Pro-Con Debate: Superior Versus Inferior Triangle Needle Placement in Transforaminal Epidural Injections.

Although transforaminal epidural injections have long been used for radicular pain, there is no universal standard injection approach to the neural foramen. The intervertebral foramen and its surrounding structures comprise an anatomically sensitive area that includes bone and joint structures, the intervertebral disk, blood vessels (in particular, the radicular arteries), the epidural sheath, and the spinal nerve root. Given the relatively high risk of inadvertent injury or injection to these nearby structures, image guidance for transforaminal epidural steroid injections (TFESIs) is standard of care. However, there is a lack of consensus regarding the optimal approach to the neural foramen: from the traditional superior ("safe") triangle or from the inferior (Kambin's) triangle. In this Pro-Con commentary article, we discuss the relative advantages and disadvantages of each approach for TFESIs.

An overview of painful diabetic peripheral neuropathy: Diagnosis and treatment advancements.

Diabetes mellitus remains a public health problem, affecting 422 million people worldwide. Currently, there is no consensus around treating painful diabetic peripheral neuropathy in a step-wise manner. Among the non-pharmacological interventions, neuromodulation has become a promising alternative. Over the past decade, significant clinical trials have paved the way for prompt inclusion of high-frequency spinal cord stimulation within the painful diabetic peripheral neuropathy treatment algorithm. This article aims to provide an updated evidence-based approach for the management of painful diabetic peripheral neuropathy.

The Impact of Clinical Setting on Evaluating Patients Using the PROMIS-29 Baseline Measures in the COVID Era: A Retrospective Multicenter Quantitative Analysis.

BACKGROUND: Multidimensional patient-reported outcomes are a critical part of assessing patients to better understand their well-being during treatment. The PROMIS-29 assessment tool is utilized as a component of assessing multidimensional pain scales. It includes patient-reported measures of pain, mood, sleep, social participation, and function. Currently, there are no data on whether a patient's immediate environment (remote versus in person) influences the reported patient outcomes measurement of a multidimensional tool represented as PROMIS-29 data. METHODS: Retrospective analysis of prospectively collected data was performed. Subjects were identified and consecutively enrolled upon entry into a chronic pain or spine center in the United States. The PROMIS-29 v2.1 was recorded. Statistical differences were assessed among age groups and across the seven domains of the assessment. RESULTS: A total of 25,187 distinct patients were enrolled in the study from August 2018 to December 2020 with a presenting baseline measurement of PROMIS-29. The PROMIS-29 v2.1 was evaluated across the seven domains, and subgroup age analysis was performed for patients completing surveys in the clinical setting (non-remote group) and those completing the survey in the remote setting (remote group) during entry into spine and pain practices across the United States. For mental health scores, those less than 40 years of age and those over 80 years of age showed significant differences in ratings of anxiety and depression in the remote versus non-remote setting. Regarding physical health scores, those aged 60-79 showed a significant difference in the remote versus non-remote ratings for pain interference (p = 0.005; 63.9 vs. 64.4), physical function (p = 0.000; 36.4 vs. 35.7), and fatigue (p = 0.020; 57.2 vs. 57.7), while subjects over 80 years of age showed a statistical difference between the remote versus non-remote setting only in rating physical function (p = 0.025; 33.0 vs. 34). Notably, the rating of sleep disturbance in the remote versus non-remote setting was the only significant variable in the 40-59 age category (p = 0.000; 60.0 vs. 59.1). Those less than 40 years of age also reported a significant difference in the remote versus non-remote setting when rating sleep disturbance (p = 0.000; 60.5 vs. 58.9). With regard to social function, only those older than 80 years showed a significant difference in rating of ability in the remote compared to the non-remote setting (p = 0.031; 39.6 vs. 40.7). CONCLUSIONS: This data set is the first published data describing the influence of environment (remote versus in person) on PROMIS-29 outcome measurements in the chronic pain population.

Interventional Spine and Pain Procedure Credentialing: Guidelines from the American Society of Pain & Neuroscience.

BACKGROUND: The discipline of interventional pain management has changed significantly over the past decade with an expected greater evolution in the next decade. Not only have the number of procedures increased, some of the procedures that were created for spine surgeons are becoming more facile in the hands of the interventional pain physician. Such change has outpaced academic institutions, societies, and boards. When a pain physician is in the credentialing process for novel procedure privileges, it can leave the healthcare system in a challenging situation with little to base their decision upon. METHODS: This paper was developed by a consensus working group from the American Society of Pain and Neuroscience from various disciplines. The goal was to develop processes and resources to aid in the credentialing process. RESULTS: These guidelines from the American Society of Pain and Neuroscience provide background information to help facilities create a process to appropriately credential physicians on novel procedures. They are not intended to serve as a standard or legal precedent. CONCLUSION: This paper serves as a guide for facilities to credential physicians on novel procedures.

Effect of Patient Characteristics on Clinical Outcomes More Than 12 Months Following Dorsal Root Ganglion Stimulation Implantation: A Retrospective Review.

INTRODUCTION: Dorsal root ganglion (DRG) stimulation is an effective treatment option for lower extremity complex regional pain syndrome and other focal pain conditions. However, the patient characteristics that may predict long-term outcomes have not been defined. MATERIALS AND METHODS: This was a retrospective observational study that included 93 patients who were implanted with a DRG stimulator at a single private practice institution. A variety of demographic data was collected. Follow-up results were reviewed from multiple time points more than 12 months. Patients were classified as either "responder" or "nonresponder" status using two different thresholds, "greater than or equal to 50% pain relief" and "greater than or equal to 80% pain relief." RESULTS: A history of prior chronic opioid use was associated with significantly lower rates of responder status based on both a 50% pain relief threshold and 80% pain relief threshold at the one week to one month, three months, and 12-months visits. CONCLUSIONS: This single-center retrospective study found patients prescribed chronic opioids at the time of DRG stimulator implantation had a higher likelihood of less than 50% pain relief and 80% pain relief at one month, three months, and 12 months follow-up visits.

Effect of Patient Characteristics on Reported Outcomes Over 12 Months Following Lumbar Radiofrequency Ablation: A Retrospective Review of 500 Patients.

BACKGROUND: Low back pain is the leading cause of years lost to disability worldwide. Approximately 15% to 45% of chronic low back pain is due to facet joint arthropathy. Currently, no large-scale retrospective studies have investigated long-term clinical predictors of success in individuals receiving radiofrequency ablation (RFA) of the medial branches for facet joint arthropathy. OBJECTIVE: To determine the clinical factors associated with success and failure of RFA of lumbar facet joints at 1-year follow-up. METHODS: Clinical data were gathered from 500 consecutive patients with an International Classification of Diseases (ICD)-10 diagnosis of lumbar spondylosis. VAS pain scores for patients undergoing lumbar medial branch RFA procedures were recorded at multiple time points, up to the 1-year follow-up visit. A responder was defined as having ≥30% improvement in VAS score from the pre-procedural VAS score. For our primary analysis, regression analysis was conducted to identify associations between responder status and patient characteristics, including age, gender, body mass index (BMI), hormone use, opiate dose, and smoking history at multiple time points, up to the 1-year follow-up visit. RESULTS: A total of 500 patients were included in the study. At the 1-year post-RFA follow-up visit, responder status was associated with a lower rate of prior opioid use (43.22% vs. 55.76%, odds ratio 0.60 [95% confidence interval (CI) 0.40 to 0.92], P = 0.018), lower pre-procedural opioid consumption in oral morphine equivalents (10.16 ± 16.02 vs. 14.67 ± 20.65, ß -4.50 [95% CI -8.57 to -0.44], P = 0.030), and a higher pre-VAS pain score (6.36 ± 2.17 vs. 5.85 ± 2.17, ß 0.50 [95% CI 0.06 to 0.95], P = 0.028). There were no significant associations between responder status and age, gender, BMI, hormone use, and smoking history at the 1-year follow-up visit. CONCLUSIONS: Our results suggest that patients prescribed opioids, particularly at higher dosages, may find less pain relief 1 year following RFA for facetogenic pain. Additionally, patients with higher pre-procedural VAS pain scores may be more likely to have a positive response at 1 year.

Pulsed Radiofrequency Ablation: An Alternative Treatment Modality for Radiation-Induced Brachial Plexopathy.

Radiation therapy is used as a form of treatment for various neoplastic diseases. There are many potential adverse effects of this therapy, including radiation-induced neurotoxicity. Radiation-induced brachial plexopathy (RIBP) may occur due to the fibrosis of neural and perineural soft tissues, leading to ischemic damage of the axons and Schwann cells. The dose of radiation exceeds 55 Gy in many patients who develop symptoms [1]. Current incidence in the United States is 1-2%, and RIBP is most commonly seen in patients who have undergone treatment for breast cancer, lung cancer, or lymphoma [1-3]. Common symptoms include numbness, paresthesia, dysesthesia, and occasional numbness of the arm. Pain is present in the shoulder and proximal arm and is typically mild to moderate in severity. Diagnosis is often made based on clinical presentation and evaluation of imaging to rule out concurrent malignant etiologies of the brachial plexus. Current recommended treatment includes physical therapy and medical management with anticonvulsants, tricyclic antidepressants, and selective serotonin-norepinephrine reuptake inhibitors.

An Observational Study of Intraoperative Neuromonitoring as a Safety Mechanism in Placement of Percutaneous Dorsal Root Ganglion Stimulation and Spinal Cord Stimulation Systems.

INTRODUCTION: Percutaneous neurostimulator device placement, specifically dorsal root ganglion (DRG) stimulation and spinal cord stimulation (SCS), involves the placement of thin wires within the spinal canal at specific locations, the DRG or dorsal column of the spinal cord, respectively, to provide an electrical current that modifies the pain signal as it enters the central nervous system from the periphery. Placement of neurostimulator devices is generally safe overall, but not without risk of major and minor complications. In this study, we assess the use of intraoperative neuromonitoring (IONM) as a tool to improve the safety of placing neurostimulator devices and subsequently minimizing postoperative complications. METHODS: After IRB approval, an observational study was performed in 115 procedures to evaluate safety during placement of both temporary and permanent DRG and SCS systems and to document retrospectively any long-standing adverse events. RESULTS: The rate of intraoperative neuromonitoring abnormal activity was 1.7% (n = 2), which allowed prompt recognition of nerve irritation and lead repositioning. Of the 115 consecutive implant cases performed with IONM, the postoperative minor adverse event rate was 1.7% (n = 2), which were transient and corrected with reprogramming. There were no long-standing neurological complications. CONCLUSION: In the largest observational study to date, we show that IONM creates a safe environment for patients undergoing SCS and DRG neurostimulator placement with the potential to decrease neurological complication rates. The use of IONM may be an alternative method to improve patient safety and outcomes as compared to monitor anesthesia care.

Proclaim™ DRG Neurostimulator System for the management of chronic, intractable pain.

Chronic pain is consistently listed as one of the most costly and disabling health problems worldwide. In an effort to treat these suffering individuals, significant amounts of time and energy have been devoted to discover safe and effective pain relieving treatments. Dorsal root ganglion stimulation is the newest treatment modality to be created for chronic intractable pain. In this manuscript, we review the history and development, published research and safety profile of the Proclaim™ DRG Neurostimulator System (Abbott, TX, USA). At last, we offer our outlook on future developments with dorsal root ganglion stimulation.

Device profile of the Proclaim XR neurostimulation system for the treatment of chronic pain: an overview of its safety and efficacy.

INTRODUCTION: Spinal cord stimulation is becoming an increasingly used modality for the treatment of chronic pain. The Proclaim XR implantable pulse generator (IPG) is a novel device designed to supply low-dose BurstDR stimulation in a primary cell battery guaranteed to last 5-10 years with appropriate programming. AREAS COVERED: BurstDR stimulation involves specifically delivered pockets of electrical energy coupled with a passive recharge mechanism to mimic the body's natural neuronal activity. MEDLINE databases were searched with a date range from 2010 to 2020, and a review of the evidence for low amplitude BurstDR stimulation, which led to FDA approval of the Proclaim XR system, is provided. In addition, we will review the safety and precautionary measures involved with this device. EXPERT OPINION: The Proclaim XR IPG is the newest and most advanced device in SCS technology. It is designed to meet the preferences of patients by providing burst low amplitude intermittent dosing in a recharge-free manner and a guaranteed 5-10 year battery life.

Lumbosacral Radiculopathy: Inciting Events and Their Association with Epidural Steroid Injection Outcomes.

OBJECTIVE: Low back pain is the leading cause of worldwide disability, with lumbosacral radiculopathy accounting for over one-third of these cases. There are limited data on the relationship between etiologies and lumbosacral radiculopathy, and it is unknown whether specific causes predict treatment outcomes. DESIGN, SETTING, AND SUBJECTS: This study explores patient-reported etiologies for lumbosacral radiculopathy in a chronic pain clinic between January 2007 and December 2015 and examines whether these causes affected epidural steroid injection outcomes. METHODS: We reviewed the medical records of 1,242 patients with lumbosacral radiculopathy who received epidural steroid injections. The recording of an inciting event was done contemporaneously based on note templates. A positive outcome following an epidural steroid injection was defined as ≥30% pain relief sustained for six or more weeks without additional intervention. Factors associated with epidural steroid injection outcome were analyzed by multivariable logistic regression. RESULTS: Fifty point seven percent reported an inciting event, and 59.9% of patients experienced a positive epidural steroid injection outcome. The most commonly reported causes were falls (13.1%), motor vehicle collisions (10.7%), and lifting (7.8%). Individuals with a herniated disc (56.3%) were more likely to report a precipitating cause than those with stenosis (44.7%) or degenerative discs (47.8%, P = 0.012). An inciting event did not predict treatment outcome. Factors associated with negative treatment outcome included opioid consumption (odds ratio [OR] = 0.61, 95% confidence interval [CI] = 0.39-0.95, P = 0.027), secondary gain (OR = 0.69, 95% CI = 0.50-0.96, P = 0.030), and baseline pain score (OR = 0.90, 95% CI = 0.84-0.97, P = 0.006). The number of levels injected was associated with a positive outcome (OR = 2.72, 95% CI = 1.28-6.47, P = 0.008). CONCLUSIONS: Reported inciting events are common in patients with lumbosacral radiculopathy but are not associated with outcome following epidural steroid injection, and their occurrence is not always consistent with the purported mechanism of injury.

Novel Association of miR-451 with the Incidence of TEVG Stenosis in a Murine Model.

The development of a tissue-engineered vascular graft (TEVG) holds great promise for advancing the field of cardiac surgery. Despite the successful translation of this technology, previous reports identify the primary mode of graft failure as stenosis secondary to intimal hyperplasia. MicroRNAs (miRNAs) regulate gene expression by interfering with mRNA function and recent research has suggested miRNA as a potential therapeutic target. The role of miRNAs in TEVGs during neotissue formation is currently unknown. In this study, we investigated if miRNAs regulate the inhibition of graft stenosis. Biodegradable PGA-P(LA/CL) scaffolds were implanted as inferior vena cava interposition grafts in a murine model (n = 14). Mice were sacrificed 14 days following implantation and TEVGs were harvested for histological analysis and miRNA profiling using Affymetrix miRNA arrays. Graft diameters were measured histologically, and the largest grafts (patent group) and smallest grafts (stenosed group) were profiled (n = 4 for each group). Cell population in each graft was analyzed with immunohistochemistry using antismooth muscle actin (SMA) and antimacrophage (F4/80) antibodies. The graft diameter was significantly greater in the patent group (0.63 ± 0.06 mm) than in the stenosed group (0.17 ± 0.06 mm) (p < 0.01). Cell proliferation was significantly greater in the stenosed grafts than in patent grafts (p < 0.01: SMA [187 ± 11 vs. 77 ± 8 cells] vs. p = 0.025: F4/80 [245 ± 23 vs. 187 ± 11 cells]). MiRNA array of 1416 genes showed that in stenosed grafts, mir-451, mir-338, and mir-466 were downregulated and mir-154 was upregulated. Mir-451 exhibited the greatest difference in expression between stenosed and patent grafts by -3.1-fold. Significant negative correlation was found between the expression of mir-451 and cell proliferation (SMA: r = -0.86, p = 0.003; F4/80: r = -0.89, p = 0.001). Our data, along with previous evidence that mir-451 regulates tumor suppressor genes, suggest that downregulation of mir-451 promotes acute proliferation of macrophages and smooth muscle cells, thereby inducing TEVG stenosis. Adequate expression of mir-451 may be critical for improving TEVG patency.

Single center experience on dosing and adverse events of recombinant factor seven use for bleeding after congenital heart surgery.

There are limited data on the relationship between the administered dose of recombinant factor seven (rFVIIa) and the development of adverse clinical outcomes after congenital heart surgery. This single institution case series reports on dosing, adverse events, and blood product usage after the administration of rFVIIa in the congenital heart surgery patient population. A retrospective review identified 16 consecutive pediatric patients at an academic, free-standing, children's hospital who received rFVIIa to curtail bleeding following congenital heart surgery between April 2004 and June 2012. Patients were assessed for survival to hospital discharge versus in-hospital mortality and the presence or absence of a major neurological event during inpatient hospitalization. The median age at surgery was 6.8 months (range: 3 days-42 years). Seven patients (44%) survived to hospital discharge and nine patients (56%) died. The cause of mortality included major neurological events (44%), uncontrolled bleeding (33%), and sepsis (23%). Eight patients (50%) required extracorporeal membrane oxygenation support following congenital heart surgery. The median cumulative rFVIIa dose administered was 97 mcg/kg, and the median cumulative amount of blood products administered was 452 ml/kg. In conclusion, this case series underscores the need to prospectively evaluate the effect that rFVIIa has on patient survival and the incidence of adverse events, including thrombotic and major neurological events, in congenital heart surgery patients. Ideally, a randomized, multicenter study would provide the sufficient numbers of patients and events to test these relationships.

Twenty-four hour in-hospital congenital cardiac surgical coverage improves perioperative ECMO support outcomes.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) support is often required in the management of perioperative congenital heart surgery (CHS) patients. However, 24-hour in-hospital congenital cardiac surgical coverage (24-CCSC) is not available at all institutions. The purpose of this study is to evaluate the effect of 24-CCSC on perioperative ECMO outcomes in CHS patients. METHODS: An institutional review board approved, retrospective review of 128 perioperative CHS ECMO patients at a single, quaternary care children's hospital between January 2003 and December 2012 was performed. Primary endpoints evaluated were mortality in children supported with ECMO after undergoing cardiac surgery and ECMO-related morbidity after initiation of 24-CCSC with advanced congenital cardiac surgical fellows. Patients were divided into 2 groups based on whether 24-CCSC was absent (cohort 1: January 2003 to July 2007) or present (cohort 2: August 2007 to December 2012) at the time of ECMO management. RESULTS: The surgical procedures performed were similar in both cohorts based on STAT Mortality Categories (5 Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery Congenital Heart Surgery Mortality Categories). The overall mortality rate in children supported with ECMO after undergoing cardiac surgery was 53%. This mortality was significantly reduced from 68% to 43% (p = 0.007) with 24-CCSC. Multivariate logistic regression analysis revealed that 24-CCSC (p = 0.009) and lower STAT Mortality Category (p = 0.042) were independent predictors of operative survival. Cardiac arrhythmias (36% to 16%; p = 0.012) and pulmonary complications (32% to 8%; p < 0.001) were significantly reduced with 24-CCSC. CONCLUSIONS: The presence of 24-CCSC significantly decreased the rate of mortality in children supported with ECMO after undergoing cardiac surgery, as well as cardiac arrhythmias and pulmonary complications for perioperative CHS patients receiving ECMO support. This study demonstrates that CHS programs would benefit from 24-CCSC in the care of this critically ill patient population.

Presolvated low energy electron attachment to peptide methyl esters in aqueous solution: C-O bond cleavage at 77 K.

In this study, the reactions of presolvated electrons with glycine methyl ester and N-acetylalanylalanine methyl ester (N-aAAMe) are investigated by electron spin resonance (ESR) spectroscopy and DFT calculations. Electrons were produced by γ-irradiation in neutral 7.5 M LiCl-D2O aqueous glasses at low temperatures. For glycine methyl ester, electron addition at 77 K results in both N-terminal deamination to form a glycyl radical and C-O ester bond cleavage to form methyl radicals. For samples of N-acetylalanylalanine methyl ester, electrons are found to add to the peptide bonds at 77 K and cleave the carboxyl ester groups to produce methyl radicals. On annealing to 160 K, electron adducts at the peptide links undergo chain scission to produce alanyl radicals and on further annealing to 170 K α-carbon peptide backbone radicals are produced by hydrogen abstraction. DFT calculations for electron addition to the methyl ester portion of N-aAAMe show the cleavage reaction is highly favorable (free energy equals to -30.7 kcal/mol) with the kinetic barrier of only 9.9 kcal/mol. A substantial electron affinity of the ester link (38.0 kcal/mol) provides more than sufficient energy to overcome this small barrier. Protonated peptide bond electron adducts also show favorable N-C chain cleavage reactions of -12.7 to -15.5 kcal/mol with a barrier from 7.4 to 10.0 kcal/mol. The substantial adiabatic electron affinity (AEA) of the peptide bond and ester groups provides sufficient energy for the bond dissociation.

Regression of melanoma metastases after immunotherapy is associated with activation of antigen presentation and interferon-mediated rejection genes.

We present the results of a comparative gene expression analysis of 15 metastases (10 regressing and 5 progressing) obtained from 2 melanoma patients with mixed response following different forms of immunotherapy. Whole genome transcriptional analysis clearly indicate that regression of melanoma metastases is due to an acute immune rejection mediated by the upregulation of genes involved in antigen presentation and interferon mediated response (STAT-1/IRF-1) in all the regressing metastases from both patients. In contrast, progressing metastases showed low transcription levels of genes involved in these pathways. Histological analysis showed T cells and HLA-DR positive infiltrating cells in the regressing but not in the progressing metastases. Quantitative expression analysis of HLA-A,B and C genes on microdisected tumoral regions indicate higher HLA expression in regressing than in progressing metastases. The molecular signature obtained in melanoma rejection appeared to be similar to that observed in other forms of immune-mediated tissue-specific rejection such as allograft, pathogen clearance, graft versus host or autoimmune disease, supporting the immunological constant of rejection. We favor the idea that the major factor determining the success or failure of immunotherapy is the nature of HLA Class I alterations in tumor cells and not the type of immunotherapy used. If the molecular alteration is reversible by the immunotherapy, the HLA expression will be upregulated and the lesion will be recognized and rejected. In contrast, if the defect is structural the MHC Class I expression will remain unchanged and the lesion will progress.

Gene expression profiling in acute allograft rejection: challenging the immunologic constant of rejection hypothesis.

In humans, the role and relationship between molecular pathways that lead to tissue destruction during acute allograft rejection are not fully understood. Based on studies conducted in humans, we recently hypothesized that different immune-mediated tissue destruction processes (i.e. cancer, infection, autoimmunity) share common convergent final mechanisms. We called this phenomenon the "Immunologic Constant of Rejection (ICR)." The elements of the ICR include molecular pathways that are consistently described through different immune-mediated tissue destruction processes and demonstrate the activation of interferon-stimulated genes (ISGs), the recruitment of cytotoxic immune cells (primarily through CXCR3/CCR5 ligand pathways), and the activation of immune effector function genes (IEF genes; granzymes A/B, perforin, etc.). Here, we challenge the ICR hypothesis by using a meta-analytical approach and systematically reviewing microarray studies evaluating gene expression on tissue biopsies during acute allograft rejection. We found the pillars of the ICR consistently present among the studies reviewed, despite implicit heterogeneity. Additionally, we provide a descriptive mechanistic overview of acute allograft rejection by describing those molecular pathways most frequently encountered and thereby thought to be most significant. The biological role of the following molecular pathways is described: IFN-γ, CXCR3/CCR5 ligand, IEF genes, TNF-α, IL-10, IRF-1/STAT-1, and complement pathways. The role of NK cell, B cell and T-regulatory cell signatures are also addressed.