Elevated Serum Alkaline Phosphatase is an Independent Predictor of Complications After Lumbar Spinal Fusion.

BACKGROUND: Alkaline phosphatase (ALP) is an enzyme which has been proven useful as a biomarker for bone turnover and inflammation. We hypothesized that high serum ALP levels are associated with increased complication rates following lumbar spinal fusion. METHODS: Lumbar spinal fusion procedures from 2005 to 2019 were queried from the National Surgical Quality Improvement Program (NSQIP) database. Serum alkaline phosphatase levels were stratified into low <44 IU/L, normal 44-147 IU/L, and high >147 IU/L. A risk-adjusted multivariate logistic regression was used to analyze ALP as an independent risk factor for complications. RESULTS: A total of 16,441 patients who underwent lumbar fusion procedures were included. Adjusted multivariate logistic regression analysis demonstrated that patients with a high serum ALP level had a significantly increased risk for developing septic shock (OR 4.68, 95% CI 1.83-11.97), pneumonia (OR 2.89, 95% CI 1.59-5.25), requiring a transfusion (OR 2.09, 95% CI 1.68-2.59), reoperation within 30 days (OR 1.68, 95% CI 1.12-2.52), readmission within 30 days (OR 1.60, 95% CI 1.16-2.21), increased length of stay (OR 1.87, 95% CI 1.49-2.36), and nonhome discharge (OR 2.18, 95% CI 1.80-2.66). CONCLUSIONS: Elevated serum ALP in patients undergoing lumbar fusion procedures is associated with increased risk for multiple in-hospital complications as well as higher rates of readmission and reoperation.

Cervical Spine Surgery Following COVID-19 Infection: When is it Safe to Proceed?

STUDY DESIGN: Retrospective. OBJECTIVE: We utilized the NIH National COVID Cohort Collaborative (N3C) database to characterize the risk profile of patients undergoing spine surgery during multiple time windows following the COVID-19 infection. SUMMARY OF BACKGROUND DATA: While the impact of COVID-19 on various organ systems is well documented, there is limited knowledge regarding its effect on perioperative complications following spine surgery or the optimal timing of surgery after an infection. METHODS: We asked the National COVID Cohort Collaborative for patients who underwent cervical spine surgery. Patients were stratified into those with an initial documented COVID-19 infection within 3 time periods: 0-2 weeks, 2-6 weeks, or 6-12 weeks before surgery. RESULTS: A total of 29,449 patients who underwent anterior approach cervical spine surgery and 46,379 patients who underwent posterior approach cervical spine surgery were included. Patients who underwent surgery within 2 weeks of their COVID-19 diagnosis had a significantly increased risk for venous thromboembolic events, sepsis, 30-day mortality, and 1-year mortality, irrespective of the anterior or posterior approach. Among patients undergoing surgery between 2 and 6 weeks after COVID-19 infection, the 30-day mortality risk remained elevated in patients undergoing a posterior approach only. Patients undergoing surgery between 6 and 12 weeks from the date of the COVID-19 infection did not show significantly elevated rates of any complications analyzed. CONCLUSIONS: Patients undergoing either anterior or posterior cervical spine surgery within 2 weeks from the initial COVID-19 diagnosis are at increased risk for perioperative venous thromboembolic events, sepsis, and mortality. Elevated perioperative complication risk does not persist beyond 2 weeks, except for 30-day mortality in posterior approach surgeries. On the basis of these results, it may be warranted to postpone nonurgent spine surgeries for at least 2 weeks following a COVID-19 infection and advise patients of the increased perioperative complication risk when urgent surgery is required.

Advances in Imaging (Intraop Cone-Beam Computed Tomography, Synthetic Computed Tomography, Bone Scan, Low-Dose Protocols).

Spine surgery has seen a rapid advance in the refinement and development of 3-dimensional and nuclear imaging modalities in recent years. Cone-beam CT has proven to be a valuable tool for improving the accuracy of pedicle screw placement. The use of synthetic CT and low-dose CT have also emerged as modalities which allow for little to no radiation while streamlining imaging workflows. Bone scans also serve to provide functional information about bone metabolism in both the preoperative and postoperative monitoring phases.

Statistical Fragility of Randomized Controlled Trials Evaluating Platelet-Rich Plasma Use for Knee Osteoarthritis: A Systematic Review.

Background: Numerous studies have been published on the use of platelet-rich plasma (PRP) for knee osteoarthritis (OA), with conflicting results. Purpose: To determine the fragility index (FI) and fragility quotient (FQ) of randomized controlled trials (RCTs) that evaluated the use of PRP to treat knee OA. Study Design: Systematic review. Methods: RCTs evaluating the efficacy of PRP injections for knee OA from 2000 to 2020 were included for analysis according to PRISMA guidelines. The FI was determined by calculating the number of outcome event reversals required to change the statistical significance. The associated FQ was determined by dividing the FI by the sample size. Results: Our initial search resulted in 41,149 studies, of which 8 RCTs (678 patients, 72 outcome events) were included in the analysis. One study failed to report PRP formulation details, whereas 87.5% of studies reported using either leukocyte-rich or leukocyte-poor PRP. The platelet concentration was reported in 25% of the included trials. The overall FI of the 72 outcome events was 8.5. Accounting for sample size, the associated FQ was determined to be 0.14, suggesting that the reversal of 14% of outcome events was required to change outcome significance. There were 51 statistically significant outcomes, of which the FI and FQ were 12 and 0.164, respectively. Conclusion: Comprehensive fragility analysis suggested that the published literature evaluating the efficacy of PRP use for knee OA may lack statistical stability. We recommend the reporting of both an FI and FQ in addition to P value analysis to provide a clear and thorough understanding of the statistical integrity of studies reporting on PRP use for knee OA.

A temporal analysis of perioperative complications following COVID-19 infection in patients undergoing lumbar spinal fusion: When is it safe to proceed?

Background Context: COVID-19 has been shown to adversely affect multiple organ systems, yet little is known about its effect on perioperative complications after spine surgery or the optimal timing of surgery after an infection. We used the NIH National COVID Cohort Collaborative (N3C) database to characterize the risk profile in patients undergoing spine surgery during multiple time windows following COVID-19 infection. Methods: We queried the National COVID Cohort Collaborative, a database of 17.4 million persons with 6.9 million COVID-19 cases, for patients undergoing lumbar spinal fusion surgery. Patients were stratified into those with an initial documented COVID-19 infection within 3 time periods: 0 to 2 weeks, 2 to 6 weeks, or 6 to 12 weeks before surgery. Results: A total of 60,541 patients who underwent lumbar spinal fusion procedures were included. Patients who underwent surgery within 2 weeks of their COVID-19 diagnosis had a significantly increased risk for venous thromboembolic events (OR 2.29, 95% CI 1.58-3.32), sepsis (OR 1.56, 95% CI 1.03-2.36), 30-day mortality (OR 5.55, 95% CI 3.53-8.71), and 1-year mortality (OR 2.70, 95% CI 1.91-3.82) compared with patients who were COVID negative during the same period. There was no significant difference in the rates of acute kidney injury or surgical site infection. Patients undergoing surgery between 2 and 6 weeks or between 6 and 12 weeks from the date of COVID-19 infection did not show significantly elevated rates of any complication analyzed. Conclusions: Patients undergoing lumbar spinal fusion within 2 weeks from initial COVID-19 diagnosis are at increased risk for perioperative venous thromboembolic events and sepsis. This effect does not persist beyond 2 weeks, however, so it may be warranted to postpone non-urgent spine surgeries for at least 2 weeks following a COVID-19 infection or to consider a more aggressive VTE chemoprophylaxis regimen for urgent surgery in COVID-19 patients.

Hand Replantation With Dorsal Spanning Plate Following a Self-Inflicted Radiocarpal Amputation.

Upper extremity amputations represent a prime opportunity to restore function through replantation. There are a variety of options that treating surgeons use to protect neurovascular repairs and restore function including Kirschner wire fixation, external fixation, wrist arthrodesis, and proximal row carpectomy. Additionally, the dorsal spanning plate may be a valuable tool for protecting neurovascular repairs. Compared to temporary immobilization with Kirschner wire fixation, which has previously been described in conjunction with upper extremity replantation, dorsal spanning plates can be left in place for longer durations with a lower risk of loosening and loss of fixation and for preventing postoperative sabotage or repeat amputation of the replant by the patient. In this article, we describe a unique case of a patient with acute psychiatric illness that presented with a self-inflicted amputation through the radiocarpal joint and was initially treated with emergent replantation and application of a dorsal spanning plate to protect the neurovascular repair from patient sabotage and allow for early rehabilitation. We found the dorsal spanning plate to be an effective option in this complex clinical scenario. This case illustrates the utility of the dorsal spanning plate in protecting complex neurovascular repairs in the setting of severe skeletal and psychiatric instability.

Patient Likelihood to Repeat Surgery After Highly "Successful" Hand Procedures.

BACKGROUND: Outcomes for routine hand procedures, such as carpal tunnel release, trigger finger release, and first dorsal compartment release, are typically reported as "highly successful" with "infrequent complications" based on classic literature. No contemporary study has utilized a large prospective registry to assess patient willingness to repeat surgery. We utilized a prospective hand registry to evaluate the proportion of patients that would repeat surgery after common hand procedures. METHODS: We utilized a prospective, hand surgery registry to collect postoperative patient likelihood to repeat surgery in patients undergoing surgery for 9 common hand procedures. All measures were reported at 12, 24, or 52 weeks. We analyzed the percentage of patients that would repeat the procedure for all diagnoses, as well as stratified by the most common 9 isolated diagnoses. RESULTS: At the time of analysis, 1905 patients met our inclusion criteria. The average percentage of patients across all procedures that would repeat surgery was 81.6%. When stratified by the most common 9 diagnoses the percentage of patients that would repeat surgery ranged from 51.9% (ulnar nerve surgery at the elbow) up to 87.5% (endoscopic carpal tunnel release). CONCLUSIONS: After undergoing routine hand procedures, a significant percentage of patients would choose not to repeat surgery. Hand surgeons can do better in setting clear and realistic preoperative expectations when counseling patients prior to even routine hand surgeries.

Return to Work and Sport After Distal Femoral Osteotomy: A Systematic Review.

CONTEXT: Distal femoral osteotomy (DFO) is a joint preservation procedure that corrects genu valgum deformities and patellofemoral maltracking, thereby restoring kinematics and unloading contact pressures in the lateral tibiofemoral and patellofemoral compartments. OBJECTIVE: To evaluate the rates of return to work (RTW) and return to sport (RTS) after DFO for valgus malalignment and lateral compartment osteoarthritis through a systematic review of the literature. DATA SOURCES: A systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was conducted on the PubMed, Cochrane, and Embase databases. STUDY SELECTION: The search terms femoral osteotomy AND (sports OR work) were used. Studies in which patients underwent concomitant total knee arthroplasty were excluded. STUDY DESIGN: Systematic review. LEVEL OF EVIDENCE: Level 4 (systematic review of level 4 studies). DATA EXTRACTION: Data included the number of patients, age, gender, laterality of operation, time to follow-up, rate of RTW and RTS, time to RTS, activity level on return, and activity level scores (Tegner, Marx, Lysholm, and the International Knee Documentation Committee). Risk of bias was assessed using the Methodological Index for Non-Randomized Studies (MINORS) criteria. RESULTS: Seven articles with 194 patients were included. The average age ranged from 19 to 49 years with a mean postoperative follow-up range of 36 to 90 months. RTW data were available for 125 patients, of whom 42.1% to 91.3% returned by final follow-up. Data on RTS were available for 149 patients, of whom 70% to 100% returned at a range of 8.3 to 16.9 months postoperatively, and 41.6% to 100% returned to the same or greater level of sports activity. The Tegner and Marx activity level scores ranged from 3 to 4 and from 5 to 11, respectively, at final follow-up. CONCLUSION: Patients treated with DFO reported high rates of RTW and RTS, with most patients being able to return to recreational sport after surgery.

Blood Coagulation Factor Fibrinogen in Tumor Pathogenesis of Central Nervous System B-Cell Lymphoma.

Central nervous system (CNS) lymphoma is an extranodal non-Hodgkin B-cell lymphoma characterized by malignant lymph tissue arising in the brain or spinal cord, associated with inflammation and blood-brain barrier (BBB) disruption. Although BBB disruption is known to occur in patients with CNS lymphoma, a direct link between these two has not been shown. Herein, abundant deposition of the blood coagulation protein fibrinogen around B-cell lymphoma was detected in CNS lymphoma patients and in the CNS parenchyma in an orthotopic mouse model. Functional enrichment analysis of unbiased cerebrospinal fluid proteomics of CNS B-cell lymphoma patients showed that coagulation protein networks were highly connected with tumor-associated biological signaling pathways. In vivo two-photon imaging demonstrated that lymphoma growth was associated with BBB disruption, and in vitro experiments identified a role for fibrinogen in promoting lymphoma cell adhesion. Overall, these results identify perivascular lymphoma clustering at sites of fibrinogen deposition, and suggest that fibrinogen may be a target for pharmacologic intervention in metastatic B-cell lymphoma associated with BBB disruption.

Human motor endplate remodeling after traumatic nerve injury.

OBJECTIVE: Current management of traumatic peripheral nerve injuries is variable with operative decisions based on assumptions that irreversible degeneration of the human motor endplate (MEP) follows prolonged denervation and precludes reinnervation. However, the mechanism and time course of MEP changes after human peripheral nerve injury have not been investigated. Consequently, there are no objective measures by which to determine the probability of spontaneous recovery and the optimal timing of surgical intervention. To improve guidance for such decisions, the aim of this study was to characterize morphological changes at the human MEP following traumatic nerve injury. METHODS: A prospective cohort (here analyzed retrospectively) of 18 patients with traumatic brachial plexus and axillary nerve injuries underwent biopsy of denervated muscles from the upper extremity from 3 days to 6 years after injury. Muscle specimens were processed for H & E staining and immunohistochemistry, with visualization via confocal and two-photon excitation microscopy. RESULTS: Immunohistochemical analysis demonstrated varying degrees of fragmentation and acetylcholine receptor dispersion in denervated muscles. Comparison of denervated muscles at different times postinjury revealed progressively increasing degeneration. Linear regression analysis of 3D reconstructions revealed significant linear decreases in MEP volume (R = -0.92, R2 = 0.85, p = 0.001) and surface area (R = -0.75, R2 = 0.56, p = 0.032) as deltoid muscle denervation time increased. Surprisingly, innervated and structurally intact MEPs persisted in denervated muscle specimens from multiple patients 6 or more months after nerve injury, including 2 patients who had presented > 3 years after nerve injury. CONCLUSIONS: This study details novel and critically important data about the morphology and temporal sequence of events involved in human MEP degradation after traumatic nerve injuries. Surprisingly, human MEPs not only persisted, but also retained their structures beyond the assumed 6-month window for therapeutic surgical intervention based on previous clinical studies. Preoperative muscle biopsy in patients being considered for nerve transfer may be a useful prognostic tool to determine MEP viability in denervated muscle, with surviving MEPs also being targets for adjuvant therapy.

Examination of the human motor endplate after brachial plexus injury with two-photon microscopy.

INTRODUCTION: After traumatic nerve injury, neuromuscular junction remodeling plays a key role in determining functional outcomes. Immunohistochemical analyses of denervated muscle biopsies may provide valuable prognostic data regarding clinical outcomes to supplement electrodiagnostic studies. METHODS: We performed biopsies on nonfunctioning deltoid muscles in two patients after gunshot wounds and visualized the neuromuscular junctions using two-photon microscopy with immunohistochemistry. RESULTS: Although the nerves in both patients showed evidence of acute Wallerian degeneration, some of the motor endplates were intact but exhibited significantly decreased surface area and volume. Both patients exhibited substantial recovery of motor function over several weeks postinjury. DISCUSSION: Two-photon microscopic assessment of neuromuscular junction integrity and motor endplate morphometry in muscle biopsies provided evidence of partial sparing of muscle innervation. This finding supported the clinical judgment that eventual recovery would occur. With further study, this technique may help to guide operative decisionmaking after traumatic nerve injuries.

Lessons From Leprosy: Peripheral Neuropathies and Deformities in Chronic Demyelinating Diseases.

In light of the World Health Organization's push to accelerate progress toward a leprosy-free world by 2020, it is fitting to look back on the evolution of progress in treating lepromatous neuropathy and limb deformities. To date, no surgeon has had as great an impact on the understanding and treatment of this disease as Dr Paul Brand. Before Dr Brand's accomplishments, few surgeons participated in the management of the deformed leprous patient. By challenging conventional beliefs, Dr Brand revealed that many of the deformities associated with leprosy were in fact caused by nerve damage and subsequent limb anesthesia. His pioneering work centered on tendon transfers to provide hand and foot mobility to leprous patients, revolutionizing the surgical management of this patient population and restoring functionality to the lives of otherwise stigmatized and functionally handicapped individuals. In the process, he provided us with the surgical principles and techniques that we still apply today. Because of its predilection for the peripheral nervous system, leprosy also provides an excellent opportunity to investigate mechanisms of demyelination and chronic nerve degeneration in nonacute peripheral neuropathies. Processes underlying demyelination of infectious, traumatic, and genetic etiologies overlap and precede the onset of acute neuronal derangement. Glial pathology has been shown to be a common pathological element in leprosy, Charcot-Marie-Tooth type I, multiple sclerosis, and chronic nerve compression injury. The aim of this article is to provide an overview of lepromatous neuropathy with its subsequent deformities as it relates to the pathophysiology, surgical management, and potential therapeutic targets of other modern peripheral neuropathies.

Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration.

Activation of innate immunity and deposition of blood-derived fibrin in the central nervous system (CNS) occur in autoimmune and neurodegenerative diseases, including multiple sclerosis (MS) and Alzheimer's disease (AD). However, the mechanisms that link disruption of the blood-brain barrier (BBB) to neurodegeneration are poorly understood, and exploration of fibrin as a therapeutic target has been limited by its beneficial clotting functions. Here we report the generation of monoclonal antibody 5B8, targeted against the cryptic fibrin epitope γ377-395, to selectively inhibit fibrin-induced inflammation and oxidative stress without interfering with clotting. 5B8 suppressed fibrin-induced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and the expression of proinflammatory genes. In animal models of MS and AD, 5B8 entered the CNS and bound to parenchymal fibrin, and its therapeutic administration reduced the activation of innate immunity and neurodegeneration. Thus, fibrin-targeting immunotherapy inhibited autoimmunity- and amyloid-driven neurotoxicity and might have clinical benefit without globally suppressing innate immunity or interfering with coagulation in diverse neurological diseases.

p75 Neurotrophin Receptor Regulates Energy Balance in Obesity.

Obesity and metabolic syndrome reflect the dysregulation of molecular pathways that control energy homeostasis. Here, we show that the p75 neurotrophin receptor (p75(NTR)) controls energy expenditure in obese mice on a high-fat diet (HFD). Despite no changes in food intake, p75(NTR)-null mice were protected from HFD-induced obesity and remained lean as a result of increased energy expenditure without developing insulin resistance or liver steatosis. p75(NTR) directly interacts with the catalytic subunit of protein kinase A (PKA) and regulates cAMP signaling in adipocytes, leading to decreased lipolysis and thermogenesis. Adipocyte-specific depletion of p75(NTR) or transplantation of p75(NTR)-null white adipose tissue (WAT) into wild-type mice fed a HFD protected against weight gain and insulin resistance. Our results reveal that signaling from p75(NTR) to cAMP/PKA regulates energy balance and suggest that non-CNS neurotrophin receptor signaling could be a target for treating obesity and the metabolic syndrome.

Blood coagulation protein fibrinogen promotes autoimmunity and demyelination via chemokine release and antigen presentation.

Autoimmunity and macrophage recruitment into the central nervous system (CNS) are critical determinants of neuroinflammatory diseases. However, the mechanisms that drive immunological responses targeted to the CNS remain largely unknown. Here we show that fibrinogen, a central blood coagulation protein deposited in the CNS after blood-brain barrier disruption, induces encephalitogenic adaptive immune responses and peripheral macrophage recruitment into the CNS leading to demyelination. Fibrinogen stimulates a unique transcriptional signature in CD11b(+) antigen-presenting cells inducing the recruitment and local CNS activation of myelin antigen-specific Th1 cells. Fibrinogen depletion reduces Th1 cells in the multiple sclerosis model, experimental autoimmune encephalomyelitis. Major histocompatibility complex (MHC) II-dependent antigen presentation, CXCL10- and CCL2-mediated recruitment of T cells and macrophages, respectively, are required for fibrinogen-induced encephalomyelitis. Inhibition of the fibrinogen receptor CD11b/CD18 protects from all immune and neuropathologic effects. Our results show that the final product of the coagulation cascade is a key determinant of CNS autoimmunity.

Nuclear pore complex remodeling by p75(NTR) cleavage controls TGF-ß signaling and astrocyte functions.

Astrocytes modulate neuronal activity and inhibit regeneration. We show that cleaved p75 neurotrophin receptor (p75(NTR)) is a component of the nuclear pore complex (NPC) required for glial scar formation and reduced gamma oscillations in mice via regulation of transforming growth factor (TGF)-ß signaling. Cleaved p75(NTR) interacts with nucleoporins to promote Smad2 nucleocytoplasmic shuttling. Thus, NPC remodeling by regulated intramembrane cleavage of p75(NTR) controls astrocyte-neuronal communication in response to profibrotic factors.