead to more effective therapeutic interventions for diseases of the CNS.

Emerging Applications of Therapeutic Ultrasound in Neuro-oncology: Moving Beyond Tumor Ablation.

: Transcranial focused ultrasound (FUS) can noninvasively transmit acoustic energy with a high degree of accuracy and safety to targets and regions within the brain. Technological advances, including phased-array transducers and real-time temperature monitoring with magnetic resonance thermometry, have created new opportunities for FUS research and clinical translation. Neuro-oncology, in particular, has become a major area of interest because FUS offers a multifaceted approach to the treatment of brain tumors. FUS has the potential to generate cytotoxicity within tumor tissue, both directly via thermal ablation and indirectly through radiosensitization and sonodynamic therapy; to enhance the delivery of therapeutic agents to brain tumors by transiently opening the blood-brain barrier or improving distribution through the brain extracellular space; and to modulate the tumor microenvironment to generate an immune response. In this review, we describe each of these applications for FUS, the proposed mechanisms of action, and the preclinical and clinical studies that have set the foundation for using FUS in neuro-oncology. ABBREVIATIONS BBB, blood-brain barrierCED, convection-enhanced delivery5-Ala, 5-aminolevulinic acidFUS, focused ultrasoundGBM, glioblastoma multiformeHSP, heat shock proteinMRgFUS, magnetic resonance-guided focused ultrasoundpFUS, pulsed focused ultrasound.

Predictors of intramedullary lesion expansion rate on MR images of patients with subaxial spinal cord injury

OBJECT Studies of preclinical spinal cord injury (SCI) in rodents indicate that expansion of intramedullary lesions (IMLs) seen on MR images may be amenable to neuroprotection. In patients with subaxial SCI and motor-complete American Spinal Injury Association (ASIA) Impairment Scale (AIS) Grade A or B, IML expansion has been shown to be approximately 900 μm/hour. In this study, the authors investigated IML expansion in a cohort of patients with subaxial SCI and AIS Grade A, B, C, or D. METHODS Seventy-eight patients who had at least 2 MRI scans within 6 days of SCI were enrolled. Data were analyzed by regression analysis. RESULTS In this cohort, the mean age was 45.3 years (SD 18.3 years), 73 patients were injured in a motor vehicle crash, from a fall, or in sport activities, and 77% of them were men. The mean Injury Severity Score (ISS) was 26.7 (SD 16.7), and the AIS grade was A in 23 patients, B in 7, C in 7, and D in 41. The mechanism of injury was distraction in 26 patients, compression in 22, disc/osteophyte complex in 29, and Chance fracture in 1. The mean time between injury onset and the first MRI scan (Interval 1) was 10 hours (SD 8.7 hours), and the mean time to the second MRI scan (Interval 2) was 60 hours (SD 29.6 hours). The mean IML lengths of the first and second MR images were 38.8 mm (SD 20.4 mm) and 51 mm (SD 36.5 mm), respectively. The mean time from the first to the second MRI scan (Interval 3) was 49.9 hours (SD 28.4 hours), and the difference in IML lengths was 12.6 mm (SD 20.7 mm), reflecting an expansion rate of 366 μm/ hour (SD 710 μm/hour). IML expansion in patients with AIS Grades A and B was 918 μm/hour (SD 828 μm/hour), and for those with AIS Grades C and D, it was 21 μm/hour (SD 304 μm/hour). Univariate analysis indicated that AIS Grade A or B versus Grades C or D (p < 0.0001), traction (p= 0.0005), injury morphology (p < 0.005), the surgical approach (p= 0.009), vertebral artery injury (p= 0.02), age (p < 0.05), ISS (p < 0.05), ASIA motor score (p < 0.05), and time to decompression (p < 0.05) were all predictors of lesion expansion. In multiple regression analysis, however, the sole determinant of IML expansion was AIS grade (p < 0.005). CONCLUSIONS After traumatic subaxial cervical spine or spinal cord injury, patients with motor-complete injury (AIS Grade A or B) had a significantly higher rate of IML expansion than those with motor-incomplete injury (AIS Grade C or D).

Pulsed ultrasound expands the extracellular and perivascular spaces of the brain.

Diffusion within the extracellular and perivascular spaces of the brain plays an important role in biological processes, therapeutic delivery, and clearance mechanisms within the central nervous system. Recently, ultrasound has been used to enhance the dispersion of locally administered molecules and particles within the brain, but ultrasound-mediated effects on the brain parenchyma remain poorly understood. We combined an electron microscopy-based ultrastructural analysis with high-resolution tracking of non-adhesive nanoparticles in order to probe changes in the extracellular and perivascular spaces of the brain following a non-destructive pulsed ultrasound regimen known to alter diffusivity in other tissues. Freshly obtained rat brain neocortical slices underwent sham treatment or pulsed, low intensity ultrasound for 5min at 1MHz. Transmission electron microscopy revealed intact cells and blood vessels and evidence of enlarged spaces, particularly adjacent to blood vessels, in ultrasound-treated brain slices. Additionally, ultrasound significantly increased the diffusion rate of 100nm, 200nm, and 500nm nanoparticles that were injected into the brain slices, while 2000nm particles were unaffected. In ultrasound-treated slices, 91.6% of the 100nm particles, 20.7% of the 200nm particles, 13.8% of the 500nm particles, and 0% of the 2000nm particles exhibited diffusive motion. Thus, pulsed ultrasound can have meaningful structural effects on the brain extracellular and perivascular spaces without evidence of tissue disruption.

Intramedullary Lesion Length on Postoperative Magnetic Resonance Imaging is a Strong Predictor of ASIA Impairment Scale Grade Conversion Following Decompressive Surgery in Cervical Spinal Cord Injury

BACKGROUND Evidence indicates that, over time, patients with spinal cord injury (SCI) improve neurologically in various degrees. We sought to further investigate indicators of grade conversion in cervical SCI. OBJECTIVE To detect predictors of ASIA impairment scale (AIS) grade conversion in SCI following surgical decompression. METHODS In a retrospective study, demographics, clinical, imaging, and surgical data from 100 consecutive patients were assessed for predictors of AIS grade conversion. RESULTS American Spinal Injury Association motor score was 17.1. AIS grade was A in 52%, B in 29%, and C in 19% of patients. Surgical decompression took place on an average of 17.6 h following trauma (≤12 h in 51 and >12 h in 49). Complete decompression was verified by magnetic resonance imaging (MRI) in 73 patients. Intramedullary lesion length (IMLL) on postoperative MRI measured 72.8 mm, and hemorrhage at the injury epicenter was noted in 71 patients. Grade conversion took place in 26.9% of AIS grade A patients, 65.5% of AIS grade B, and 78.9% of AIS grade C. AIS grade conversion had statistical relationship with injury severity score, admission AIS grade, extent of decompression, presence of intramedullary hemorrhage, American Spinal Injury Association motor score, and IMLL. A stepwise multiple logistic regression analysis indicated IMLL was the sole and strongest indicator of AIS grade conversion (odds ratio 0.950, 95% CI 0.931-0.969). For 1- and 10-mm increases in IMLL, the model indicates 4% and 40% decreases, respectively, in the odds of AIS grade conversion. CONCLUSION Compared with other surrogates, IMLL remained as the only predictor of AIS grade conversion.

175 Safety of Anticoagulation for the Treatment of Cerebral Venous Sinus Thrombosis in Adult Trauma Patients.

INTRODUCTION Cerebral venous sinus thrombosis (CVST) is a potentially devastating neurological outcome of closed head trauma. Current guidelines recommend anticoagulation in adults with spontaneous CVST. Although intracranial hemorrhage resulting from a sinus thrombosis is not considered a contraindication to treatment, less is known regarding the treatment of CVST in patients with acute traumatic brain injury, who often have intracranial hemorrhages unrelated to the thrombosis. METHODS A prospectively collected database at a level 1 trauma center was retrospectively reviewed. Demographic, clinical, radiographic, and follow-up data were collected for adult patients with one or more skull fractures in the setting of blunt trauma who underwent venous imaging. Patients admitted from January 2004 through December 2013 were included. RESULTS Of 541 patients with skull fractures, 113 (21%) patients underwent venous imaging to assess the patency of the venous sinuses. Fifty-six (49%) of these patients had no evidence of venous sinus injury, whereas 38 (34%) were found to have a CVST, and an additional 19 (17%) had external compression of a sinus by an extra-axial hemorrhage. Of the 38 patients with CVST, 22 (58%) patients were treated with anticoagulation. The mean duration of anticoagulation was 3.35 months (range 0.07-8.57 months). The thrombosis resolved by 3 months in 11 (50%) patients, and was stable at 6 months in 3 (14%) patients. Three (14%) patients developed minor complications (eg, gastrointestinal bleeding), whereas an additional 3 (14%) patients developed new or worsening intracranial hemorrhage, resulting in 1 mortality. CONCLUSION Skull fractures resulting from blunt trauma should prompt a high index of suspicion for underlying venous sinus pathology. However, it is important to distinguish between intrinsic CVST and external sinus compression by an extra-axial hemorrhage. In cases of CVST, patients on anticoagulation must be monitored closely and undergo repeat imaging to rule out new or worsening intracranial hemorrhage.INTRODUCTION:Cerebral venous sinus thrombosis (CVST) is a potentially devastating neurological outcome of closed head trauma. Current guidelines recommend anticoagulation in adults with spontaneous CVST. Although intracranial hemorrhage resulting from a sinus thrombosis is not considered a contraind

Differential expression of the TWEAK receptor Fn14 in IDH1 wild-type and mutant gliomas

The TNF receptor superfamily member Fn14 is overexpressed by many solid tumor types, including glioblastoma (GBM), the most common and lethal form of adult brain cancer. GBM is notable for a highly infiltrative growth pattern and several groups have reported that high Fn14 expression levels can increase tumor cell invasiveness. We reported previously that the mesenchymal and proneural GBM transcriptomic subtypes expressed the highest and lowest levels of Fn14 mRNA, respectively. Given the recent histopathological re-classification of human gliomas by the World Health Organization based on isocitrate dehydrogenase 1 (IDH1) gene mutation status, we extended this work by comparing Fn14 gene expression in IDH1 wild-type (WT) and mutant (R132H) gliomas and in cell lines engineered to overexpress the IDH1 R132H enzyme. We found that both low-grade and high-grade (i.e., GBM) IDH1 R132H gliomas exhibit low Fn14 mRNA and protein levels compared to IDH1 WT gliomas. Forced overexpression of the IDH1 R132H protein in glioma cells reduced Fn14 expression, while treatment of IDH1 R132H-overexpressing cells with the IDH1 R132H inhibitor AGI-5198 or the DNA demethylating agent 5-aza-2′-deoxycytidine increased Fn14 expression. These results support a role for Fn14 in the more aggressive and invasive phenotype associated with IDH1 WT tumors and indicate that the low levels of Fn14 gene expression noted in IDH1 R132H mutant gliomas may be due to epigenetic regulation via changes in DNA methylation.

Pulsed focused ultrasound effects on the brain interstitium

The ability to generate changes in the interstitial components of various tissues has a host of potential clinical applications. These include enhancing the delivery of drugs and genes, increasing oxygenation and blood flow for radiosensitization, altering fluid and pressure dynamics in the setting of inflammation, and increasing the clearance of detrimental factors such as amyloid plaques in the brain of patients with Alzheimers disease. Our previous studies have shown how pulsed focused ultrasound (pFUS) can enhance the delivery of various chemotherapeutic agents in solid tumor models for reduced growth rates and improved survival. More recently we showed how pulsed ultrasound exposures can safely enlarge both the extracellular and perivascular spaces in an ex vivo brain model. The goal of the current study was to determine whether these effects could be reproduced noninvasively in the living brain.

Pediatric cerebral venous sinus thrombosis or compression in the setting of skull fractures from blunt head trauma

OBJECTIVE Pediatric cerebral venous sinus thrombosis has been previously described in the setting of blunt head trauma; however, the population demographics, risk factors for thrombosis, and the risks and benefits of detection and treatment in this patient population are poorly defined. Furthermore, few reports differentiate between different forms of sinus pathology. A series of pediatric patients with skull fractures who underwent venous imaging and were diagnosed with intrinsic cerebral venous sinus thrombosis or extrinsic sinus compression is presented. METHODS The medical records of patients at 2 pediatric trauma centers were retrospectively reviewed. Patients who were evaluated for blunt head trauma from January 2003 to December 2013, diagnosed with a skull fracture, and underwent venous imaging were included. RESULTS Of 2224 pediatric patients with skull fractures following blunt trauma, 41 patients (2%) underwent venous imaging. Of these, 8 patients (20%) had intrinsic sinus thrombosis and 14 patients (34%) displayed extrinsic compression of a venous sinus. Three patients with intrinsic sinus thrombosis developed venous infarcts, and 2 of these patients were treated with anticoagulation. One patient with extrinsic sinus compression by a depressed skull fracture underwent surgical elevation of the fracture. All patients with sinus pathology were discharged to home or inpatient rehabilitation. Among patients who underwent follow-up imaging, the sinus pathology had resolved by 6 months postinjury in 80% of patients with intrinsic thrombosis as well as 80% of patients with extrinsic compression. All patients with intrinsic thrombosis or extrinsic compression had a Glasgow Outcome Scale score of 4 or 5 at their last follow-up. CONCLUSIONS In this series of pediatric trauma patients who underwent venous imaging for suspected thrombosis, the yield of detecting intrinsic thrombosis and/or extrinsic compression of a venous sinus was high. However, few patients developed venous hypertension or infarction and were subsequently treated with anticoagulation or surgical decompression of the sinus. Most had spontaneous resolution and good neurological outcomes without treatment. Therefore, in the setting of pediatric skull fractures after blunt injury, venous imaging is recommended when venous hypertension or infarction is suspected and anticoagulation is being considered. However, there is little indication for pervasive venous imaging after pediatric skull fractures, especially in light of the potential risks of CT venography or MR venography in the pediatric population and the unclear benefits of anticoagulation.

Symptomatic Acute-on-Chronic Subdural Hematoma: A Clinicopathological Study.

Abstract The pathophysiology of acute-on-chronic subdural hematoma (ACSDH) is complex and incompletely understood. Evidence to date indicates that the overall process is initiated by rotational force with movement of the brain inside the skull, which exerts tensile strain and rupture of bridging veins, leading in turn to acute hemorrhage in the subdural potential space. This is followed by the proliferation of mesenchymal elements with angiogenesis and inflammation, which in turn becomes a substrate for repeated hemorrhage and expansion of the lesion. Given the prevalence of traumatic subdural processes in the forensic setting and the importance of proper assessment of timing, etiology, risk factors, and clinicopathological correlation, we studied 47 patients presenting to the University of Maryland Shock Trauma Center, all of whom underwent craniotomy with resection of the outer membrane due to symptomatic ACSDH. The surgically resected tissue was examined for histopathologic features in all cases. Our findings highlight that ACSDH is a condition precipitated by trauma that affects middle-aged and older adults, is relatively indolent, is unilateral or asymmetric, and has a low in-hospital mortality rate. Pathological analysis demonstrates a substantial outer membrane in all cases with varying degrees of inflammation and organization that cannot be precisely dated as a function of clinical presentation. The extrapolation of adult ACSDH to mixed acute and chronic subdural hemorrhage in the pediatric setting is problematic due to substantial differences in clinical presentation, severity of underlying brain injury, gross and microscopic findings, and outcome.