Radiographic lead migration in percutaneous spinal cord stimulator trials.

INTRODUCTION: Lead migration during spinal cord stimulator (SCS) trials is relatively neglected in the literature and presents a different set of challenges compared with fully implanted leads. There is no consensus on what constitutes a clinically significant amount of radiographic lead migration during SCS trials. We wished to evaluate the incidence and extent of radiographic lead migration during percutaneous SCS trials, to investigate the risk factors for lead migration and whether this has impacted on trial success. METHODS: This prospective observational study of percutaneous SCS trials took place in a tertiary referral center in the UK between April 2021 and January 2022. Radiographs of SCS lead position were taken at baseline and prior to lead removal. Lead migration ≥50% of a vertebral level was deemed significant. RESULTS: One hundred trials were included comprising 162 leads. Mean migration distance was 0.55 vertebral levels (SD 0.85) or 12.5 mm (SD 18.2) in a caudal direction. Significant radiographic migration occurred in 50% of all leads (81 of 162 leads), at least one lead in 62% of cases and all leads in 44% of cases. Radiographic lead migration was not found to be associated with reduced trial success. A single lead and mechanical anchors were associated with greater incidence of lead migration. CONCLUSION: Radiographic lead migration of approximately half of a vertebral level in a caudal direction can be expected during percutaneous SCS trials and this can be anticipated by siting leads half of a vertebral level higher to accommodate for this. Additional factors should be considered in the setting of radiographic lead migration to determine whether this can be considered clinically significant.

Cerebrospinal fluid immune cells appear similar across neuropathic and non-neuropathic pain conditions.

Background: Microglia have been implicated in the pathophysiology of neuropathic pain. Here, we sought to investigate whether cerebrospinal fluid (CSF) might be used as a proxy-measure of microglial activation in human participants. Methods: We preformed fluorescence-activated cell sorting (FACS) of CSF immune cell populations derived from individuals who experienced pain with neuropathic features. We sorted CD4+, CD8+ T cells and monocytes and analyzed their transcriptome using RNA sequencing. We also performed Cellular Indexing of Transcriptomes and Epitopes (CITE) sequencing to characterize the expression of all CSF immune cells in a patient with postherpetic neuralgia and in a patient with neuropathic pain after failed back surgery. Results: Immune cell numbers and phenotypes were not obviously different between individuals regardless of the etiology of their pain. This was true when examining our own dataset, as well as when comparing it to previously published single-cell RNA sequencing data of human CSF. In all instances, CSF monocytes showed expression of myeloid cell markers commonly associated with microglia ( P2RY12, TMEM119 and OLFML3), which will make it difficult to ascertain the origin of CSF proteins: do they derive directly from circulating CSF monocytes or could some originate in spinal cord microglia in the parenchyma? Conclusions: We conclude that it will not be straightforward to use CSF as a biomarker for microglial function in humans.

Examination and characterisation of the effect of amitriptyline therapy for chronic neuropathic pain on neuropeptide and proteomic constituents of human cerebrospinal fluid.

INTRODUCTION: Amitriptyline is prescribed to reduce the intensity of chronic neuropathic pain. There is a paucity of validated in vivo evidence in humans regarding amitriptyline's mechanism of action. We examined the effect of amitriptyline therapy on cerebrospinal fluid (CSF) neuropeptides and proteome in patients with chronic neuropathic pain to identify potential mechanisms of action of amitriptyline. METHODS: Patients with lumbar radicular neuropathic pain were selected for inclusion with clinical and radiological signs and a >50% reduction in pain in response to a selective nerve root block. Baseline (pre-treatment) and 8-week (post-treatment) pain scores with demographics were recorded. CSF samples were taken at baseline (pre-treatment) and 8 weeks after amitriptyline treatment (post-treatment). Proteome analysis was performed using mass spectrometry and secreted cytokines, chemokines and neurotrophins were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: A total of 9/16 patients experienced a >30% reduction in pain after treatment with amitriptyline and GO analysis demonstrated that the greatest modulatory effect was on immune system processes. KEGG analysis also identified a reduction in PI3K-Akt and MAPK signalling pathways in responders but not in non-responders. There was also a significant decrease in the chemokine eotaxin-1 (p â€‹= â€‹0.02) and a significant increase in the neurotrophin VEGF-A (p â€‹= â€‹0.04) in responders. CONCLUSION: The CSF secretome and proteome was modulated in responders to amitriptyline verifying many pre-clinical and in vitro models. The predominant features were immunomodulation with a reduction in pro-inflammatory pathways of neuronal-glia communications and evidence of a neurotrophic effect.

Multicentre, clinical trial of burst spinal cord stimulation for neck and upper limb pain NU-BURST: a trial protocol.

BACKGROUND: Spinal cord stimulation (SCS) is an established therapy for chronic neuropathic pain and most frequently utilised for Failed Back Surgery Syndrome (FBSS). BurstDR™ also known as DeRidder Burst-SCS, a novel waveform, has demonstrated superiority to conventional tonic stimulation of the thoracic spine in FBSS. There are case reports of an improvement in multidimensional pain outcomes using DeRidder Burst-SCS in the cervical spine for chronic neck and cervical radicular pain. The safety and efficacy of cervical DeRidder Burst-SCS stimulation still however remain undetermined. METHODS/DESIGN: This is a prospective, multicentre feasibility trial evaluating the safety and therapeutic efficacy of DeRidder Burst-SCS stimulation for the treatment of chronic intractable neck pain with or without radiation to the arm, shoulder, and upper back. After baseline evaluation, subjects will undergo an SCS trial using the Abbott Invisible Trial system according to standard clinical procedures. During the trial phase, SCS leads will be implanted in the cervical epidural space. At the end of the SCS trial, subjects experiencing at least 50% pain relief will be considered for permanent implant. Pain intensity, medication usage, and other multidimensional pain outcomes will be collected. The timing of these will be at baseline, end of the SCS trial and at 3-, 6-, and 12-month visits. Incidence of adverse events will be collected throughout the study duration. DISCUSSION: The results of this feasibility study will validate the efficacy and safety of DeRidder Burst-SCS stimulation in the cervical spine. The results obtained in this study will potentially be used to generate a level 1 evidence-based study with formal statistical hypotheses testing. TRIAL REGISTRATION: www.clinicaltrials.gov Identifier: NCT03159169.

Cascade Programming for 10 kHz Spinal Cord Stimulation: A Single Center Case Series of 114 Patients With Neuropathic Back and Leg Pain.

OBJECTIVE: Ten kilohertz spinal cord stimulation (SCS) is usually initiated in a single-bipolar configuration over the radiological reference point T9/T10 intervertebral disc space for neuropathic back and leg pain. Cascade is a duty-cycled, multi-bipolar contact configuration across an entire eight-contact lead. Potential advantages by using a broader area of SCS coverage include mitigation against minor lead migration and a reduction in the need for reprogramming. We report here the results of a retrospective case series of 114 patients using Cascade. MATERIALS AND METHODS: Retrospective data were collected over two years. We selected patients with neuropathic back with or without/leg pain who had a trial of SCS. Pain assessments using Numerical Rating Scales (NRS) and Patient Global Impression of Change (PGIC) scores were collected at baseline, six months, and last follow-up beyond 12 months (mean 15.1 months). Patients were programmed with 10 kHz SCS using Cascade during the trial, which was continued unless reporting inadequate pain relief. Morbidity and deviations from Cascade programming were also obtained. RESULTS: At six months, 87 of 97 (90.6%) patients with active devices were using Cascade and 58 of 72 (81%) patients at the last follow-up >12 months. There was a significant reduction in back NRS (8.3 vs. 3.9 [p < 0.0001], N = 97) and leg pain (7.53 vs. 3.83 [p < 0.0001], N = 77) at 6 months and last follow-up >12 months back (8.3 vs. 3.95 [p < 0.0001] N = 72), leg (7.53 vs. 3.534 [p < 0.0001], N = 58). The PGIC score was 6 of 7 or all of 7 in 72% of patients (70/97) at six months and in 68% (49/72) of patients at the last follow-up beyond 12 months. CONCLUSION: Cascade is an effective programming methodology that may have benefits over a single-bipole configuration for 10 kHz SCS, particularly during a trial of stimulation. Results from this study suggest it is a durable program for patients with neuropathic back and leg pain.

An Investigation into Proteomic Constituents of Cerebrospinal Fluid in Patients with Chronic Peripheral Neuropathic Pain Medicated with Opioids- a Pilot Study.

The pharmacodynamics of opioids for chronic peripheral neuropathic pain are complex and likely extend beyond classical opioid receptor theory. Preclinical evidence of opioid modulation of central immune signalling has not been identified in vivo in humans. Examining the cerebrospinal fluid (CSF) of patients medicated with opioids is required to identify potential pharmacodynamic mechanisms. We compared CSF samples of chronic peripheral neuropathic pain patients receiving opioids (n = 7) versus chronic peripheral neuropathic pain patients not taking opioids (control group, n = 13). Baseline pain scores with demographics were recorded. Proteome analysis was performed using mass spectrometry and secreted neuropeptides were measured by enzyme-linked immunosorbent assay. Based on Gene Ontology analysis, proteins involved in the positive regulation of nervous system development and myeloid leukocyte activation were increased in patients taking opioids versus the control group. The largest decrease in protein expression in patients taking opioids were related to neutrophil mediated immunity. In addition, notably higher expression levels of neural proteins (85%) and receptors (80%) were detected in the opioid group compared to the control group. This study suggests modulation of CNS homeostasis, possibly attributable to opioids, thus highlighting potential mechanisms for the pharmacodynamics of opioids. We also provide new insights into the immunomodulatory functions of opioids in vivo.

Explant rates of electrical neuromodulation devices in 1177 patients in a single center over an 11-year period.

INTRODUCTION: The publication of explant rates has established risk factors and a definitive objective outcome of failure for spinal cord stimulation (SCS) treating neuropathic pain. We present a UK study analyzing explants of electrical neuromodulation devices for different conditions over 11 years in a single center specializing in neuromodulation. METHODS: A retrospective analysis was performed using a departmental database between 2008 and 2019. Explants were analyzed according to condition, mode of stimulation and other demographics using logistic regression and Kaplan-Meier graphs with log-rank (Mantel-Cox) test. RESULTS: Out of a total of 1177 patients, the explant rate was 17.8% at 5 years and 25.2% at 10 years. Loss of efficacy was the most frequent reason for explant 119/181 (65%). Multivariant regression analysis indicated patients with back pain without prior surgery had a reduced risk of explant (p=0.03). Patients with SCS systems that had 10 kHz, options of multiple waveforms, and rechargeable batteries also had a decreased risk of explant (p<0.001). None of these findings were confirmed when comparing Kaplan-Meier graphs, however. Contrary to other studies, we found gender and age were not independent variables for explant. CONCLUSION: These data contribute to a growing list of explant data in the scientific literature and give indications of what factors contribute to long-term utilization of electrical neuromodulation devices.

Examination and characterisation of burst spinal cord stimulation on cerebrospinal fluid cellular and protein constituents in patient responders with chronic neuropathic pain - A Pilot Study.

INTRODUCTION: Patients with neuropathic pain have altered proteomic and neuropeptide constituents in cerebrospinal fluid (CSF) compared to controls. Tonic spinal cord stimulation (SCS) has demonstrated differential expression of neuropeptides in CSF before and after treatment suggesting potential mechanisms of action. Burst-SCS is an evidence-based paraesthesia free waveform utilised for neuropathic pain with a potentially different mechanistic action to tonic SCS. This study examines the dynamic biological changes of CSF at a cellular and proteome level after Burst-SCS. METHODS: Patients with neuropathic pain selected for SCS had CSF sampled prior to implant of SCS and following 8 weeks of continuous Burst-SCS. Baseline and 8-week pain scores with demographics were recorded. T cell frequencies were analysed by flow cytometry, proteome analysis was performed using mass spectrometry and secreted cytokines, chemokines and neurotrophins were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: 4 patients (2 females, 2 males) with a mean age of 51 years (+/-SEM 2.74, SD 5.48) achieved a reduction in pain of >50% following 8 weeks of Burst-SCS. Analysis of the CSF proteome indicated a significant alteration in protein expression most related to synapse assembly and immune regulators. There was significantly lower expression of the proteins: growth hormone A1 (PRL), somatostatin (SST), nucleobindin-2 (NUCB2), Calbindin (CALB1), acyl-CoA binding protein (DBI), proSAAS (PCSK1N), endothelin-3 (END3) and cholecystokinin (CCK) after Burst-SCS. The concentrations of secreted chemokines and cytokines and the frequencies of T cells were not significantly changed following Burst-SCS. CONCLUSION: This study characterised the alteration in the CSF proteome in response to burst SCS in vivo. Functional analysis indicated that the alterations in the CSF proteome is predominately linked to synapse assembly and immune effectors. Individual protein analysis also suggests potential supraspinal mechanisms.

Multicentre, double-blind, randomised, sham-controlled trial of 10 khz high-frequency spinal cord stimulation for chronic neuropathic low back pain (MODULATE-LBP): a trial protocol.

INTRODUCTION: Chronic neuropathic low back pain (CNLBP) is a debilitating condition in which established medical treatments seldom alleviate symptoms. Evidence demonstrates that high-frequency 10 kHz spinal cord stimulation (SCS) reduces pain and improves health-related quality of life in patients with failed back surgery syndrome (FBSS), but evidence of this effect is limited in individuals with CNLBP who have not had surgery. The aim of this multicentre randomised trial is to assess the clinical and cost-effectiveness of 10 kHz SCS for this population. METHODS: This is a multicentre, double-blind, randomised, sham-controlled trial with a parallel economic evaluation. A total of 96 patients with CNLBP who have not had spinal surgery will be implanted with an epidural lead and a sham lead outside the epidural space without a screening trial. Patients will be randomised 1:1 to 10 kHz SCS plus usual care (intervention group) or to sham 10 kHz SCS plus usual care (control group) after receiving the full implant. The SCS devices will be programmed identically using a cathodal cascade. Participants will use their handheld programmer to alter the intensity of the stimulation as per routine practice. The primary outcome will be a 7-day daily pain diary. Secondary outcomes include the Oswestry Disability Index, complications, EQ-5D-5 L, and health and social care costs. Outcomes will be assessed at baseline (pre-randomisation) and at 1 month, 3 months and 6 months after device activation. The primary analyses will compare primary and secondary outcomes between groups at 6 months, while adjusting for baseline outcome scores. Incremental cost per quality-adjusted life year (QALY) will be calculated at 6 months and over the lifetime of the patient. DISCUSSION: The outcomes of this trial will inform clinical practice and healthcare policy on the role of high-frequency 10 kHz SCS for use in patients with CNLBP who have not had surgery. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03470766. Registered on 20 March 2018. DISCLAIMER: The views expressed here are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The NIHR had no role in the study design, writing of the manuscript or the decision to submit for publication. ROLES AND RESPONSIBILITIES: AK, SP, DP, SW, RST, AC, SE, LM, RD and JF all contributed to the trial design and to securing trial funding. AK, JR, SP, DP, and SE are involved in the recruitment, the intervention and the follow-up. SW will perform data collection and analysis. RST will be responsible for the statistical analysis, and RD will be responsible for the health economic analysis. All authors read and approved the final manuscript.

An investigation into the modulation of T cell phenotypes by amitriptyline and nortriptyline.

Amitriptyline is prescribed for treating the symptoms of neuroinflammatory disorders including neuropathic pain and fibromyalgia. As amitriptyline has evidence of modulating the neuroimmune interface; the effects of amitriptyline treatment on T-cell phenotype and function were examined in vitro. Peripheral blood mononuclear cells(PBMCs) were isolated and treated with amitriptyline, nortriptyline and a combination of both drugs. Toxicity for T-cells was assessed by Annexin V/Propidium Iodide staining. Activation status and cytokine expression by T-cells post treatment was assessed by flow cytometry. The levels of secreted cytokines, chemokines and neurotrophins were measured by ELISA in the supernatants. There was no significant increase in T-cell death following 24 or 48 h compared to controls. There were significantly lower frequencies of CD8+ T-cells after treatment with amitriptyline, nortriptyline and a combination of both compared to a Vehicle Control(VC)(p<0.001). The frequencies of naive CD8+CD45RA+ cells were significantly lower after amitriptyline, nortriptyline and a combination of both (p<0001). The frequencies of CD27+CD4+(p<0.05) and CD27+CD8+(p<0.01) T-cells were also significantly lower following combination drug treatment. Significantly lower frequencies of IFN-γ-producing CD8+ T-cells were observed with all treatment combinations(p<0.05) and frequencies of IL-17-producing CD4+ and CD8+ T-cells were significantly lower following amitriptyline treatment (p<0.05). Frequencies of Natural Killer T-cells were significantly higher following treatment with nortriptyline (p<0.05). Significantly higher levels of IL-16 (p<0.001) and lower levels of TNF-ß (p<0.05) were observed in supernatants. This data indicates that both amitriptyline and nortriptyline modulate the phenotype and function of T-cells and this may have clinical relevance in the pathologies of its off-label applications.

Effectiveness of "Transgrade" Epidural Technique for Dorsal Root Ganglion Stimulation. A Retrospective, Single-Center, Case Series for Chronic Focal Neuropathic Pain.

BACKGROUND: The recent interest in targeting the dorsal root ganglion (DRG) has led to the development of new techniques of electrode placement. In this article, we describe a new "Transgrade" approach to the DRG, accessing the contralateral interlaminar space and steering the lead out the opposite foramen. OBJECTIVES: The purpose of this study was to evaluate the Transgrade technique to the DRG in the management of focal neuropathic pain, predominately complex regional pain syndrome in terms of efficacy and safety. STUDY DESIGN: A retrospective, observational review of all patients selected for DRG stimulation using the Transgrade technique to the DRG. SETTING: Pain Management and Neuromodulation Centre, Guys and St. Thomas NHS Foundation Trust, London, United Kingdom. METHODS: Data were taken from a hospital password-protected database. All patients were contacted by telephone for Numeric Rating Scale (NRS-11) score, Patient Global Impression of Change (PGIC) score, and complications. A patient responder was defined as having a PGIC score of 6 or 7, and a 2-point reduction from baseline NRS-11. RESULTS: A total of 39 patients (46% women) with a mean age of 46 years (± 2) underwent a trial of DRG stimulation that resulted in an implantation rate of 82% (32 of 39). The responder rates, according to NRS-11 and PGIC results, were 87% (28 of 32) at 6 weeks and 66% (21 of 32) at a mean of 18 months (± 1.8) follow-up. Pocket pain was the most common complication, occurring in 7 of 32 (22%) patients, and the lead migration rate was 3 out of 57 leads placed (5.2%). A burst protocol was the favored method of stimulation in the majority of patients, 25 of 32 (78%). LIMITATIONS: Retrospective nature of design, small sample size. CONCLUSIONS: The Transgrade technique of placing DRG leads offers an alternative method that is safe and effective. New methods of stimulation to the DRG offer more choice and potentially better efficacy for patients with chronic neuropathic pain. KEY WORDS: Neuromodulation, dorsal root ganglion, neuropathic pain, complex regional pain syndrome, spinal cord stimulation, chronic pain, implantable neurostimulators, spinal nerve root stimulation.

Achieving proficiency in rigid bronchoscopy-a study in manikins.

BACKGROUND: Rigid bronchoscopy may be used to relieve acute airway obstruction following induction of anaesthesia and is a recommended option for management of the difficult airway. The ability of anaesthetists to perform rigid bronchoscopy has not been reported. We sought to explore the acquisition of procedural skill in rigid bronchoscopy by anaesthesiologists in a manikin. METHODS: In a prospective interventional study, participants were asked to perform 40 rigid bronchoscopies in a TruCorp AirSim Advance airway manikin, configured to a randomised sequence of easy or difficult laryngoscopic grades to which the participants were blinded. The primary outcome was stabilisation (the attempt after which no further reduction in procedural time occurred). Dental injury and oesophageal intubation were also recorded. Forty anaesthesiologists and 40 unskilled controls (without laryngoscopic skills) participated. RESULTS: In the easy model, stabilisation occurred at attempt 8 in the anaesthesiology group and 10 in the unskilled controls. In the difficult model, stabilisation occurred at attempt 10 in both groups. Dental injury was less common in the anaesthesiology group. The proportion of participants achieving procedural competency did not differ between groups in either the easy (35/40 vs. 30/40) or difficult model (32/40 vs. 25/40). CONCLUSIONS: This study shows that the technical skill of rigid bronchoscopy can be acquired within 10 repetitions in a manikin model. As procedural competence and complication frequency vary with the laryngoscopic grade of the model, both easy and difficult configurations should be used for training. Advanced laryngoscopic skills are not required prior to training in this technique.

The accuracy of locating the cricothyroid membrane by palpation - an intergender study.

BACKGROUND: The cricothyroid membrane (CTM) is the recommended site of access to the airway during cricothyrotomy to provide emergency oxygenation. We sought to compare the ability of physicians to correctly identify the CTM in male and female patients. METHODS: In a prospective observational study, anaesthetists were asked to locate the CTM by palpation which was then identified using ultrasound and the distance between the actual and estimated margin of the CTM was measured. Participants assessed the ease of CTM palpation using a visual analog scale. In a second series, the angulation of the posterior junction of the thyroid laminae was measured using ultrasound. RESULTS: 23 anaesthetists and 44 subjects participated. A total of 36 assessments were carried out in each gender. Incorrect identification of the CTM was more common in females (29/36 vs. 11/36, P < 0.001) and the distance from the CTM in the vertical plane was greater (11.0 [6.5-20.0] vs. 0.0 [0.0-10.0] mm, P < 0.001). In females distance from the CTM correlated positively with neck circumference (P = 0.005) and BMI (P = 0.00005) and negatively with subject height (P = 0.01). Posterior thyroid cartilage angulation was greater in females (118.6 ± 9.4° vs. 95.9 ± 12.9°, P = 0.02) and was lower in patients with correctly identified CTMs (100.0 ± 14.9° vs. 115.6 ± 15.9°, P = 0.02). VRS palpation correlated with decreased posterior thyroid cartilage angulation (P = 0.04). CONCLUSIONS: CTM localisation is more difficult in female subjects irrespective of body habitus. It may be prudent to localize this structure by additional means (e.g. ultrasound) in advance of any airway manoeuvres or to modify the cricothyrotomy technique in the event that it is necessary in an emergency.

Umbilical hernia rupture with evisceration of omentum from massive ascites: a case report.

INTRODUCTION: The incidence of hernias is increased in patients with alcoholic liver disease with ascites. To the best of our knowledge, this is the first report of an acute rise in intra-abdominal pressure from straining for stool as the cause of a ruptured umbilical hernia. CASE PRESENTATION: An 81-year-old Caucasian man with a history of alcoholic liver disease presented to our emergency department with an erythematous umbilical hernia and clear, yellow discharge from the umbilicus. On straining for stool, after initial clinical assessment, our patient noted a gush of fluid and evisceration of omentum from the umbilical hernia. An urgent laparotomy was performed with excision of the umbilicus and devitalized omentum. CONCLUSION: We report the case of a patient with a history of alcoholic liver disease with ascites. Ascites causes a chronic increase in intra-abdominal pressure. A sudden increase in intra-abdominal pressure, such as coughing, vomiting, gastroscopy or, as in this case, straining for stool can cause rupture of an umbilical hernia. The presence of discoloration, ulceration or a rapid increase in size of the umbilical hernia signals impending rupture and should prompt the physician to reduce the intra-abdominal pressure.