Consensus Review on Strategies to Improve Delivery Across the BBB Including Focused Ultrasound.

Drug delivery to the central nervous system (CNS) has been a major challenge for CNS tumors due to the impermeability of the blood brain barrier (BBB). There have been a multitude of techniques aimed at overcoming the BBB obstacle aimed at utilizing natural transport mechanisms or bypassing the BBB which we review here. Another approach that has generated recent interest in the recently published literature is to use new technologies (Laser Interstitial Thermal Therapy, LITT; or Low Intensity Focused Ultrasound, LIFU) to temporarily increase BBB permeability. This review overviews the advantages, disadvantages, and major advances of each method. LIFU has been a major area of research to allow for chemotherapeutics to cross the BBB which has a particular emphasis in this review. While most of the advances remain in animal studies, there are an increasing number of translational clinical trials which will have results in the next few years.

Advances in computational and translational approaches for malignant glioma.

Gliomas are the most common primary brain tumors in adults and carry a dismal prognosis for patients. Current standard-of-care for gliomas is comprised of maximal safe surgical resection following by a combination of chemotherapy and radiation therapy depending on the grade and type of tumor. Despite decades of research efforts directed towards identifying effective therapies, curative treatments have been largely elusive in the majority of cases. The development and refinement of novel methodologies over recent years that integrate computational techniques with translational paradigms have begun to shed light on features of glioma, previously difficult to study. These methodologies have enabled a number of point-of-care approaches that can provide real-time, patient-specific and tumor-specific diagnostics that may guide the selection and development of therapies including decision-making surrounding surgical resection. Novel methodologies have also demonstrated utility in characterizing glioma-brain network dynamics and in turn early investigations into glioma plasticity and influence on surgical planning at a systems level. Similarly, application of such techniques in the laboratory setting have enhanced the ability to accurately model glioma disease processes and interrogate mechanisms of resistance to therapy. In this review, we highlight representative trends in the integration of computational methodologies including artificial intelligence and modeling with translational approaches in the study and treatment of malignant gliomas both at the point-of-care and outside the operative theater in silico as well as in the laboratory setting.

Is a Video Worth a Thousand Words? Educating Preclinical Medical Students on Sterile Scrubbing, Gowning, and Gloving Virtually and In-Person.

INTRODUCTION: Programs that offer early exposure to surgery for medical students foster interest in and positive perceptions of surgery. The COVID-19 pandemic led to suspension of these activities at our institution, the University of Kansas School of Medicine. In response to the lack of virtual alternatives, a pilot virtual surgery enrichment program was implemented for first-year students in place of in-person surgical exposure. The aim of this study was to compare the efficacy of in-person and virtual-based surgical education programs to expose preclinical medical students about the surgical realm of medicine. METHODS: First-year medical students participated in either a virtual (Group A) or in-person (Group B) week-long surgical enrichment program. Group assignments were dictated by COVID restrictions on each of our three medical school campuses: Salina, Wichita, and Kansas City. Pre- and post-surveys with a 14-question multiple-choice assessment of surgical knowledge were distributed to participants. Paired Wilcoxon Signed Rank tests and Mann-Whitney-U tests were used for statistical analysis. RESULTS: There were 14 participants in Group A and 7 participants in Group B. Both groups improved significantly from pre- to post-assessment score. (Group A, p = 0.01; Group B, p = 0.04). There was no difference between groups in the magnitude of score improvement from pre- to post-assessment (p = 0.59). CONCLUSIONS: This pilot program demonstrated that virtual platforms can be a method to provide meaningful clinical experiences in surgery to preclinical medical students restricted from clinical activities. Further development of mentorship in virtual surgical programs and assessment of subjective experience is needed.

Intrathoracic migration of ventriculo-peritoneal shunt via Morgagni hernia.

We present the case of a 5-month-old patient presenting with pleural migration of ventriculo-peritoneal shunt catheter who returned 2 months later with respiratory distress. Ultimately, the diagnosis of a Morgagni hernia was made. This diagnosis, though rare, should be entertained in certain clinical settings.

Unrepaired decompressive craniectomy worsens motor performance in a rat traumatic brain injury model.

Decompressive craniectomy (DC) is often required to manage rising intracranial pressure after traumatic brain injury (TBI). Syndrome of the trephine (SoT) is a reversible neurologic condition that often occurs following DC as a result of the unrepaired skull. The purpose of the present study is to characterize neurological impairment following TBI in rats with an unrepaired craniectomy versus rats with a closed cranium. Long Evans male rats received a controlled cortical impact (CCI) over the caudal forelimb area (CFA) of the motor cortex. Immediately after CCI, rats received either a hemi-craniectomy (TBI Open Skull Group) or an immediate acrylic cranioplasty restoring cranial anatomy (TBI Closed Skull Group). Motor performance was assessed on a skilled reaching task on post-CCI weeks 1-4, 8, 12, and 16. Three weeks after the CCI injury, the TBI Closed Skull Group demonstrated improved motor performance compared to TBI Open Skull Group. The TBI Closed Skull Group continued to perform better than the TBI Open Skull Group throughout weeks 4, 8, 12 and 16. The protracted recovery of CFA motor performance demonstrated in rats with unrepaired skulls following TBI suggests this model may be beneficial for testing new therapeutic approaches to prevent SoT.

Manifestations of Apprehension and Anxiety in a Sprague Dawley Cranial Defect Model.

BACKGROUND: Syndrome of the trephined is a neurologic condition that commonly arises in patients who undergo craniectomy and have a prolonged cranial defect. Symptoms of this condition include headache, difficulties concentrating, diminished fine motor/dexterity skills, mood changes, and anxiety/apprehension. The authors hypothesize that an animal model demonstrating anxiety/apprehension in rats who undergo craniectomy is feasible utilizing standardized animal behavioral testing. METHODS: Sprague Dawley rats were the stratified to 1 of 2 groups for comparison of neurobehavioral outcomes. Group #1 (closed cranial group) had their cranial trephination immediately closed with acrylic to restore normal cranial anatomy and Group #2 (open cranial group) had their cranial trephination enlarged to represent a decompressive hemicraniectomy immediately. Anxiety/apprehension was studied using a standardized rodent open field test. Statistical comparison of differences among the 2 groups was performed. RESULTS: Ten rats were studied with 5 rats in each group. Standard rodent open field testing of anxiety demonstrated no difference among the 2 groups at 1 week. Rats in the "Open cranial group" demonstrated progressively more anxiety over the following 3-month period. Rats in the "Open cranial group" demonstrated increasing anxiety levels as compared with rats in the "Closed cranial group." At week 16, the "Open cranial group" anxiety levels were significantly greater than week 4 (t = 2.24, P = 0.04) demonstrating a significant linear trend over time (R = 0.99; P = 0.002). The "Closed cranial group" did not show this trend (R = 07; P = 0.74). CONCLUSION: Our study demonstrates that anxiety and apprehension are more prevalent in rats with an open, prolonged cranial defect in comparison to those with a closed cranium. This correlates with similar finds in humans with syndrome of the trephined.

Effects of distance and transport method on intervention and mortality in aneurysmal subarachnoid hemorrhage.

OBJECTIVE Most patients suffering from aneurysmal subarachnoid hemorrhage (aSAH) initially present to a hospital that lacks a neurosurgical unit. These patients require interhospital transfer (IHT) to tertiary facilities capable of multidisciplinary neurosurgical intervention. Yet, little is known about the effects of IHT on the outcomes of patients suffering from aSAH. In this study, the authors examined the effects of IHT and transport method on the timing of treatment, rebleed rates, and overall outcomes of patients who have experienced aSAH. METHODS A retrospective review of medical records identified all consecutive patients who presented with aSAH at an outside hospital and subsequently underwent IHT to a tertiary aneurysm care center and patients who initially presented directly to a tertiary aneurysm care facility between 2008 and 2015. Demographic, operative, radiological, hospital of initial evaluation, transfer method, and outcome data were retrospectively collected. RESULTS The authors identified 763 consecutive patients who were evaluated for aSAH at a tertiary aneurysm care facility either directly or following IHT. For patients who underwent IHT and after accounting for these patients' clinical variability and dichotomizing the patients into groups transferred less than 20 miles and more than 20 miles, the authors noted a significant increase in mortality rates: 7% (< 20 miles) and 18.8% (> 20 miles) (p = 0.004). The increased mortality rate was partially explained by an increased rate of initial presentation to an accredited stroke center in patients undergoing IHT of less than 20 miles (p = 0.000). The method of transport (ground or air ambulance) was found to have significant effect on the patients' outcomes as measured by the Glasgow Outcome Scale score (p = 0.021); patients who underwent ground transport demonstrated a higher likelihood of discharge to home (p = 0.004). The increased severity of presentation in the patient cohort undergoing IHT by air as defined by the Glasgow Coma Scale score, a need for an external ventricular drain, Hunt and Hess grade, and intubation status at presentation did not result in increased mortality when compared with the ground cohort (p = 0.074). In addition, there was an 8-hour increase in duration of time from admission to treatment for the air cohort as compared with the ground cohort (p = 0.054), indicating a potential for further improvement in the overall outcome of this patient group. CONCLUSIONS Aneurysmal SAH remains a challenging neurosurgical disease process requiring highly coordinated care in tertiary referral centers. In this study, the overall distance traveled and the transport method affected patient outcomes. The time from admission to treatment should continue to improve. Further analysis of IHT with a focus on patient monitoring and treatment during transport is warranted.

Utility of the intensive care unit in patients undergoing microvascular decompression: a multiinstitution comparative analysis.

OBJECTIVE Use of the ICU during admission to a hospital is associated with a significant portion of the total health care costs for that stay. Patients undergoing microvascular decompression (MVD) for cranial neuralgias are routinely admitted postoperatively to the ICU for monitoring. The primary purpose of this study was to compare complication rates of patients with and without a postoperative ICU stay following MVD. The secondary intents were to identify predictors of complications, to analyze variables of health care resource utilization, and to estimate the cost of postoperative management. METHODS The authors performed a retrospective comparative analysis of consecutive patients undergoing MVD at 2 institutions. A total of 199 patients without a postoperative ICU stay from Institution A and 119 patients with an ICU stay from Institution B were reviewed. Inclusion criteria included any adult (i.e., 18 years of age or older) undergoing MVD for trigeminal neuralgia, hemifacial spasm, glossopharyngeal neuralgia, or geniculate neuralgia. Patients with incomplete medical records were excluded. Medical comorbidities, intraoperative variables, complications, postoperative interventions, and variables indicating health care resource utilization were reviewed. RESULTS The study compared 190 patients without a postoperative ICU stay from Institution A with 90 patients with an ICU stay from Institution B. Seven patients without an ICU stay and 5 patients with an ICU stay experienced complications after surgery (p = 0.53). Multivariate analysis identified coronary artery disease to be a predictor of complications (p = 0.037, OR 6.23, 95% CI 1.12-34.63). Patients from Institution A without a postoperative ICU stay had a significantly shorter length of stay, by approximately 16 hours (p < 0.001), and received less postoperative imaging (p < 0.001, OR 14.39, 95% CI 7.75-26.74) and postoperative diagnostic testing (p < 0.001) than patients from Institution B with an ICU stay. Estimated cost savings in patients without an ICU stay and 1 less day of inpatient recovery was calculated as $1400 per patient. CONCLUSIONS Selective versus routine use of ICU care as well as postoperative imaging and diagnostic testing may be safe after MVD and can lead to a reduction in overall health care costs.

A Compact Blast-Induced Traumatic Brain Injury Model in Mice.

Blast-induced traumatic brain injury (bTBI) is a common injury on the battlefield and often results in permanent cognitive and neurological abnormalities. We report a novel compact device that creates graded bTBI in mice. The injury severity can be controlled by precise pressures that mimic Friedlander shockwave curves. The mouse head was stabilized with a head fixator, and the body was protected with a metal shield; shockwave durations were 3 to 4 milliseconds. Reflective shockwave peak readings at the position of the mouse head were 12 6 2.6 psi, 50 6 20.3 psi, and 100 6 33.1 psi at 100, 200, and 250 psi predetermined driver chamber pressures, respectively. The bTBIs of 250 psi caused 80% mortality, which decreased to 27% with the metal shield. Brain and lung damage depended on the shockwave duration and amplitude. Cognitive deficits were assessed using the Morris water maze, Y-maze, and open-field tests. Pathological changes in the brain included disruption of the blood-brain barrier, multifocal neuronal and axonal degeneration, and reactive gliosis assessed by Evans Blue dye extravasation, silver and Fluoro-Jade B staining, and glial fibrillary acidic protein immunohistochemistry, respectively. Behavioral and pathological changes were injury severity-dependent. This mouse bTBI model may be useful for investigating injury mechanisms and therapeutic strategies associated with bTBI.

Microsurgical ligation of spinal arteriovenous fistulae: techniques.

Spinal dural arteriovenous fistula (dAVF) is an acquired abnormal arterial-to-venous connection within the spinal dura with a wide range of clinical presentations and natural history. Spinal dAVF occurs when a radicular artery makes a direct anomalous shunt with a radicular vein within the dura of the nerve root sleeve. Spinal dAVFs are the most common vascular malformation of the spine. The authors present a patient who presented with sudden temporary lower extremity weakness secondary to an L-1 spinal dAVF. The details of microsurgical techniques to disconnect the fistula are discussed in this video. The video can be found here: http://youtu.be/F9Kiffs3s6A.

Semi-interpenetrating network of polyethylene glycol and photocrosslinkable chitosan as an in-situ-forming nerve adhesive.

An ideal adhesive for anastomosis of severed peripheral nerves should tolerate strains imposed on rejoined nerves. We use blends of photocrosslinkable 4-azidobenzoic acid-modified chitosan (Az-C) and polyethylene glycol (PEG) as a new in-situ-forming bioadhesive for anastomosing and stabilizing the injured nerves. Cryo-scanning electron microscopy suggests that the polymer blends form a semi-interpenetrating network (semi-IPN), where PEG interpenetrates the Az-C network and reinforces it. Az-C/PEG semi-IPN gels have higher storage moduli than Az-C gel alone and fibrin glue. Nerves anastomosed with an Az-C/PEG gel tolerate a higher force than those with fibrin glue prior to failure. A series of ex vivo and in vitro cell experiments indicate the Az-C/PEG gels are compatible with nerve tissues and cells. In addition, Az-C/PEG gels release PEG over a prolonged period, providing sustained delivery of PEG, a potential aid for nerve cell preservation through membrane fusion. Az-C/PEG semi-IPN gels are promising bioadhesives for repairing severed peripheral nerves not only because of their improved mechanical properties but also because of their therapeutic potential and tissue compatibility.

Rapidly photo-cross-linkable chitosan hydrogel for peripheral neurosurgeries.

Restoring continuity to severed peripheral nerves is crucial to regeneration and enables functional recovery. However, the two most common agents for coaptation, sutures and fibrin glues, have drawbacks such as inflammation, pathogenesis, and dehiscence. Chitosan-based adhesives are a promising alternative, reported to have good cytocompatibility and favorable immunogenicity. A photo-cross-linkable hydrogel based on chitosan is proposed as a new adhesive for peripheral nerve anastomosis. Two Az-chitosans were synthesized by conjugating 4-azidobenzoic acid with low (LMW, 15 kDa) and high (HMW, 50-190 kDa) molecular weight chitosans. These solutions formed a hydrogel in less than 1 min under UV light. The LMW Az-chitosan was more tightly cross-linked than the HMW variant, undergoing significantly less swelling and possessing a higher rheological storage modulus, and both Az-chitosan gels were stiffer than commercial fibrin glue. Severed nerves repaired by Az-chitosan adhesives tolerated longitudinal forces comparable or superior to fibrin glue. Adhesive exposure to intact nerves and neural cell culture showed both Az-chitosans to be nontoxic in the acute (minutes) and chronic (days) time frames. These results demonstrate that Az-chitosan hydrogels are cytocompatible and mechanically suitable for use as bioadhesives in peripheral neurosurgeries.