Large-Volume Intrathecal Administrations: Impact on CSF Pressure and Safety Implications.

The increasing number of studies demonstrates the high potency of the intrathecal (IT) route for the delivery of biopharmaceuticals to the central nervous system (CNS). Our earlier data exhibited that both the infused volume and the infusion rate can regulate the initial disposition of the administered solute within the cerebrospinal fluid (CSF). This disposition is one of key factors in defining the subsequent transport of the solute to its intended target. On the other hand, fast additions of large volumes of liquid to the CSF inevitably raise the CSF pressure [a.k.a. intracranial pressure (ICP)], which may in turn lead to adverse reactions if the physiologically delimited threshold is exceeded. While long-term biological effects of elevated ICP (hydrocephalus) are known, the safety thresholds pertaining to short-term ICP elevations caused by IT administrations have not yet been characterized. This study aimed to investigate the dynamics of ICP in rats and non-human primates (NHPs) with respect to IT infusion rates and volumes. The safety regimes were estimated and analyzed across species to facilitate the development of translational large-volume IT therapies. The data revealed that the addition of a liquid to the CSF raised the ICP in a rate and volume-dependent manner. At low infusion rates (<0.12 ml/min in rats and <2 ml/min in NHPs), NHPs and rats displayed similar tolerance patterns. Specifically, safe accommodations of such added volumes were mainly facilitated by the accelerated pressure-dependent CSF drainage into the blood, with I stabilizing at different levels below the safety threshold of 28 ± 4 mm Hg in rats and 50 ± 5 mm Hg in NHPs. These ICPs were safely tolerated for extended durations (of at least 2-25 min). High infusion rates (including boluses) caused uncompensated exponential ICP elevations rapidly exceeding the safety thresholds. Their tolerance was species-dependent and was facilitated by the compensatory role of the varied components of craniospinal compliance while not excluding the possibility of other contributing factors. In conclusion, large volumes of liquids can safely be delivered via IT routes provided that ICP is monitored as a safety factor and cross-species physiological differences are accounted for.

Cerebrospinal Fluid Leaks and Pseudomeningocele after Posterior Fossa Surgery: Effect of an Autospray Dural Sealant.

Background Posterior fossa craniotomies can be complicated by cerebrospinal fluid (CSF) leaks, infection, meningitis, neurologic deficits, and intracranial hypotension caused by defective closure of the dura. Secondary dural closures such as pericranial graft, muscle graft, glue, sealants, or fat graft are used. However, there have been few studies examining the use of sealants with a polyethylene glycol and polyethylenimine component. Objective We studied the effect of one such sealant, Adherus® (HyperBranch Medical Technology, Durham, NC, USA), as an adjunct to secondary closure methods in the reduction of the use of abdominal fat grafting and lumbar puncture/drains. Methods We retrospectively reviewed the surgical records of all patients undergoing posterior fossa cranial surgery during a two-year period at a tertiary university affiliated medical center. Results Overall, data a total of 122 patients (62 in the no Adherus and 60 in the Adherus group) were collected. There was no statistically significant difference in the 30-day incisional CSF leak rate (4.1% vs. 6.5%; p=0.183), 30-day non-incisional CSF leak rate (11.3% vs. 5.0%; p=0.205), and 30-day pseudomeningocele rate (16.1% vs. 13.3%; p=0.663) in the no Adherus and Adherus groups, respectively. However, there was a significant reduction in the use of abdominal fat grafting (0% vs. 30.7%; p<0.001) and intraoperative CSF diversion techniques (58.1% vs. 23.3%; p<0.001). Every instance of the use of Adherus saved on average, $809.36. Conclusions A statistically significant reduction in the use of CSF shunting procedures during posterior fossa craniotomy/craniectomy was achieved after the introduction of Adherus with no increase in CSF leak rate.

Long-Term Clinical and Neuronuclear Imaging Sequelae of Cancer Therapy, Trauma, and Brain Injury.

Neuronuclear imaging has been used for several decades in the study of primary neurodegenerative conditions, such as dementia and parkinsonian syndromes, both for research and for clinical purposes. There has been a relative paucity of applications of neuronuclear imaging to evaluate nonneurodegenerative conditions that can also have long-term effects on cognition and function. This article summarizes clinical and imaging aspects of 3 such conditions that have garnered considerable attention in recent years: cancer- and chemotherapy-related cognitive impairment, posttraumatic stress disorder, and traumatic brain injury. Further, we describe current research using neuroimaging tools aimed to better understand the relationships between the clinical presentations and brain structure and function in these conditions.

The Configuration of the Perivascular System Transporting Macromolecules in the CNS.

Large blood vessels entering the CNS are surrounded by perivascular spaces that communicate with the cerebrospinal fluid and, at their termini, with the interstitial space. Solutes and particles can translocate along these perivascular conduits, reportedly in both directions. Recently, this prompted a renewed interest in the intrathecal therapy delivery route for CNS-targeted therapeutics. However, the extent of the CNS coverage by the perivascular system is unknown, making the outcome of drug administration to the CSF uncertain. We traced the translocation of model macromolecules from the CSF into the CNS of rats and non-human primates. Conduits transporting macromolecules were found to extend throughout the parenchyma from both external and internal (fissures) CNS boundaries, excluding ventricles, in large numbers, on average ca. 40 channels per mm2 in rats and non-human primates. The high density and depth of extension of the perivascular channels suggest that the perivascular route can be suitable for delivery of therapeutics to parenchymal targets throughout the CNS.

The effect of an organ procurement experience on preclinical medical student perceptions of transplant surgery.

Transplant surgery is a predominantly male specialty with high burnout rates. There are currently limited data regarding how programs can attract a diverse applicant pool to the field of transplant surgery. This study evaluated the effect of an Organ Procurement Experience elective on preclinical medical students' perceptions of transplant surgery in a prospective, longitudinal study. Preclinical medical students were anonymously surveyed before and after attending a deceased donor organ procurement. Questions focused on the following themes: Personal Beliefs, Personal/Professional Life, Diversity, and Gender Equality. Responses were rated on a five-point Likert scale. Ninety-nine and 45 students completed pre/post-procurement survey, respectively. Post-procurement responses demonstrated increased education about the field (2.1/5 vs 3.89/5, P < 0.001) and perceptions of the personalities and collegiality between surgeons (3.06/5 vs 3.73/5, P = 0.005). Post-procurement, women were less likely to feel that female transplant surgeons are treated differently (3.98/5 vs. 3.45/5, P < 0.017). Post-procurement, 19% agreed that transplant surgeons have a high quality of life. One percent of respondents felt the current gender distribution in transplant surgery is satisfactory. The Organ Procurement Experience significantly improved preclinical students' perceptions of the field. However, there remains a strong concern about quality of life and gender diversity within the field.

Prognostic factors and survival in low grade gliomas of the spinal cord: A population-based analysis from 2006 to 2012.

PURPOSE: Primary spinal cord tumors are rare, and evidence-based management of these patients remains a source of controversy. This study used a large cohort of low-grade spinal cord astrocytomas to determine the effectiveness of prognostic factors and survival. METHODS: The Surveillance, Epidemiology, and End Results (SEER) cancer registry was used to identify patients with WHO grade I-II primary spinal cord astrocytomas from 1973 to 2012; however, patients before 2006 were excluded due to ambiguity diagnosis. Univariate and multivariate Cox proportional hazard models were created to compare survival across covariates and summarized using the Kaplan-Meier method. RESULTS: A total of 561 patients with low-grade glioma (astrocytoma) were identified. Among these, 15.5% of patients received a gross total resection (GTR), 26.1% subtotal resection (STR), and 46.2% unidentified extent of resection. 59.4% did not receive any radiation therapy at any point of the treatment course, while 40.6% underwent radiation therapy. In our cohort, only patients with GTR demonstrated statistically improved survival (HR: 0.22, P < 0.001). Patients with STR had nearly identical survival compared to patients with no surgery (HR: 0.98), and radiotherapy was associated with increased odds of mortality (HR: 1.47, P < 0.001). Multivariate analysis demonstrated a significant survival benefit among patients with younger age, GTR and absence of radiotherapy. Histologic grade did not statistically impact survival. CONCLUSION: Our study suggests that GTR results in improved survival among patients with low-grade gliomas within the spinal cord. Future, considerable data research efforts will aim to better define the role of radiotherapy and tumor grading in this patient population.

Emergent Neurosurgical Management of a Rapidly Deteriorating Patient with Acute Intracranial Hemorrhage and Alcohol-Related Thrombocytopenia.

Alcohol intoxication is a common risk factor of traumatic brain injury (TBI) and carries a significant health-care burden on underserved patients. Patients with chronic alcohol use may suffer a spectrum of bleeding diatheses from hepatic dysfunction not well studied in the context of TBI. A feared sequela of TBI is the development of coagulopathy resulting in worsened intracranial bleeding. We report the clinical course of an intoxicated patient found down with blunt head trauma and concurrent alcoholic cirrhosis who was awake and responsive in the field. Hospital course was characterized by a rapidly deteriorating neurological examination with progressive subdural and subarachnoid hemorrhage and precipitating neurosurgical decompression and critical care management. Our experience dictates the need for timely consideration of the possibility of rapid deterioration from coagulopathic intracranial bleeding in the initial assessment of intoxicated patients with head trauma of unknown severity, for which a high index of suspicion for extra-axial hemorrhage should be maintained, along with the immediate availability of operating room and the necessary medical personnel.

Surgical management of camptocormia in Parkinson's disease: systematic review and meta-analysis.

OBJECTIVE: Camptocormia is a potentially debilitating condition in the progression of Parkinson's disease (PD). It is described as an abnormal forward flexion while standing that resolves when lying supine. Although the condition is relatively common, the underlying pathophysiology and optimal treatment strategy are unclear. In this study, the authors systematically reviewed the current surgical management strategies for camptocormia. METHODS: PubMed was queried for primary studies involving surgical intervention for camptocormia in PD patients. Studies were excluded if they described nonsurgical interventions, provided only descriptive data, or were case reports. Secondarily, data from studies describing deep brain stimulation (DBS) to the subthalamic nuclei were extracted for potential meta-analysis. Variables showing correlation to improvement in sagittal plane bending angle (i.e., the vertical angle caused by excessive kyphosis) were subjected to formal meta-analysis. RESULTS: The query resulted in 9 studies detailing treatment of camptocormia: 1 study described repetitive trans-spinal magnetic stimulation (rTSMS), 7 studies described DBS, and 1 study described deformity surgery. Five studies were included for meta-analysis. The total number of patients was 66. The percentage of patients with over 50% decrease in sagittal plane imbalance with DBS was 36.4%. A duration of camptocormia of 2 years or less was predictive of better outcomes (OR 4.15). CONCLUSIONS: Surgical options include transient, external spinal stimulation; DBS targeting the subthalamic nuclei; and spinal deformity surgery. Benefit from DBS stimulation was inconsistent. Spine surgery corrected spinal imbalance but was associated with a high complication rate.