Rapid presentation of a de novo intracranial aneurysm: illustrative case.

BACKGROUND: Intracranial aneurysms are prevalent, particularly with advancing age. De novo aneurysms, occurring independently from the initial lesion, pose a unique challenge because of their unpredictable nature. Although risk factors such as female sex, smoking history, and hypertension have been proposed, the mechanisms underlying de novo aneurysm development remain unclear. OBSERVATIONS: A 79-year-old female developed a de novo saccular aneurysm within a year after management of a ruptured vertebral artery dissecting aneurysm. Her complex clinical course involved subarachnoid hemorrhage with diffuse vasospasm, stent occlusion of a dissecting aneurysm, discovery of a right 7- to 8-mm de novo middle cerebral artery aneurysm at the 1-year magnetic resonance angiography follow-up, and successful coil embolization. LESSONS: This rare occurrence challenges established timelines, as most de novo aneurysms manifest over a longer interval. Studies have attempted to identify risk factors, yet consensus remains elusive, particularly regarding the influence of treatment modality on de novo formation rates. This unique case urges reconsideration of posttreatment surveillance protocols, proposing shorter intervals for imaging and more vigilant follow-up strategies to detect asymptomatic de novo aneurysms. Timelier identification could significantly impact patient outcomes by averting potential ruptures. This emphasizes the need for further research to delineate effective monitoring and preventive measures for these enigmatic lesions.

Systematic review of the therapeutic use of Schwann cells in the repair of peripheral nerve injuries: Advancements from animal studies to clinical trials.

Objective: To systematically evaluate the literature on the therapeutic use of Schwann cells (SC) in the repair of peripheral nerve injuries. Methods: The Cochrane Library and PubMed databases were searched using terms [("peripheral nerve injury" AND "Schwann cell" AND "regeneration") OR ("peripheral nerve injuries")]. Studies published from 2008 to 2022 were eligible for inclusion in the present study. Only studies presenting data from in-vivo investigations utilizing SCs in the repair of peripheral nerve injuries qualified for review. Studies attempting repair of a gap of ≥10 mm were included. Lastly, studies needed to have some measure of quantifiable regenerative outcome data such as histomorphometry, immunohistochemical, electrophysiology, or other functional outcomes. Results: A search of the PubMed and Cochrane databases revealed 328 studies. After screening using the abstracts and methods, 17 studies were found to meet our inclusion criteria. Good SC adherence and survival in conduit tubes across various studies was observed. Improvement in morphological and functional outcomes with the use of SCs in long gap peripheral nerve injuries was observed in nearly all studies. Conclusion: Based on contemporary literature, SCs have demonstrated clear potential in the repair of peripheral nerve injury in animal studies. It has yet to be determined which nerve conduit or graft will prove superior for delivery and retention of SCs for nerve regeneration. Recent developments in isolation and culturing techniques will enable further translational utilization of SCs in future clinical trials.

Optimal Technique for Introducing Schwann Cells Into Peripheral Nerve Repair Sites.

Peripheral nerve injury (PNI) is found in a relatively large portion of trauma patients. If the injury is severe, such as with the presence of a long segmental gap, PNI can present a challenge for treatment. The current clinical standard of nerve harvest for the repair of long segmental gap PNI can lead to many potential complications. While other methods have been utilized, recent evidence indicates the relevance of cell therapies, particularly through the use of Schwann cells, for the treatment of PNI. Schwann cells (SCs) are integral in the regeneration and restoration of function following PNI. SCs are able to dedifferentiate and proliferate, remove myelin and axonal debris, and are supportive in axonal regeneration. Our laboratory has demonstrated that SCs are effective in the treatment of severe PNI when axon guidance channels are utilized. However, in order for this treatment to be effective, optimal techniques for cellular placement must be used. Thus, here we provide relevant background information, preclinical, and clinical evidence for our method in the treatment of severe PNI through the use of SCs and axon guidance channels.

Scalable culture techniques to generate large numbers of purified human Schwann cells for clinical trials in human spinal cord and peripheral nerve injuries.

OBJECTIVE: Schwann cells (SCs) have been shown to play an essential role in axon regeneration in both peripheral nerve injuries (PNIs) and spinal cord injuries (SCIs). The transplantation of SCs as an adjunctive therapy is currently under investigation in human clinical trials due to their regenerative capacity. Therefore, a reliable method for procuring large quantities of SCs from peripheral nerves is necessary. This paper presents a well-developed, validated, and optimized manufacturing protocol for clinical-grade SCs that are compliant with Current Good Manufacturing Practices (CGMPs). METHODS: The authors evaluated the SC culture manufacturing data from 18 clinical trial participants who were recruited for autologous SC transplantation due to subacute SCI (n = 7), chronic SCI (n = 8), or PNIs (n = 3). To initiate autologous SC cultures, a mean nerve length of 11.8 ± 3.7 cm was harvested either from the sural nerve alone (n = 17) or with the sciatic nerve (n = 1). The nerves were digested with enzymes and SCs were isolated and further expanded in multiple passages to meet the dose requirements for transplantation. RESULTS: An average yield of 87.2 ± 89.2 million cells at P2 and 150.9 ± 129.9 million cells at P3 with high viability and purity was produced. Cell counts and rates of expansion increased with each subsequent passage from P0 to P3, with the largest rate of expansion between P2 and P3. Larger harvest nerve lengths correlated significantly with greater yields at P0 and P1 (p < 0.05). In addition, a viability and purity above 90% was sustained throughout all passages in nearly all cell products. CONCLUSIONS: This study presents reliable CGMP-compliant manufacturing methods for autologous SC products that are suitable for regenerative treatment of patients with SCI, PNI, or other conditions.

Osteoporosis treatment in patients undergoing spinal fusion: a systematic review and meta-analysis.

OBJECTIVE: Bisphosphonates and teriparatide are the most common therapies used in the treatment of osteoporosis. Their impact on fusion rates in osteoporotic patients following spinal fusion has yet to be concretely defined, with previous systematic reviews focusing heavily on bisphosphonates and lacking clinical insight on the utility of teriparatide. Herein the authors present an updated meta-analysis of the utility of both bisphosphonates and teriparatide in improving spinal fusion outcomes in osteoporotic patients. METHODS: After a comprehensive search of the English-language literature in the PubMed and Embase databases, 11 clinical studies were included in the final qualitative and quantitative analyses. Of these studies, 9 investigated bisphosphonates, 7 investigated teriparatide, and 1 investigated a combination of teriparatide and denosumab. Odds ratios and 95% confidence intervals were calculated where appropriate. RESULTS: A meta-analysis of the postoperative use of bisphosphonate demonstrated better odds of successful fusion as compared to that in controls during short-term monitoring (OR 3.33, 95% CI 1.72-6.42, p = 0.0003) but not long-term monitoring (p > 0.05). Bisphosphonate use was also shown to significantly reduce the likelihood of postoperative vertebral compression fracture (VCF; OR 0.07, 95% CI 0.01-0.59, p = 0.01) and significantly reduce Oswestry Disability Index scores (mean difference [MD] = -2.19, 95% CI -2.94 to -1.44, p < 0.00001) and visual analog scale pain scores (MD = -0.58, 95% CI -0.79 to -0.38, p < 0.00001). Teriparatide was found to significantly increase fusion rates at long-term postoperative periods as compared to rates after bisphosphonate therapy, with patients who received postoperative teriparatide therapy 2.05 times more likely to experience successful fusion (OR 2.05, 95% CI 1.17-3.59, p = 0.01). CONCLUSIONS: The authors demonstrate the benefits of bisphosphonate and teriparatide therapy independently in accelerating fusion during the first 6 months after spinal fusion surgery in osteoporotic patients. In addition, they show that teriparatide may have superior benefits in spinal fusion during long-term monitoring as compared to those with bisphosphonates. Bisphosphonates may be better suited in preventing VCFs postoperatively in addition to minimizing postoperative disability and pain.

A Retrospective Pilot Study for Preoperative Screening to Prevent Iatrogenic Cervical Spinal Cord Injury.

PURPOSE: The preoperative medical clearance process is well established to screen for medical comorbidities and therefore must be thorough. However, screening for potential cervical spine disease is often overlooked. In older surgical candidates, the presence of cervical spondylosis can increase risk of iatrogenic cervical spine injury during prolonged neck extension in non-spinal surgeries. We present a standard protocol for cervical spine clearance and a novel sustained neck extension maneuver through a retrospective case series. METHODS: Sixty-three consecutive cases that underwent preoperative cervical clearance between April 2012 and December 2019 were reviewed. Referral for clearance occurred through the department of anesthesiology after concerning radiographic or physical exam findings were noted. A standard preoperative screening protocol with a sustained one-minute neck extension maneuver was implemented. Recommendations were made for standard neck precautions with or without neuromonitoring or for cervical spine decompression surgery prior to the planned procedure. RESULTS: There were 25 patients with symptoms of myelopathy, 11 with radiculopathy and 13 with neck pain at baseline. Cervical spondylosis was observed in 51 patients, cervical canal stenosis in 29 and cervical myelomalacia in six. Fifty-seven patients underwent neck extension exam and 25 exhibited new or worsening symptoms. Myelopathic symptoms and radicular pain at baseline and positive Hoffman's and Spurling's sign, independently, were significantly associated with a positive neck extension exam (p<0.05). Fourteen patients were recommended for cervical decompression prior to planned procedure. CONCLUSIONS: Our preoperative cervical spine clearance protocol is safe and may aid in identifying patients susceptible to iatrogenic cervical spine injury.

Schwann cell delivery via a novel 3D collagen matrix conduit improves outcomes in critical length nerve gap repairs.

OBJECTIVE: The current clinical standard of harvesting a nerve autograft for repair of long-segment peripheral nerve injuries (PNIs) is associated with many potential complications. Guidance channels offer an alternative therapy. The authors investigate whether autologous Schwann cells (SCs) implanted within a novel collagen-glycosaminoglycan conduit will improve axonal regeneration in a long-segment PNI model. METHODS: Novel NeuraGen 3D collagen matrix conduits were implanted with autologous SCs to investigate axonal regeneration across a critical size defect (13 mm) in male Fischer rat sciatic nerve. Reversed sciatic nerve autografts served as positive controls, and conduits filled with serum only as negative controls. Electrophysiological assessments were made in vivo. Animals were killed at 4 or 16 weeks postinjury, muscle weights were measured, and grafts underwent immunohistochemical and morphometric analysis. RESULTS: SC survival was confirmed by the presence of green fluorescent protein-labeled SCs within regenerated fibers. Regeneration and elongation of myelinated axons in all segments of the graft were significantly enhanced at 16 weeks in the SC-filled conduits compared to the conduit alone and were statistically similar to those of the autograft. Nerves repaired with SC-filled conduits exhibited onset latencies and nerve conduction amplitudes similar to those of the contralateral controls and autograft (p < 0.05). Adding SCs to the conduit also significantly reduced muscle atrophy compared to conduit alone (p < 0.0001). CONCLUSIONS: Repair of long-segment PNI of rat sciatic nerve is significantly enhanced by SC-filled NeuraGen 3D conduits. Improvements in the total number of myelinated axons, axon diameter, and myelin thickness throughout SC-filled conduits allow for significant recovery in nerve conduction and a decrease in muscle atrophy.

Posterior Surgical Approach for Ventral Cervical Spinal Cord Herniation: 2-Dimensional Operative Video.

Spinal cord herniation (SCH) is a rare condition that is typically of idiopathic origin. Although SCH is mostly found in the thoracic region because of a dural defect, there are some reports of cervical SCH following surgery or trauma.1-3 Spinal cord tethering can be a result of SCH or as a standalone issue.4,5 These conditions can lead to progressive neurological deficits, including numbness, gait disturbances, and decreased muscle strength, requiring surgical correction. There are limited reports of surgical procedures for ventral SCHs. Several reports exist using a ventral approach for intradural tumors, but it is not commonly employed because of the inability to obtain adequate dural closure.6 Much of the literature on SCH comes from idiopathic and congenital cases in the thoracic spine.7,8 Posterior and posterolateral approaches for a ventral thoracic SCH have been described, as well as an anterior approach for a ventral cervical SCH.9-12 In this video, we describe a posterior approach for a ventral cervical SCH. A 38-yr-old male presented with progressive cervical myelopathy 9 yr after a C2-C3 schwannoma resection requiring an anterior approach and corpectomy of C3 with partial corpectomies of C2 and C4. A preoperative magnetic resonance imaging showed a ventrally herniated spinal cord at the top of the C3 vertebral body and below the C4 vertebral body. Informed consent was obtained. The posterior surgical approach involved a C1-C5 laminectomy, sectioning the dentate ligament, ventral cord untethering, removal of residual tumor, and placement of a ventral sling. A significant improvement in sensory and motor function was observed postoperatively.

Ultrasound-Guided Needle Localization Wires in Peripheral Nerve Injuries With Long Segmental Defects: Technical Case Report.

BACKGROUND AND IMPORTANCE: In cases of severe nerve trauma with significant local soft tissue damage, identification and subsequent repair of nerve stumps can pose a technical challenge. Ultrasound (US) localization in peripheral nerve surgery has recently become popular. We present a case report illustrating the use of needle-wire localization systems to identify proximal and several distal branches of an injured femoral nerve with a large segmental defect in order to illustrate how such techniques can be used to make surgical repair more efficient, particularly with identifying the distal stump(s). CLINICAL PRESENTATION: We illustrate a case of a 16-yr-old female involved in a traumatic accident that lead to a severe injury of the femoral nerve and artery. The patient presented with a 7.3-cm defect between the proximal and distal aspect of the femoral nerve and its branches, respectively. High-resolution US was used to identify the proximal, large femoral nerve, and 3 distal stumps. By enlisting our musculoskeletal radiology team, we were able to trace distal branches of the femoral nerve and see their target muscles. Three separate US flexible needles were used to locate small muscular branches of the femoral nerve and 1 to locate the proximal stump. Intraoperatively, the localization wires allowed for safe and efficient dissection of proximal and distal nerve stumps in a significantly scarred and edematous plane. CONCLUSION: US-guided needle-wire localization has shown promise in identifying the distal stumps and minimizing tissue dissection. Preoperative US guidance significantly aided in nerve repair for this severe injury without increasing morbidity.

Minority Enrollment in Parkinson's Disease Clinical Trials: Meta-Analysis and Systematic Review of Studies Evaluating Treatment of Neuropsychiatric Symptoms.

BACKGROUND: Randomized clinical trials (RCTs) in Parkinson's disease (PD) have historically enrolled a low number of underrepresented minorities, lessening the generalizability of therapeutic developments. Although there are racial disparities in PD, little is known regarding neuropsychiatric symptoms and other nonmotor manifestations across all races/ethnicities. OBJECTIVE: To assess minority participation in PD trials evaluating the treatment of neuropsychiatric symptoms and explore underlying reasons. METHODS: We systematically searched PubMed and Embase for RCTs with a primary goal of treating neuropsychiatric symptoms in PD patients from 2000-2019. The pooled prevalence and 95% confidence interval (CI) of being white and enrolled in a clinical trial was calculated using the inverse variance method. I-square was calculated as a measure of heterogeneity and meta-regression was used to evaluate temporal trends. RESULTS: We included 63 RCTs with a total of 7,973 patients. In pooled analysis, 11 (17.5%) RCTs reported race/ethnicity. Of studies reporting this data, 5 African American (0.2%), 16 Hispanics (0.64%), and 539 Asians (21.44%) were enrolled. The pooled prevalence of being white in clinical trials was 98% (CI 0.97-0.98, p < 0.001), with 1,908 patients (75.8%). NIH-funded studies were most likely to report racial data when compared to non-NIH trials (p = 0.032). CONCLUSION: This large pooled analysis found a small percentage of RCTs reporting race/ethnicity when evaluating treatment of neuropsychiatric symptoms in PD. There was a disproportionally high number of white patients when compared to African Americans and Hispanics. More studies are needed to investigate this discrepancy and improve rates of & minority enrollment in PD trials.

Trends of inpatient palliative care use among hospitalized patients with Parkinson's disease.

INTRODUCTION: Palliative care in Parkinson's Disease (PD) is an effective intervention to improve quality of life, although historically, access and availability have been very restricted. METHODS: We performed a retrospective cohort study using the National Inpatient Sample (NIS) data from 2007 to 2014. Diagnostic codes were used to identify patients with PD and palliative care referral. Trends were calculated and logistic analysis performed to identify predictors of palliative care use. RESULTS: We identified 397,963 hospitalizations from 2007 to 2014 for patients with PD. Of these, 10,639 (2.67%) were referred to palliative care. The rate of consultation increased from 0.85% in 2007 to 4.49% in 2014. For 1 unit in year increase, there was 1.23 time the odds of receiving palliative consultation (OR 1.23, CI 1.21-1.25, p < 0.0001). Hispanics (OR 0.90, CI 0.81-1.01, p = 0.0550), Black (OR 0.90, CI 0.81-1.01, p = 0.0747) and White patients had similar rates of referral after adjustment. Women were less likely to be referred to palliative care (OR 0.90, CI 0.87-0.94, p < 0.0001). Other factors strongly associated with a higher rate of referrals included private insurance when compared to Medicare (OR 2.14, CI 1.89-2.41, p < 0.0001) and higher income (OR 1.41, CI 1.30-1.53, p < 0.0001). CONCLUSION: There has been a significant increase in palliative care referrals among hospitalized patients with PD in the US, although the overall rate remains low. After controlling for confounders, racial and ethnic disparities were not found. Women, patients with Medicare/Medicaid, and those with lower income were less likely to be referred to palliative care.

Individualized Anatomy-Based Targeting for VIM-cZI DBS in Essential Tremor.

BACKGROUND: Deep brain stimulation of the ventral intermediate nucleus (VIM) or caudal zona incerta (cZI) is effective for refractory essential tremor (ET). To refine stereotactic planning for lead placement, we developed a unique individualized anatomy-based planning protocol that targets both the VIM and the cZI in patients with ET. METHODS: 33 patients with ET underwent VIM-cZI lead implantation with targeting based on our protocol. Indirect targeting was adjusted based on anatomic landmarks as reference lines bisecting the red nuclei and ipsilateral subthalamus. Outcomes were evaluated through the follow-up of 31.1 ± 18.4 months. Active contact coordinates were obtained from reconstructed electrodes in the Montreal Neurological Institute space using the MATLAB Lead-DBS toolbox. RESULTS: Mean tremor improvement was 79.7% ± 22.4% and remained stable throughout the follow-up period. Active contacts at last postoperative visit had mean Montreal Neurological Institute coordinates of 15.5 ± 1.6 mm lateral to the intercommissural line, 15.3 ± 1.8 mm posterior to the anterior commissure, and 1.4 ± 2.9 mm below the intercommissural plane. No hemorrhagic complications were observed in the analyzed group. CONCLUSIONS: Individualized anatomy-based VIM-cZI targeting is feasible and safe and is associated with favorable tremor outcomes.

Safety of Noncontrast Imaging-Guided Deep Brain Stimulation Electrode Placement in Parkinson Disease.

BACKGROUND: Deep brain stimulation (DBS) is considered standard of care for the treatment of medically refractory Parkinson disease (PD). The placement of brain electrodes is performed using contrast imaging to enhance blood vessel identification during stereotactic planning. We present our experience with a series of patients implanted using noncontrast imaging. METHODS: All cases of DBS surgery for PD performed between 2012 and 2018 with noncontrast imaging were retrospectively reviewed. Clinical features, postoperative imaging, and complications were analyzed. RESULTS: A total of 287 deep-seated electrodes were implanted in 152 patients. Leads were placed at the subthalamic nucleus and globus pallidus internus in 258 and 29 hemispheres, respectively. We identified 2 cases of intracranial hemorrhage (0.7%). CONCLUSIONS: DBS lead placement can be performed without the use of intravenous contrast with a postoperative intracranial hemorrhage rate comparable with other reported series.

Long-Term Outcomes of Mechanical Thrombectomy for Stroke: A Meta-Analysis.

Mechanical thrombectomy (MT) has become the standard treatment for large vessel occlusion (LVO) in acute ischemic stroke (AIS). Few studies have investigated long-term outcomes for AIS treated with MT. Therefore, a pooled meta-analysis using data from randomized clinical trials (RCT) was performed to assess for long-term clinical outcomes. A systematic literature search was conducted on 27 September 2017, by searching the English literature in the Cochrane Library, MEDLINE, and Embase for RCTs investigating long-term outcomes (greater than standard 3-month timepoint) of endovascular intervention versus medical management for patients with AIS. The study was carried out according to PRISMA guidelines and random effects analysis was carried out to account for heterogeneity. Three trials were included: IMS III, MR CLEAN, and REVASCAT, comprising a total of 1,362 patients. Long-term clinical outcomes were available for 1-year follow-up in IMS III and REVASCAT and at 2 years in MR CLEAN. Functional independence at long-term follow-up favored endovascular stroke intervention (OR 1.51; p = 0.02). When stratified by LVO inclusion criteria, greater endovascular functional independence benefits were observed (OR 1.85; p = 0.0005). There was a significant difference between the 2 arms in favor of endovascular therapy for the quality of life at long-term follow-up (mean difference 0.11; p = 0.0002). No difference in mortality at long-term follow-up was observed (OR 0.82; p = 0.12). We conclude that endovascular therapy results in favorable outcomes at long-term follow-up for patients with acute ischemic stroke compared to standard medical treatment alone and that the 90-day timepoint offers a fair representation of the long-term outcomes.

The role of peroxiredoxin II in chemoresistance of breast cancer cells.

Peroxiredoxin (Prx)II belongs to a family of redox-active proteins that use redox-sensitive cysteine in the active site to reduce peroxides. PrxII is induced by various oxidative stimuli and plays an important protective role against oxidative radical damage by reactive oxygen species. PrxII expression levels are correlated with resistance to radiation therapy or certain anti-cancer drugs in radioresistant breast cancer cells, glioblastomas, and head and neck cancer cells as well as in tissue isolated from head and neck patients who do not respond to radiation therapy. Small interfering RNA (siRNA) that inhibits the PrxII gene expression has been shown to partially reverse the radioresistant phenotype in radiation resistant breast cancer cells and sensitizes glioma cells to oxidative stress, highlighting the potential clinical importance of PrxII in radiation resistance in cancer. This article focuses on the role that PrxII may play in chemoresistant breast cancer cells.

Enhanced radiation response in radioresistant MCF-7 cells by targeting peroxiredoxin II.

In our previous study, we identified that a protein target, peroxiredoxin II (PrxII), is overexpressed in radioresistant MCF+FIR3 breast-cancer cells and found that its expression and function is associated with breast-cancer radiation sensitivity or resistance. Small interference RNA (siRNA) targeting PrxII gene expression was able to sensitize MCF+FIR3 radioresistant breast-cancer cells to ionizing radiation. The major focus of this work was to investigate how the radiation response of MCF+FIR3 radioresistant cells was affected by the siRNA that inhibits PrxII gene expression. Our results, presented here, show that silencing PrxII gene expression increased cellular toxicity by altering cellular thiol status, inhibiting Ca(2+) efflux from the cells, and perturbing the intracellular Ca(2+) homeostasis. By combining radiotherapy and siRNA technology, we hope to develop new therapeutic strategies that may have potential to enhance the efficacy of chemotherapeutic agents due to this technology's property of targeting to specific cancer-related genes.

Potential for transcriptional upregulation of cochlin in glaucomatous trabecular meshwork: a combinatorial bioinformatic and biochemical analytical approach.

PURPOSE: To determine the existence of a relatively higher abundance of potential TFs in glaucomatous trabecular meshwork (TM) that may bind putative promoter regions and affect cochlin protein expression in glaucomatous compared to normal TM. METHODS: Combinatorial bioinformatics and biochemical analyses, using human glaucomatous and normal donor tissue (n = 4 each). Biochemical analysis included electrophoretic mobility shift assays (EMSAs), filter binding assays (FBAs), coupled in vitro transcription-translation (TNT) assays and promoter mutation analysis. RESULTS: Combinatorial bioinformatics and biochemical analyses revealed the existence of a higher abundance of TFs in glaucomatous than in normal TM nuclear extracts. The evidence of a relatively high abundance of TFs, leading to increased expression of cochlin predicted by bioinformatic and biochemical analyses (EMSA and FBA), was further supported by TNT and promoter mutation TNT assays. CONCLUSIONS: These results support the finding that the observed increased cochlin expression in glaucomatous TM is due to relative elevated abundance of TFs. The results also demonstrate the utility of combinatorial bioinformatic and biochemical analyses for genes with uncharacterized promoter regions.