Safety and Efficacy of 10 kHz Spinal Cord Stimulation for the Treatment of Refractory Chronic Migraine: A Prospective Long-Term Open-Label Study.

BACKGROUND: Refractory chronic migraine (rCM) is a highly disabling condition for which novel safe and effective treatments are needed. Safety and long-term efficacy of paresthesia-free high cervical 10 kHz spinal cord stimulation (SCS) were here prospectively evaluated for the treatment of rCM. MATERIALS AND METHODS: Twenty adults with rCM (mean numbers of preventive treatments failed: 12.2 ± 3.1) were enrolled in this single-center, open-label, prospective study and implanted with a 10 kHz SCS system (Senza™ system, Nevro Corp), with the distal tip of the lead(s) positioned epidurally at the C2 vertebral level. Safety and effectiveness outcomes, such as adverse events, headache and migraine reductions, responder rates, Migraine Disability Assessment (MIDAS), Headache Impact Test-6 (HIT-6), and Migraine-Specific Quality-of-Life (MSQ), were captured up to 52 weeks after implantation. RESULTS: Compared to baseline, at 52 weeks postimplantation, there was a significant reduction of mean monthly migraine days (MMD) by 9.3 days (p < 0.001). Sixty percent and 50% of patients obtained respectively at least 30% and at least 50% reduction in mean MMD. By week 52, 50% of patients' chronic pattern converted to an episodic pattern. The proportion of subjects classified with severe headache-related disability on the HIT-6, decreased from 100% to 60% at week 52. Meaningful improvements of headache-related quality of life measured by the MSQ scale were observed with mean gain of 24.9 ± 23.1 (p < 0.001) points at 52 weeks. No unanticipated adverse device effects occurred. No patients required any additional device surgical revision. CONCLUSION: 10 kHz SCS may a be safe and effective neurostimulation option for rCM patients. The paresthesia-free waveform constitutes an unprecedented advantage for future methodologically sound sham-controlled studies in headache neuromodulation.

Comparison of Paresthesia Mapping With Anatomic Placement in Burst Spinal Cord Stimulation: Long-Term Results of the Prospective, Multicenter, Randomized, Double-Blind, Crossover CRISP Study.

OBJECTIVES: Spinal cord stimulation (SCS) is an effective therapy for chronic intractable pain. Conventional SCS involves electrode placement based on intraoperative paresthesia mapping; however, newer paradigms like burst may allow for anatomic placement of leads. Here, for the first time, we report the one-year safety and efficacy of burst SCS delivered using a lead placed with conventional, paresthesia mapping, or anatomic placement approach in subjects with chronic low back pain (CLBP). MATERIALS AND METHODS: Subjects with CLBP were implanted with two leads. The first lead was placed to cross the T8/T9 disc and active contacts for this lead were chosen through paresthesia mapping. The second lead was placed at the T9/T10 spinal anatomic landmark. Subjects initially underwent a four-week, double-blinded, crossover trial with a two-week testing period with burst SCS delivered through each lead in a random order. At the end of trial period, subjects expressed their preference for one of the two leads. Subsequently, subjects received burst SCS with the preferred lead and were followed up at 3, 6, and 12 months. Pain intensity (visual analog scale), quality-of-life (EuroQol-5D instrument), and disability (Oswestry Disability Index) were evaluated at baseline and follow-up. RESULTS: Forty-three subjects successfully completed the trial. Twenty-one preferred the paresthesia mapping lead and 21 preferred the anatomic placement lead. Anatomic placement lead was activated in one subject who had no preference. The pain scores (for back and leg) significantly improved from baseline for both lead placement groups at all follow-up time points, with no significant between-group differences. CONCLUSIONS: This study demonstrated that equivalent clinical benefits could be achieved with burst SCS using either paresthesia mapping or anatomic landmark-based approaches for lead placement. Nonparesthesia-based approaches, such as anatomic landmark-based lead placement investigated here, have the potential to simplify implantation of SCS and improve current surgical practice.

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.

Successful and unsuccessful recruitment and retainment strategies in a UK multicentre drug trial for a rare chronic pain condition which performed above target.

INTRODUCTION: Recruitment into trials in rare chronic pain conditions can be challenging, so such trials consequently are underpowered or fail. METHODS: Drawing from our experience in conducting, to date, the largest academic trial in a rare chronic pain condition, complex regional pain syndrome, we have identified recruitment and retention strategies for successful trial conduct. RESULTS: We present 13 strategies grouped across the categories of 'setting the recruitment rate', 'networking', 'patient information', 'trial management' and 'patient retention'. Moreover, six recruitment risks are also discussed. A conservative recruitment estimate, based on audits of newly referred patients to the trial centres without taking into account availability of 'old' patients or recruitment from outside centres, and assuming a 55% patient refusal rate yielded accurate numbers. CONCLUSION: Appreciation of these identified recruitment challenges and opportunities may contribute to supporting prospective investigators when they design clinical trials for chronic pain patient population groups where it has been historically difficult to conduct high-quality and robust clinical trials.

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.

Comparison of Paresthesia Mapping to Anatomical Placement in Burst Spinal Cord Stimulation: Initial Trial Results of the Prospective, Multicenter, Randomized, Double-Blinded, Crossover, CRISP Study.

INTRODUCTION: In this prospective, multicenter, double-blinded, randomized, crossover study, we compared the therapeutic efficacy of burst SCS delivered using a lead implanted with the paresthesia mapping approach to a lead implanted with an anatomic placement approach. MATERIALS AND METHODS: Subjects with chronic low back pain were implanted with two leads, one using paresthesia-mapping approach (PM) and the second using anatomical placement procedure (AP). Stimulation contacts were chosen using the standard intraoperative paresthesia-testing procedure for the paresthesia-mapped lead or an activated bipole overlapping the T9-T10 junction for the anatomical lead. Amplitude for either lead was selected such that no sensory percepts were generated. Subjects were assessed at baseline and after a trial period during which they tested each lead for two weeks in random order. Eligible subjects had the option to receive permanent implants using their preferred AP or PM approach at end-of-trial. RESULTS: Of the 53 subjects who completed both trial periods, 43 (81.1%) experienced at least 50% back pain relief with at least one lead. Nearly half of these (20; 46.5%) were profound responders who experienced at least 80% back pain relief with either leads. Primary and secondary outcomes, at the end of trial, showed significant improvements for both AP and PM leads from baseline yet were not significantly different from each other. DISCUSSION: The trial results of this study suggest that similar clinical outcomes can be achieved in burst SCS when performing lead placement either using paresthesia mapping or anatomical placement with imaging references.

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.

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.

Prospective, Randomized, Sham-Control, Double Blind, Crossover Trial of Subthreshold Spinal Cord Stimulation at Various Kilohertz Frequencies in Subjects Suffering From Failed Back Surgery Syndrome (SCS Frequency Study).

INTRODUCTION: The increasing use of high frequency paresthesia-free spinal cord stimulation has been associated with improved outcomes in the therapy of neuropathic pain. What is unknown is the effect of varying frequency on pain relief and the placebo effect. MATERIALS AND METHODS: This is a prospective, randomized, sham-controlled double blind crossover study. Subjects with predominantly axial low back pain undergoing spinal cord stimulation therapy for failed back surgery syndrome were randomized to sham, 1200 Hz, 3030 Hz, and 5882 Hz with a four-phase crossover design over 12 weeks. RESULTS: Twenty-four patients were randomized in the study. The mean low back pain score at baseline was 7.75. The mean low back pain scores on a 10 cm visual analog scale during the randomized crossover phase were 4.83, 4.51, 4.57, and 3.22, for sham, 1200 Hz, 3030 Hz, and 5882 Hz, respectively, with the lowest low back pain score observed in the 5882 Hz frequency group (p = 0.002). Of note, sham stimulation resulted in a reduction of pain by -2.92 cm and was not significantly different from stimulation at 1200 Hz and 3030 Hz. CONCLUSIONS: This randomized crossover study demonstrated that 5882 Hz stimulation can produce significant pain relief for axial low back pain compared with lower frequencies and sham stimulation. Sham stimulation produced similar analgesic effects to 1200 Hz and 3030 Hz and this effect may influence future neuromodulation clinical trial designs.

Influence of acute salinity changes on biochemical, hematological and immune characteristics of Fenneropenaeus indicus during white spot syndrome virus challenge.

The present study reports the influence of salinity (5, 15, 25 and 35 g/L) on the biochemical and immune characteristics of Fenneropenaeus indicus challenged with 5. 5 × 10(4) copy number of white spot syndrome virus (WSSV). F. indicus that had been reared in 25 g/L, injected with WSSV and transferred to 5, 15, 25 (control) and 35 g/L were examined after 0-120 hrs for total hemocyte count (THC), phenoloxidase (PO) and respiratory burst (RB) activity and alkaline and acid phosphatase activities. It was concluded that F. indicus that had been transferred from 25 g/L to lower and higher salinity levels (5, 15 and 35 g/L) had poorer immune indices and decreased resistance against WSSV infection. After 120 hrs, the mortality rate in WSSV-injected F. indicus experimental groups (5 and 35 g/L) was significantly higher than for F. indicus exposed to 25 and 15 g/L salinities. During the experimental period (0-120 hrs), biochemical variables, namely total protein, carbohydrate, and lipid concentrations, were measured in hemolymph of both experimental and control groups. Acute salinity changes induced an increase in protein variations across the tested salinity ranges in shrimp. After 24 hrs, THC and PO activity decreased significantly whereas RB, alkaline phosphatase and acid phosphatase activities increased in shrimps kept at the lower salinities of 5, 15 and 35 g/L.

Biomonitoring fallout 137Cs in resident and migratory fishes collected along the southern coast of India and assessment of dose.

The globally distributed fallout radionuclide (137)Cs was monitored in 25 resident and 22 migratory fish species collected from some regions of west and east coast of southern India to establish a baseline data. The samples were collected during June 2008 to June 2009. Higher level of (137)Cs was noted in planktivorous fishes and lower level in herbivores. A significant variation in (137)Cs was observed between fishes with different feeding habits and different migratory pattern. Oceanodromic migratory fishes displayed higher cesium levels than other migratory types. Similarly, migratory fishes displayed higher (137)Cs concentration compared to resident fishes. The overall range of (137)Cs varied from 0.06 to 0.3 Bq/kg in fishes. The biological concentration varied from 55 to 250. The average external dose rate to fishes was calculated to be 2.7 × 10(-7) µGy/h, while the internal dose rate varied from 8.50 × 10(-6) to 5.27 × 10(-5) µGy/h. The hazard quotient for fishes was found to be less than 1. The average intake of (137)Cs via fishes to the public was calculated to be 3.5 Bq/year and subsequently the committed effective dose was 0.05 µSv/year. The data obtained were less than global average and comparable to those of many regions.

Tissue distribution of 210Po and 210Pb in select marine species of the coast of Kudankulam, southern coast of Gulf of Mannar, India.

Activities of 210Po and 210Pb in various tissues of four species of decapod crabs and two species of cephalopod mollusks (cuttlefishes) of Kudankulam coast were studied. A non-uniform distribution of these radionuclides was observed between the organs. Of all the tissues, 210Po and 210Pb were found accumulated more in the hepatopancreas and intestine of crabs and in the digestive gland, shell gland, and intestine of cephalopods. Among crabs, Charybdis lucifera registered a little higher 210Po and 210Pb activities. The cephalopod species Loligo duvauceli displayed higher 210Po and 210Pb in some organs when compared to Sepia pharaonis. The muscle of all the species registered lower activity. In cephalopods, the activity ratio of 210Po/210Pb fell within the range of 1-2 for most of the organs, and in crab tissues, it varied from 1.7 to 31.4. The biological concentration factor for organs of cephalopods ranged from 1.2×10(3) to 4.3×10(5) for 210Po and 4.8×10(2) to 8.4×10(4) for 210Pb and for organs of crabs it varied between 2.0×10(4) and 1.9×10(6) for 210Po and 9.2×10(2) and 2.4×10(4) for 210Pb. The study revealed that the organs associated with digestion and metabolism displayed a higher activity concentration than the other tissues. A significant variation in the accumulation of 210Po and 210Pb was noted between species (P<0.05). The activity levels recorded are in agreement with values recorded in related organisms in other parts of the world. The data generated will act as a reference database for these organisms of this coast in which a nuclear power station is under construction.