Contrast-Induced Encephalopathy and the Blood-Brain Barrier.

BACKGROUND: Contrast-induced encephalopathy (CIE) is an adverse event associated with diagnostic and therapeutic endovascular procedures. Decades of animal and human research support a mechanistic role for pathological blood-brain barrier dysfunction (BBBd). Here, we describe an institutional case series and review the literature supporting a mechanistic role for BBBd in CIE. METHODS: A literature review was conducted by searching MEDLINE, Web of Science, Embase, CINAHL and Cochrane databases from inception to January 31, 2022. We searched our institutional neurovascular database for cases of CIE following endovascular treatment of cerebrovascular disease during a 6-month period. Informed consent was obtained in all cases. RESULTS: Review of the literature revealed risk factors for BBBd and CIE, including microvascular disease, pathological neuroinflammation, severe procedural hypertension, iodinated contrast load and altered cerebral blood flow dynamics. In our institutional series, 6 of 52 (11.5%) of patients undergoing therapeutic neuroendovascular procedures developed CIE during the study period. Four patients were treated for ischemic stroke and two patients for recurrent cerebral aneurysms. Mechanical stenting or thrombectomy were utilized in all cases. CONCLUSION: In this institutional case series and literature review of animal and human data, we identified numerous shared risk factors for CIE and BBBd, including microvascular disease, increased procedure length, large contrast volumes, severe intraoperative hypertension and use of mechanical devices that may induce iatrogenic endothelial injury.

Memantine inhibits cortical spreading depolarization and improves neurovascular function following repetitive traumatic brain injury.

Cortical spreading depolarization (CSD) is a promising target for neuroprotective therapy in traumatic brain injury (TBI). We explored the effect of NMDA receptor antagonism on electrically triggered CSDs in healthy and brain-injured animals. Rats received either one moderate or four daily repetitive mild closed head impacts (rmTBI). Ninety-three animals underwent craniectomy with electrocorticographic (ECoG) and local blood flow monitoring. In brain-injured animals, ketamine or memantine inhibited CSDs in 44 to 88% and 50 to 67% of cases, respectively. Near-DC/AC-ECoG amplitude was reduced by 44 to 75% and 52 to 67%, and duration by 39 to 87% and 61 to 78%, respectively. Daily memantine significantly reduced spreading depression and oligemia following CSD. Animals (N = 31) were randomized to either memantine (10 mg/kg) or saline with daily neurobehavioral testing. Memantine-treated animals had higher neurological scores. We demonstrate that memantine improved neurovascular function following CSD in sham and brain-injured animals. Memantine also prevented neurological decline in a blinded, preclinical randomized rmTBI trial.

Mitochondrial dysfunction underlies impaired neurovascular coupling following traumatic brain injury.

Traumatic brain injury (TBI) involves an acute injury (primary damage), which may evolve in the hours to days after impact (secondary damage). Seizures and cortical spreading depolarization (CSD) are metabolically demanding processes that may worsen secondary brain injury. Metabolic stress has been associated with mitochondrial dysfunction, including impaired calcium homeostasis, reduced ATP production, and elevated ROS production. However, the association between mitochondrial impairment and vascular function after TBI is poorly understood. Here, we explored this association using a rodent closed head injury model. CSD is associated with neurobehavioral decline after TBI. Craniotomy was performed to elicit CSD via electrical stimulation or to induce seizures via 4-aminopyridine application. We measured vascular dysfunction following CSDs and seizures in TBI animals using laser doppler flowmetry. We observed a more profound reduction in local cortical blood flow in TBI animals compared to healthy controls. CSD resulted in mitochondrial dysfunction and pathological signs of increased oxidative stress adjacent to the vasculature. We explored these findings further using electron microscopy and found that TBI and CSDs resulted in vascular morphological changes and mitochondrial cristae damage in astrocytes, pericytes and endothelial cells. Overall, we provide evidence that CSDs induce mitochondrial dysfunction, impaired cortical blood flow, and neurobehavioral deficits in the setting of TBI.

Perception of frailty in spinal metastatic disease: international survey of the AO Spine community.

OBJECTIVE: Frailty has not been clearly defined in the context of spinal metastatic disease (SMD). Given this, the objective of this study was to better understand how members of the international AO Spine community conceptualize, define, and assess frailty in SMD. METHODS: The AO Spine Knowledge Forum Tumor conducted an international cross-sectional survey of the AO Spine community. The survey was developed using a modified Delphi technique and was designed to capture preoperative surrogate markers of frailty and relevant postoperative clinical outcomes in the context of SMD. Responses were ranked using weighted averages. Consensus was defined as ≥ 70% agreement among respondents. RESULTS: Results were analyzed for 359 respondents, with an 87% completion rate. Study participants represented 71 countries. In the clinical setting, most respondents informally assess frailty and cognition in patients with SMD by forming a general perception based on clinical condition and patient history. Consensus was attained among respondents regarding the association between 14 preoperative clinical variables and frailty. Severe comorbidities, extensive systemic disease burden, and poor performance status were most associated with frailty. Severe comorbidities associated with frailty included high-risk cardiopulmonary disease, renal failure, liver failure, and malnutrition. The most clinically relevant outcomes were major complications, neurological recovery, and change in performance status. CONCLUSIONS: The respondents recognized that frailty is important, but they most commonly evaluate it based on general clinical impressions rather than using existing frailty tools. The authors identified numerous preoperative surrogate markers of frailty and postoperative clinical outcomes that spine surgeons perceived as most relevant in this population.

Subarachnoid Hemorrhage, Delayed Cerebral Ischemia, and Milrinone Use in Canada.

INTRODUCTION: Delayed cerebral ischemia (DCI) is a complication of aneurysmal subarachnoid hemorrhage (aSAH) and is associated with significant morbidity and mortality. There is little high-quality evidence available to guide the management of DCI. The Canadian Neurosurgery Research Collaborative (CNRC) is comprised of resident physicians who are positioned to capture national, multi-site data. The objective of this study was to evaluate practice patterns of Canadian physicians regarding the management of aSAH and DCI. METHODS: We performed a cross-sectional survey of Canadian neurosurgeons, intensivists, and neurologists who manage aSAH. A 19-question electronic survey (Survey Monkey) was developed and validated by the CNRC following a DCI-related literature review (PubMed, Embase). The survey was distributed to members of the Canadian Neurosurgical Society and to Canadian members of the Neurocritical Care Society. Responses were analyzed using quantitative and qualitative methods. RESULTS: The response rate was 129/340 (38%). Agreement among respondents was limited to the need for intensive care unit admission, use of clinical and radiographic monitoring, and prophylaxis for the prevention of DCI. Several inconsistencies were identified. Indications for starting hyperdynamic therapy varied. There was discrepancy in the proportion of patients who felt to require IV milrinone, IA vasodilators, or physical angioplasty for treatment of DCI. Most respondents reported their facility does not utilize a standardized definition for DCI. CONCLUSION: DCI is an important clinical entity for which no homogeneity and standardization exists in management among Canadian practitioners. The CNRC calls for the development of national standards in the definition, identification, and treatment of DCI.

Work-up and Management of Asymptomatic Extracranial Traumatic Vertebral Artery Injury.

BACKGROUND: Non-penetrating head and neck trauma is associated with extracranial traumatic vertebral artery injury (eTVAI) in approximately 1-2% of cases. Most patients are initially asymptomatic but have an increased risk for delayed stroke and mortality. Limited evidence is available to guide the management of asymptomatic eTVAI. As such, we sought to investigate national practice patterns regarding screening, treatment, and follow-up domains. METHODS: A cross-sectional, electronic survey was distributed to members of the Canadian Neurosurgical Society and Canadian Spine Society. We presented two cases of asymptomatic eTVAI, stratified by injury mechanism, fracture type, and angiographic findings. Screening questions were answered prior to presentation of angiographic findings. Survey responses were analyzed using descriptive statistics. RESULTS: One hundred-eight of 232 (46%) participants, representing 20 academic institutions, completed the survey. Case 1: 78% of respondents would screen for eTVAI with computed topography angiography (CTA) (97%), immediately (88%). The majority of respondents (97%) would treat with aspirin (89%) for 3-6 months (46%). Respondents would follow up clinically (89%) or radiographically (75%), every 1-3 months. Case 2: 73% of respondents would screen with CTA (96%), immediately (88%). Most respondents (94%) would treat with aspirin (50%) for 3-6 months (35%). Thirty-six percent of respondents would utilize endovascular therapy. Respondents would follow up clinically (97%) or radiographically (89%), every 1-3 months. CONCLUSION: This survey of Canadian practice patterns highlights consistency in the approach to screening, treatment, and follow-up of asymptomatic eTVAI. These findings are relevant to neurosurgeons, spinal surgeons, stroke neurologists, and neuro-interventionalists.

A Canadian National Survey of the Neurosurgical Management of Intracranial Abscesses.

OBJECTIVE: Intracerebral abscess is a life-threatening condition for which there are no current, widely accepted neurosurgical management guidelines. The purpose of this study was to investigate Canadian practice patterns for the medical and surgical management of primary, recurrent, and multiple intracerebral abscesses. METHODS: A self-administered, cross-sectional, electronic survey was distributed to active staff and resident members of the Canadian Neurosurgical Society and Canadian Neurosurgery Research Collaborative. Responses between subgroups were analyzed using the Chi-square test. RESULTS: In total, 101 respondents (57.7%) completed the survey. The majority (60.0%) were staff neurosurgeons working in an academic, adult care setting (80%). We identified a consensus that abscesses >2.5 cm in diameter should be considered for surgical intervention. The majority of respondents were in favor of excising an intracerebral abscess over performing aspiration if located superficially in non-eloquent cortex (60.4%), located in the posterior fossa (65.4%), or causing mass effect leading to herniation (75.3%). The majority of respondents were in favor of reoperation for recurrent abscesses if measuring greater than 2.5 cm, associated with progressive neurological deterioration, the index operation was an aspiration and did not include resection of the abscess capsule, and if the recurrence occurred despite prior surgery combined with maximal antibiotic therapy. There was no consensus on the use of topical intraoperative antibiotics. CONCLUSION: This survey demonstrated heterogeneity in the medical and surgical management of primary, recurrent, and multiple brain abscesses among Canadian neurosurgery attending staff and residents.

Evaluating Instability in Degenerative Lumbar Spondylolisthesis: Objective Variables Versus Surgeon Impressions.

The subjective degenerative spondylolisthesis instability classification (S-DSIC) system attempts to define preoperative instability associated with degenerative lumbar spondylolisthesis (DLS). The system guides surgical decision-making based on numerous indicators of instability that surgeons subjectively assess and incorporate. A more objective classification is warranted in order to decrease variation among surgeons. In this study, our objectives included (1) proposing an objective version of the DSIC system (O-DSIC) based on the best available clinical and biomechanical data and (2) comparing subjective surgeon perceptions (S-DSIC) with an objective measure (O-DSIC) of instability related to DLS. Methods: In this multicenter cohort study, we prospectively enrolled 408 consecutive adult patients who received surgery for symptomatic DLS. Surgeons prospectively categorized preoperative instability using the existing S-DSIC system. Subsequently, an O-DSIC system was created. Variables selected for inclusion were assigned point values based on previously determined evidence quality. DSIC types were derived by point summation: 0 to 2 points was considered stable, Type I); 3 points, potentially unstable, Type II; and 4 to 5 points, unstable, Type III. Surgeons' subjective perceptions of instability (S-DSIC) were retrospectively compared with O-DSIC types. Results: The O-DSIC system includes 5 variables: presence of facet effusion, disc height preservation (≥6.5 mm), translation (≥4 mm), a kyphotic or neutral disc angle in flexion, and low back pain (≥5 of 10 intensity). Type I (n = 176, 57.0%) and Type II (n = 164, 53.0%) were the most common DSIC types according to the O-DSIC and S-DSIC systems, respectively. Surgeons categorized higher degrees of instability with the S-DSIC than the O-DSIC system in 130 patients (42%) (p < 0.001). The assignment of DSIC types was not influenced by demographic variables with either system. Conclusions: The O-DSIC system facilitates objective assessment of preoperative instability related to DLS. Surgeons assigned higher degrees of instability with the S-DSIC than the O-DSIC system in 42% of cases. Level of Evidence: Diagnostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Systemic considerations for the surgical treatment of spinal metastatic disease: a scoping literature review.

Systemic assessment is a pillar in the neurological, oncological, mechanical, and systemic (NOMS) decision-making framework for the treatment of patients with spinal metastatic disease. Despite this importance, emerging evidence relating systemic considerations to clinical outcomes following surgery for spinal metastatic disease has not been comprehensively summarised. We aimed to conduct a scoping literature review of this broad topic. We searched MEDLINE, Embase, Scopus, Cochrane Central Register of Controlled Trials, Web of Science, and CINAHL databases from Jan 1, 2000, to July 31, 2021. 61 articles were included, accounting for a total of 22 335 patients. Preoperative systemic variables negatively associated with postoperative clinical outcomes included demographics (eg, older age [>60 years], Black race, male sex, low or elevated body-mass index, and smoking status), medical comorbidities (eg, cardiac, pulmonary, hepatic, renal, endocrine, vascular, and rheumatological), biochemical abnormalities (eg, hypoalbuminaemia, atypical blood cell counts, and elevated C-reactive protein concentration), low muscle mass, generalised motor weakness (American Spinal Cord Injury Association Impairment Scale grade and Frankel grade) and poor ambulation, reduced performance status, and systemic disease burden. This is the first comprehensive scoping review to broadly summarise emerging evidence relevant to the systemic assessment component of the widely used NOMS framework for spinal metastatic disease decision making. Medical, surgical, and radiation oncologists can consider these findings when prognosticating spinal metastatic disease-related surgical outcomes on the basis of patients' systemic condition. These factors might inform a shared decision-making approach with patients and their families.

Modic Change and Clinical Assessment Scores in Patients Undergoing Lumbar Surgery for Disk Herniation.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To examine the relationship between preoperative Modic change (MC) and postoperative clinical assessment scores for patients receiving lumbar discectomy or transforaminal lumbar interbody fusion for lumbar disk herniation. SUMMARY OF BACKGROUND DATA: Lumbar disk herniation is a risk factor for MC development. MC on spinal magnetic resonance imaging (MRI) has been associated with worse preoperative and postoperative clinical assessment scores. MATERIALS AND METHODS: We reviewed data for 285 primary single-level surgeries. Preoperative and 12-month postoperative assessment scores were recorded using the visual analog scale leg pain, Oswestry Disability Index, and Short Form-36 Physical Component Summary. MC subgroup on preoperative MRI was recorded by a single neuroradiologist. RESULTS: One hundred seventy-nine patients (female, 56%; age-53±13 y) with preoperative MRI were included. Age and sex were similar across MC subgroups. The sample prevalence of MC on preoperative MRI was 62%, and MC2 was the most common subgroup (35%). No differences in preoperative assessment scores were identified, regardless of presence or absence of MC. For the overall cohort, improvement in assessment scores were observed: Short Form-36 improved an average of 8.2 points [95% CI (95% CI), 5.8-10.7], Oswestry Disability Index by 11.3 points (95% CI, 8.7-14.0), and visual analog scale by 2.8 points (95% CI, 2.1-3.5). In nearly all cases, MCID values were met, even when stratifying by MC subgroup. Few differences in postoperative assessment scores were identified when comparing across MC1, MC2, or no MC groups. CONCLUSIONS: Statistically and clinically significant improvement in postoperative clinical assessment scores was observed for both lumbar discectomy and transforaminal lumbar interbody fusion groups. MC on preoperative MRI was not associated with worse preoperative or postoperative clinical assessment scores. LEVEL OF EVIDENCE: Level III.

Gender differences in the surgical management of lumbar degenerative disease: a scoping review.

OBJECTIVE: Despite efforts toward achieving gender equality in clinical trial enrollment, females are often underrepresented, and gender-specific data analysis is often unavailable. Identifying and reducing gender bias in medical decision-making and outcome reporting may facilitate equitable healthcare delivery. Gender disparity in the utilization of surgical therapy has been exemplified in the orthopedic literature through studies of total joint arthroplasty. A paucity of literature is available to guide the management of lumbar degenerative disease, which stratifies on the basis of demographic factors. The objective of this study was to systematically map and synthesize the adult surgical literature regarding gender differences in pre- and postoperative patient-reported clinical assessment scores for patients with lumbar degenerative disease (disc degeneration, disc herniation, spondylolisthesis, and spinal canal stenosis). METHODS: A systematic scoping review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines. MEDLINE, Embase, and the Cochrane Registry of Controlled Trials were searched from inception to September 2018. Study characteristics including patient demographics, diagnoses, procedures, and pre- and postoperative clinical assessment scores (pain, disability, and health-related quality of life [HRQoL]) were collected. RESULTS: Thirty articles were identified, accounting for 32,951 patients. Six studies accounted for 84% of patients; 5 of the 6 studies were published by European groups. The most common lumbar degenerative conditions were disc herniation (59.0%), disc degeneration (20.3%), and spinal canal stenosis (15.9%). The majority of studies reported worse preoperative pain (93.3%), disability (81.3%), and HRQoL (75%) among females. The remainder reported equivalent preoperative scores between males and females. The majority of studies (63.3%) did not report preoperative duration of symptoms, and this represents a limitation of the data. Eighty percent of studies found that females had worse absolute postoperative scores in at least one outcome category (pain, disability, or HRQoL). The remainder reported equivalent absolute postoperative scores between males and females. Seventy-three percent of studies reported either an equivalent or greater interval change for females. CONCLUSIONS: Female patients undergoing surgery for lumbar degenerative disease (disc degeneration, disc herniation, spondylolisthesis, and spinal canal stenosis) have worse absolute preoperative pain, disability, and HRQoL. Following surgery, females have worse absolute pain, disability, and HRQoL, but demonstrate an equal or greater interval change compared to males. Further studies should examine gender differences in preoperative workup and clinical course.

Complete recovery following transorbital penetrating head injury traversing the brainstem: case report.

Transorbital penetration accounts for one-quarter of the penetrating head injuries (PHIs) in adults and half of those in children. Injuries that traverse (with complete penetration of) the brainstem are often fatal, with survivors rarely seen in clinical practice. Here, the authors describe the case of a 16-year-old male who suffered and recovered from an accidental transorbital PHI traversing the brainstem-the first case of complete neurological recovery following such injury. Neuroimaging captured the trajectory of the initial injury. A delayed-onset carotid cavernous fistula and the subsequent development of internal carotid artery pseudoaneurysms were managed by endovascular embolization.The authors also review the relevant literature. Sixteen cases of imaging-confirmed PHI traversing the brainstem have been reported, 14 involving the pons and 12 penetrating via the transorbital route. Management and outcome of PHI are informed by object velocity, material, entry point, trajectory, relationship to neurovascular structures, and the presence of a retained foreign body. Trauma resuscitation is followed by a careful neurological examination and appropriate neuroimaging. Ophthalmological examination is performed if transorbital penetration is suspected, as injuries may be occult; the potential for neurovascular complications highlights the value of angiography. The featured case shows that complete recovery is possible following injury that traverses the brainstem.

Upright time during hospitalization for older inpatients: A prospective cohort study.

BACKGROUND: The purpose of this study was to examine: a) how long and how frequently older hospitalized patients spend upright; b) whether duration and frequency of upright time change by time of the day, the day of the week, and during hospitalization; and c) whether these relationships differ based on the mobility level of patients at admission. METHODS: This prospective cohort study included 111 patients (82.2 ±â€¯8 years old, 52% female) from the Emergency Department and a Geriatric Assessment Unit who were at least 60 years old and had an anticipated length of stay of at least three days. The main outcomes were accelerometer-measured total upright time and number of bouts of upright time during awake hours. RESULTS: Patients were upright 15.9 times/day (interquartile range (IQR): 8.4-27.4) for a total of 54.2 min/day (IQR: 17.8-88.9) during awake hours. Time of day and day of week had little impact on the outcomes. Patients who walked independently at admission had 151.5 min (95% CI: 87.7-215.3) of upright time on hospital day 1 and experienced a decline of 4.5 min/day (-7.2 to -1.8). Those who needed personal mobility assistance or were bedridden had 29.5 min (-38.5-97.4) and 25 min (-48.3-100.3) of upright time on day 1, and demonstrated an increase of 3.6 (1.3-5.9) and 2.4 (0.05-4.5) min/day, respectively. CONCLUSION: Hospitalized older adults spend only 6% of their awake hours upright while in hospital. Patients who can walk independently are more active but experience a decline in their upright time during hospitalization.

Twelve tips for medical students to establish a collaborative flashcard project.

Medical students employ various study strategies to master large amounts of information during their medical education. Digital flashcards are an interactive, self-directed study stool that may improve knowledge retention by combining the principles of active recall and spaced-repetition. They may be studied during and beyond undergraduate medical education. However, making flashcards can be an onerous task. In this article, we describe twelve tips on how to establish and maintain a collaborative digital flashcard project based on the undergraduate medical curriculum.

Diversification of edaravone via palladium-catalyzed hydrazine cross-coupling: Applications against protein misfolding and oligomerization of beta-amyloid.

N-Aryl derivatives of edaravone were identified as potentially effective small molecule inhibitors of tau and beta-amyloid aggregation in the context of developing disease-modifying therapeutics for Alzheimer's disease (AD). Palladium-catalyzed hydrazine monoarylation protocols were then employed as an expedient means of preparing a focused library of 21 edaravone derivatives featuring varied N-aryl substitution, thereby enabling structure-activity relationship (SAR) studies. On the basis of data obtained from two functional biochemical assays examining the effect of edaravone derivatives on both fibril and oligomer formation, it was determined that derivatives featuring an N-biaryl motif were four-fold more potent than edaravone.