Synthesis and Evaluation of 5-(Heteroarylmethylene)hydantoins as Glycogen Synthase Kinase-3ß Inhibitors.

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase which plays a center role in the phosphorylation of a wide variety of proteins, generally leading to their inactivation. As such, GSK-3 is viewed as a therapeutic target. An ever-increasing number of small organic molecule inhibitors of GSK-3 have been reported. Phenylmethylene hydantoins are known to exhibit a wide range of inhibitory activities including for GSK-3ß. A family of fourteen 2-heterocycle substituted methylene hydantoins (14, 17-29) were prepared and evaluated for the inhibition of GSK-3ß at 25 µM. The IC50 values of five of these compounds was determined; the two best inhibitors are 5-[(4'-chloro-2-pyridinyl)methylene]hydantoin (IC50 = 2.14 ± 0.18 µM) and 5-[(6'-bromo-2-pyridinyl)methylene]hydantoin (IC50 = 3.39 ± 0.16 µM). The computational docking of the compounds with GSK-3ß (pdb 1q41) revealed poses with hydrogen bonding to the backbone at Val135. The 5-[(heteroaryl)methylene]hydantoins did not strongly inhibit other metalloenzymes, demonstrating poor inhibitory activity against matrix metalloproteinase-12 at 25 µM and against human carbonic anhydrase at 200 µM, and were not inhibitors for Staphylococcus aureus pyruvate carboxylase at concentrations >1000 µM.

Advances and Challenges of Endoscopic Spine Surgery.

The purpose of this paper is to review the data supporting current endoscopic surgical techniques for the spine and the potential challenges and future of the field. The origins of endoscopic spine surgery can be traced back many decades, with many important innovations throughout its development. It can be applied to all levels of the spine, with many robust trials supporting its clinical outcomes. Continued clinical research is needed to explore its expanding indications. Although the limitations of starting an endoscopic program can be justified by its cost effectiveness and positive societal impact, challenges facing its widespread adoption are still present. As more residency and fellowship programs include endoscopy as part of their spine training, it will become more prevalent in hospitals in the United States. Technological advancements in spine surgery will further propel and enhance endoscopic techniques as they become an integral part of a spine surgeon's repertoire.

Peroneal Nerve Repair with Cross-Bridge Ladder Technique: Parallel End-to-Side Neurorrhaphies.

Background Multiple nerve transfer techniques are used to treat patients with nerve injuries when a primary repair is not possible. These techniques are categorized to end-to-end, end-to-side, and side-to-side neurorrhaphy. Our study aims to explore the utility of the cross-bridge ladder technique (H-shaped), which has shown promising results in animal models and probably underutilized clinically. Methods Four patients with significant loss of ankle dorsiflexion were seen in the clinic and underwent evaluation, including electrodiagnostic studies. A cross-bridge ladder repair technique was used between the tibial nerve as the donor and the common peroneal nerve as the recipient via one or two nerve grafts coapted in parallel with end-to-side neurorrhaphies. Dorsiflexion strength was measured preoperatively using the Medical Research Council (MRC) grading system and at each postoperative follow-up appointment. Results All four patients had suffered persistent and severe foot drop (MRC of 0) following trauma that had occurred between 6 and 15 months preoperatively. Three of the four patients improved to an MRC of 2 several months postoperatively. The last patient had an immediate improvement to an MRC of 2 by his first month and had a complete recovery of ankle dorsiflexion within 4 months from surgery. Conclusion We demonstrate the utility and clinical outcomes of the cross-bridge ladder technique in patients with persistent and prolonged foot drop following trauma. Both early and late recovery were seen while all patients regained motor function, with some patients continuing to improve up to the most recent follow-up. IRB Approval: Obtained 2013-1411-CP005.

Classification and Reliability of Lumbar Facet Cysts Grading Scales.

BACKGROUND: The presence of symptomatic lumbar facet cysts has been associated with segmental instability. Given this association, decompression versus decompression with fusion is a frequently debated topic. Multiple grading scales have been devised to identify patients at high risk for development of cyst recurrence; however, there exists no external evaluation of these scales. METHODS: A retrospective review of 54 patients undergoing initial treatment for lumbar synovial cysts at a single institution over the past 12 years was conducted. Surgical treatment consisted of decompression with cystectomy without fusion. Patients were assessed and classified according to the NeuroSpine Surgery Research Group (NSURG) and Rosenstock Classification systems. Five neurosurgeons reviewed the preoperative magnetic resonance images, and results were classified. Interrater reliability was assessed using both Gwet's AC1 coefficient and Krippendorff's alpha. A 1-way analysis of variance was used to evaluate predictive ability of both classification systems. RESULTS: In total, of the 54 patients who underwent decompression, 7 had cyst recurrence. Overall cyst recurrence was most common in NSURG grade 2 cysts (3/12, 25%) followed by grade 1 cysts (4/27, 14.8%). Of the NSURG grade 3 and 4 patients, none had cyst recurrence. In the Rosenstock grades the most common recurrence was in grade 3 cysts (1/4, 25%) followed by grade 1 cysts (5/26, 19.2%). Interrater reliability demonstrated good reproducibility on Gwet's AC1 and Krippendorff's alpha on both grading scales. Neither score was predictive of cyst recurrence (P > 0.05). CONCLUSIONS: The Rosenstock and NeuroSpine scores demonstrate good overall interrater reliability but are inconsistent in their ability to predict recurrence of lumbar facet cysts.

Retroperitoneal Exposure of the Anterior Lumbar Spine.

BACKGROUND: Anterior lumbar spine procedures such as anterior lumbar interbody fusion (ALIF) are used commonly to treat multiple pathologies, including pseudoarthrosis and degenerative disk disease. It is generally a safe and effective procedure, but an anterior approach to the lumbar spine requires critical navigation of the surgical window to avoid delicate structures. An operative technique should maximize the exposure without an increased risk of iatrogenic injury. OBJECTIVE: To describe in detail a retroperitoneal exposure of the anterior lumbar spine. METHODS: This surgical approach is a unique variation of standard anterior lumbar spine exposure techniques. This technique is described and illustrated in detail with an accompanying Supplemental Digital Content: video. Institutional Review Board (IRB) approval was not required because this is a variation of current techniques. Patient consent was obtained for the procedure and use of operative pictures and videos. RESULTS: Precise details of the technique are described. The surgical video demonstrates the technique for the L5-S1 ALIF approach. CONCLUSION: This technique is a novel variation of the standard retroperitoneal exposure of the anterior lumbar spine. The incision placement, size, and dynamic blunt retraction of this approach limit tissue disruption and provide an efficient exposure that has not been previously described in the literature.

Comparison of Decompression versus Decompression and Fusion for Lumbar Synovial Cysts and Predictive Factors for Cyst Recurrence.

BACKGROUND: The management of lumbar synovial cysts (LSC) has been a controversial topic for many years. Whereas many authors label LSC as markers of instability and thus necessitating fusion, others suggest that decompression alone without fusion is a viable initial treatment option. Our objective was to clarify outcomes in patients undergoing decompression alone and decompression with fusion for symptomatic LSC and identify factors for cyst recurrence. METHODS: A retrospective case series was performed of all patients undergoing initial treatment for LSC at a single institution ranging from January 1999 to February 2020. Surgical treatment included either decompression with cystectomy or decompression with cystectomy and a fusion procedure. Preoperative symptoms were collected and included radicular pain, motor deficits, sensory deficits, or bowel/bladder changes. Radiographic data were calculated individually and confirmed with radiology reports. Categorical variables were assessed using χ2 analysis and continuous variables were assessed with the 2-sample t test. RESULTS: In total, 161 patients were identified as presenting with symptomatic LSC. Of these, 104 patients underwent decompression alone versus 57 who underwent decompression and fusion. In the decompression group 11 patients required reoperation at the level of the cyst compared with none in those undergoing fusion as their initial procedure (10.5% vs. 0%, P = 0.012). On subgroup analysis of those undergoing decompression as their initial procedure, patients with cyst recurrence demonstrated a statistically significant greater coronal facet inclination angle compared with those without cyst recurrence (52.4° vs. 40.6°, P = 0.02). CONCLUSIONS: Decompression alone is a reasonable choice for the initial management of LSC, although it does carry a significant risk of same-level reoperation due to cyst recurrence and spondylolisthesis. Preoperative coronal facet inclination angle may be a useful measurement in predicting cyst recurrence following decompression.

Synthesis and evaluation of 17α-triazolyl and 9α-cyano derivatives of estradiol.

A variety of 17α-triazolyl and 9α-cyano derivatives of estradiol were prepared and evaluated for binding to human ERß in both a TR-FRET assay, as well as ERß and ERα agonism in cell-based functional assays. 9α-Cyanoestradiol (5) was nearly equipotent as estradiol as an agonist for both ERß and ERα. The potency of the 17α-triazolylestradiol analogs is considerably more variable and depends on the nature of the 4-substituent of the triazole ring. While rigid protein docking simulations exhibited significant steric clashing, induced fit docking providing more protein flexibility revealed that the triazole linker of analogs 2d and 2e extends outside of the traditional ligand binding domain with the benzene ring located in the loop connecting helix 11 to helix 12.

Association of helmet use with traumatic brain and cervical spine injuries following bicycle crashes.

Background: The use of bicycle helmets in preventing traumatic brain injuries (TBI) is frequently cited but data remain inconclusive. Additionally, the effects of helmets on cervical spine injuries (CSI) are debated.Methods: We performed a retrospective review of all adult patients with bicycle crashes presenting to one level 1 trauma center in Wisconsin from 2010 to 2016. Patients were divided into two groups: helmeted and un-helmeted.Results: In total 287 patients were included; 149 un-helmeted (51.9%) and 138 helmeted (48.9%). Helmeted riders had radiographic evidence of traumatic brain injury in 20.3% of cases compared to 40.3% of un-helmeted (p < 0.001). On average, helmeted riders had a similar injury severity score of 7.80 (standard deviation (SD) = 7.18) compared with 8.25 (SD = 9.98) in the un-helmeted group (p = 0.68). CSI occurred in 16 (10.7%) un-helmeted patients compared with 15 (10.9%) helmeted patients (p = 0.707). Of the un-helmeted group, four patients (2.7%) were found to have a cervical spine fracture compared with 12 (8.7%) helmeted patients (p = 0.037).Conclusion: Helmet use demonstrated a statistically significant advantage in the prevention of traumatic brain injuries. No significant difference was found regarding the incidence of severity of cervical spine injuries. These results do not demonstrate any statistically significant benefit in the prevention of cervical spine injuries with helmet use. In contrast, helmet use was found to convey a significant protective advantage in the prevention of traumatic brain injuries compared to no helmets.

Evaluation of α-hydroxycinnamic acids as pyruvate carboxylase inhibitors.

Through a structure-based drug design project (SBDD), potent small molecule inhibitors of pyruvate carboxylase (PC) have been discovered. A series of α-keto acids (7) and α-hydroxycinnamic acids (8) were prepared and evaluated for inhibition of PC in two assays. The two most potent inhibitors were 3,3'-(1,4-phenylene)bis[2-hydroxy-2-propenoic acid] (8u) and 2-hydroxy-3-(quinoline-2-yl)propenoic acid (8v) with IC50 values of 3.0 ±â€¯1.0 µM and 4.3 ±â€¯1.5 µM respectively. Compound 8v is a competitive inhibitor with respect to pyruvate (Ki = 0.74 µM) and a mixed-type inhibitor with respect to ATP, indicating that it targets the unique carboxyltransferase (CT) domain of PC. Furthermore, compound 8v does not significantly inhibit human carbonic anhydrase II, matrix metalloproteinase-2, malate dehydrogenase or lactate dehydrogenase.

Cranial Nerve Preservation Following Surgical Treatment for Epidermoid Cysts of the Posterior and Middle Fossae.

Epidermoid cysts are rare lesions, accounting for 0.2 to 1.8% of all intracranial tumors. They most commonly occur in the cerebellopontine angle where they may cause a breadth of neurologic complications due to mass effect on the nearby cranial nerves (CN), vascular structures, and the brain stem. Treatment of epidermoid cysts is surgical, with the goal of complete resection using microsurgical technique and even more importantly preservation of the involved CNs, vasculature, and brain parenchyma. Successful surgery can result in total resolution of symptoms, but, in certain situations, may not be advisable due to adherence, scarring, or inflammation making dissection of CN fascicles difficult and possibly hazardous. We conducted a retrospective review from 1998 to 2016 and compiled a series of 28 skull base epidermoid cysts operated on at our institution. Cases were evaluated for presenting symptoms, history of prior resection, and postoperative results including CN function, extent of resection, residual tumor, and need for reoperations. The average tumor size (largest diameter) was 3.9 cm with a range of 1 to 7cm. Eighteen of twenty-eight (64%) patients underwent a gross total resection and ten underwent subtotal resection. No patients, whether presenting with CN deficits or not, experienced permanent worsening of CN function following surgery. Complete resection of epidermoid cysts should remain a high priority of therapy, but, in our opinion, preservation of CN function should be a primary goal, determining the extent of resection to provide patients with the highest quality of life possible following surgery.

Clival meningocele causing bilateral hearing loss in a child due to superficial siderosis of the central nervous system: case report.

Superficial siderosis (SS) of the CNS is a rare and often unrecognized condition. Caused by hemosiderin deposition from chronic, repetitive hemorrhage in the subarachnoid space, it results in parenchymal damage in the subpial layers of the brain and spinal cord. T2-weighted MRI shows the characteristic hypointensity of hemosiderin deposition, classically occurring around the cerebellum, brainstem, and spinal cord. Patients present with progressive gait ataxia and sensorineural hearing impairment. Although there have been several studies, case reports, and review articles over the years, the clear pathophysiology of subarachnoid space hemorrhage remains to be elucidated. The proposed causes include prior intradural surgery, prior trauma, tumors, vascular abnormalities, nerve root avulsion, and dural abnormalities. Surgical repair of a dural defect associated with SS has been shown to be efficacious at preventing symptomatic progression. There have been several reports of dural defects within the spinal canal treated with surgery. Here, the authors present the first known case of a dural defect of the ventral skull base, namely a clival meningocele, presumed to be causing SS. In this case report, a 10-year-old girl with a history of head trauma at the age of 3 years was found to have a clival meningocele 3 years after her original trauma. On follow-up imaging, the patient was found to have radiographic growth of the meningocele along with evidence of SS of the CNS. The patient was treated conservatively until she began to have progressive hearing loss. It was presumed that the growing meningocele was the source of her SS. An endoscopic endonasal transclival approach with a multilayer dural reconstruction was performed to fix the dural defect and repair the meningocele in hopes of mitigating the progression of her symptoms. At her 12-month postoperative follow-up, she was doing well, with audiometry showing a slightly decreased hearing threshold in the left ear but improved speech discrimination bilaterally. Postoperative MRI showed a stable level of hemosiderin deposition and meningocele repair. Long-term follow-up will be necessary to evaluate for continued clinical stabilization or possible improvement.

Antibiotic prophylaxis and infection prevention for endoscopic endonasal skull base surgery: Our protocol, results, and review of the literature.

Endoscopic endonasal approaches to the skull base provide minimally invasive corridors to intracranial lesions; however, enthusiasm for this new approach is always tempered by the recognition that this route requires passage through a nonsterile sinonasal corridor. Despite an increasing number of patients undergoing these surgeries, there remains no consensus on the use of perioperative antibiotics. A retrospective review of consecutive patients undergoing endoscopic endonasal skull base surgery (EESBS) at Loyola University Medical Center by the same neurosurgeon and otolaryngologist team between February 2015 and October 2016 was performed. Antibiotic regimens, presence of an intraoperative or postoperative cerebrospinal fluid (CSF) leak, dural reconstruction method, and rates of sinusitis, meningitis, and/or intracranial abscess were analyzed. 39 patients who underwent a total of 41 EESBSs with a mean age of 46 years were identified. A vascularized nasoseptal flap was used for dural reconstruction when high flow CSF leaks were encountered intraoperatively (n = 17); otherwise, reconstruction mostly consisted of allografts and/or free mucosal grafts. There were zero postoperative cases of CSF leaks, meningitis, or intracranial infection. Our current antibiotic prophylaxis protocol coupled with the use of variable dural reconstruction techniques dictated by intraoperative findings has led to low rates of postoperative CSF leaks, intracranial infections, and meningitis. A survey was also distributed to Neurological Surgery Residency Programs to gain a better understanding of the EESBS protocols that are being used nationally. The practice of antibiotic prophylaxis for patients undergoing EESBS is quite variable and this study should provide the impetus for multi-institutional comparison studies.

Identification of Preoperative and Intraoperative Risk Factors for Complications in the Elderly Undergoing Elective Craniotomy.

BACKGROUND: Neurosurgical patients are aging as the general population is becoming older. METHODS: A retrospective review of patients ≥65 years of age who underwent an elective craniotomy from 2007 to 2015 to identify risk factors for 30-day morbidity/mortality was conducted. Key preoperative variables included age, comorbidities, and functional status based on the Karnofsky Performance Status score and modified Rankin Scale score. Outcome variables included long-term care (LTC) complications, neurologic complications, systemic/infectious complications, length of stay, functional outcomes, and mortality. RESULTS: A total of 286 patients ≥65 years underwent elective craniotomy at Loyola University Medical Center over 8 years. Seventy-two patients had a preoperative neurologic deficit and 95 had a systemic morbidity before surgery. Postoperative neurologic and systemic morbidity was 14% and 23%, respectively. 7% of patients experienced a LTC complication and 5 patients (1.7%) died. Worse preoperative scores on both the Karnofsky Performance Status and modified Rankin Scale predicted increased length of stay and mortality (P < 0.05). Univariable and multivariable analyses showed that patients with preoperative motor deficit, altered mental status, congestive heart failure, smoking history, and chronic steroid use were all more likely to have an LTC complication, and increased anesthesia time and estimated blood loss increased risk for LTC, neurologic, and systemic/infectious complications. CONCLUSIONS: This study identifies factors that predict perioperative complications for elderly patients undergoing elective craniotomies, particularly congestive heart failure, smoking history, chronic steroid use, anesthesia time, and estimated blood loss. Age alone should not preclude elective craniotomy.

Deterministic Tractography of the Descending Tract of the Spinal Trigeminal Nerve Using Diffusion Tensor Imaging.

BACKGROUND AND PURPOSE: Pain information from the face enters the pons via the trigeminal nerve before creating an anatomical "elbow" that turns caudally into the spinal trigeminal tract (SpTV). Visualization of the descending tract of the trigeminal nerve as it begins its descent from the nerve root entry zone (NREZ) in the pons would improve the accuracy of current procedures aimed at altering or lesioning the trigeminal nerve within the brainstem. The focus of this study was to develop a standardized protocol using diffusion tensor imaging (DTI) and deterministic tractography methods to image the SpTV. There are currently no standard techniques used to visualize the trigeminal nerve using DTI. METHODS: DTI and tractography were performed on 20 patients: 17 with trigeminal neuralgia (TN), 1 with hemifacial spasm, 1 with a facial nerve tumor, and 1 with an arteriovenous malformation. A standardized protocol was developed using regions of interest (ROIs) located at the SpTV, as determined by a brainstem atlas, and the NREZ. RESULTS: Using our standardized protocol, the descending tract of the trigeminal nerve was successfully visualized in all 20 patients. Trigeminal fibers entered the pons at the NREZ and descended through the SpTV. The accuracy of the visualized tract was confirmed through coregistration with a stereotactic atlas and anatomical scan. CONCLUSION: A successful, robust DTI imaging and postprocessing protocol of the SpTV contributes to our understanding of its anatomical distribution within the brainstem and is a potentially new neurosurgical planning tool.

Microsurgical Pontine Descending Tractotomy in Cases of Intractable Trigeminal Neuralgia.

BACKGROUND: Current treatment strategies in patients with trigeminal neuralgia (TN) include trials of medical therapy and surgical intervention, when necessary. In some patients, pain is not adequately managed with these existing strategies. OBJECTIVE: To present a novel technique, ventral pontine trigeminal tractotomy via retrosigmoid craniectomy, as an adjunct treatment in TN when there is no significant neurovascular compression. METHODS: We present a nonrandomized retrospective comparison between 50 patients who lacked clear or impressive arterial neurovascular compression of the trigeminal nerve as judged by preoperative magnetic resonance imaging and intraoperative observations. These patients had intractable TN unresponsive to previous treatment. Trigeminal tractotomy was performed either alone or in conjunction with microvascular decompression. Stereotactic neuronavigation was used during surgery to localize the descending tract via a ventral pontine approach for descending tractotomy. RESULTS: Follow-up was a mean of 44 months. At first follow-up, 80% of patients experienced complete relief of their pain, and 18% had partial relief. At the most recent follow-up, 74% of patients were considered a successful outcome. Only 1 (2%) patient had no relief after trigeminal tractotomy. Of those with multiple sclerosis-related TN, 87.5% experienced successful relief of pain at their latest follow-up. CONCLUSION: While patient selection is a significant challenge, this procedure represents an option for patients with TN who have absent or equivocal neurovascular compression, multiple sclerosis-related TN, or recurrent TN.