Case report: Spinal cord stimulation for pain relief in two patients with locally recurrent pelvic malignancy.

Introduction: Chronic cancer-related pain from locally recurrent infiltrative cancers within the bony confines of the pelvis is a devastating and hard to manage condition that can be refractory to many conventional pain management methods. Spinal cord stimulation (SCS) is an evolving and safe method of pain management and can be trialled in a quick and well-tolerated operation under local anaesthesia. To date, this has not been reported in the setting of locally recurrent inoperable pelvic cancers. Case description: In the present study, we report two cases of patients with severe back and lower limb pain resulting from recurrent anal and rectal cancers involving the right lumbar and sacral nerve roots as well as the bony sacrum, which severely affected quality of life and daily functioning. Discussion: Following successful SCS, effective pain relief was observed. Conclusion: SCS could represent an effective supplementary or alternative technique to conventional pain management in this challenging group of patients, especially if other available methods have been exhausted.

Restorative neurostimulation for chronic mechanical low back pain - Three year results from the United Kingdom post market clinical follow-up registry.

Introduction: Mechanical chronic low back pain is often associated with impaired neuromuscular control of the lumbar multifidus muscles, the most important stabilizers of the lumbar spine. Restorative neurostimulation is a modality for the treatment for this specific subset of patients aimed to facilitate restoration of neuromuscular control by bilateral stimulation of the L2 medial branches. Evidence from both prospective and randomised clinical trials to date has demonstrated substantial improvements in clinical outcomes such as pain, disability and health-related quality of life. Methods: This study is an open label prospective follow-up for the treatment of chronic mechanical low back pain of nociceptive origin with restorative neurostimulation. Patients completed assessments for pain, disability and health-related quality of life. Outcomes were collected at 45, 90 and 180 days, and 1, 2 and 3 years after the activation visit. Results: Forty-two patients were implanted with the device and 33 (79%) were available at the 3-year appointment. Patients in this cohort presented with severe chronic low back pain (NRS = 7.0 ± 0.2) and severe disability (ODI 46.6 ± 12.0). The health-related quality of life was also severely impacted at baseline (EQ-5D 0.426 ± 0.061). Changes in pain, disability and quality of life at three-year follow-up demonstrated a statistically significant improvement between baseline and 1, 2 and 3 years. After 3 years of therapy, average NRS scores had reduced to 2.7± 0.3 and mean ODI score to 26.0 ± 3.1 while EQ-5D-5L index improved to 0.707 ± 0.036. Conclusions: The ongoing follow-up of this post market cohort continues to demonstrate that restorative neurostimulation provides a statistically significant, clinically meaningful and durable response across pain, disability and quality-of life scores for patients suffering chronic mechanical low back pain that has been refractory to conventional management. Trial Registration: ClinicalTrials.gov Identifier: NCT01985230.

Age-related changes in tau and autophagy in human brain in the absence of neurodegeneration.

Tau becomes abnormally hyper-phosphorylated and aggregated in tauopathies like Alzheimers disease (AD). As age is the greatest risk factor for developing AD, it is important to understand how tau protein itself, and the pathways implicated in its turnover, change during aging. We investigated age-related changes in total and phosphorylated tau in brain samples from two cohorts of cognitively normal individuals spanning 19-74 years, without overt neurodegeneration. One cohort utilised resected tissue and the other used post-mortem tissue. Total soluble tau levels declined with age in both cohorts. Phosphorylated tau was undetectable in the post-mortem tissue but was clearly evident in the resected tissue and did not undergo significant age-related change. To ascertain if the decline in soluble tau was correlated with age-related changes in autophagy, three markers of autophagy were tested but only two appeared to increase with age and the third was unchanged. This implies that in individuals who do not develop neurodegeneration, there is an age-related reduction in soluble tau which could potentially be due to age-related changes in autophagy. Thus, to explore how an age-related increase in autophagy might influence tau-mediated dysfunctions in vivo, autophagy was enhanced in a Drosophila model and all age-related tau phenotypes were significantly ameliorated. These data shed light on age-related physiological changes in proteins implicated in AD and highlights the need to study pathways that may be responsible for these changes. It also demonstrates the therapeutic potential of interventions that upregulate turnover of aggregate-prone proteins during aging.

A Novel Pulsed Stimulation Pattern in Spinal Cord Stimulation: Clinical Results and Postulated Mechanisms of Action in the Treatment of Chronic Low Back and Leg Pain.

OBJECTIVES: The aim of this article is to discuss the possible mechanisms of action (MOAs) and results of a pilot study of a novel, anatomically placed, and paresthesia-independent, neurostimulation waveform for the management of chronic intractable pain. MATERIALS AND METHODS: A novel, multilayered pulsed stimulation pattern (PSP) that comprises three temporal layers, a Pulse Pattern layer, Train layer, and Dosage layer, was developed for the treatment of chronic intractable pain. During preliminary development, the utility was evaluated of anatomical PSP (aPSP) in human subjects with chronic intractable pain of the leg(s) and/or low back, compared with that of traditional spinal cord stimulation (T-SCS) and physiological PSP. The scientific theory and testing presented in this article provide the preliminary justification for the potential MOAs by which PSP may operate. RESULTS: During the pilot study, aPSP (n = 31) yielded a greater decrease in both back and leg pain than did T-SCS (back: -60% vs -46%; legs: -63% vs -43%). In addition, aPSP yielded higher responder rates for both back and leg pain than did T-SCS (61% vs 48% and 78% vs 50%, respectively). DISCUSSION: The novel, multilayered approach of PSP may provide multimechanistic therapeutic relief through preferential fiber activation in the dorsal column, optimization of the neural onset response, and use of both the medial and lateral pathway through the thalamic nuclei. The results of the pilot study presented here suggest a robust responder rate, with several subjects (five subjects with back pain and three subjects with leg pain) achieving complete relief from PSP during the acute follow-up period. These clinical findings suggest PSP may provide a multimechanistic, anatomical, and clinically effective management for intractable chronic pain. Because of the limited sample size of clinical data, further testing and long-term clinical assessments are warranted to confirm these preliminary findings.

Internal neurolysis: 'nerve combing' for trigeminal neuralgia without neurovascular conflict - early UK outcomes.

INTRODUCTION: Internal neurolysis (INL) is a surgical procedure where trigeminal nerve fibres are separated between the pons and porus trigeminus to relieve trigeminal neuralgia (TN). We report pain and functional outcomes to evaluate its safety and efficacy. MATERIALS AND METHODS: Prospective cohort of all patients undergoing retrosigmoid craniotomy and INL between 2015 and 2017 at University Hospital Southampton. Patients with type I (6) or type II (2) refractory TN and no clear neurovascular conflict were offered INL as an alternative to partial sensory rhizotomy. Barrow Pain Intensity Scale (BNI) and Brief Pain Inventory Facial scores (BPI-Facial) were assessed. Minimum follow-up was 2 years'. RESULTS: Eight patients (7F:1M) underwent INL. Two had MS. Pre-operatively, all had severe pain (BNI grade V) and the median BPI-Facial score was 115 (range 79-123).. There were no unexpected complications. On last follow-up, six (75%) had no pain (BNI grade I), while two (25%) had recurred (at 5 and 27 months). Median BPI-Facial score for all patients on the last follow-up was 20 (range 18-91) reflecting dramatically improved quality of life and activities. CONCLUSIONS: INL is a potentially safe and effective treatment for refractory TN. Long-term efficacy is unknown, but early results are promising.

Restorative Neurostimulation for Chronic Mechanical Low Back Pain: Results from a Prospective Multi-centre Longitudinal Cohort.

INTRODUCTION: Low back pain impacts most people throughout the course of their lives and contributes significantly to the global burden of disease. In some patients, symptoms resolve with little intervention, while others are amenable to surgical intervention, some cases are intractable to current care paradigms. Restorative neurostimulation is an emerging therapy for chronic mechanical low back pain. METHODS: We conducted a prospective post-market follow-up of 42 patients treated for longstanding chronic mechanical low back pain with restorative neurostimulation. Patients were followed up at 45, 90, and 180 days and 1 and 2 years following activation of the device. Pain, disability, and health-related quality of life were recorded. RESULTS: Among the 37 patients completing 2-year follow-up, numerical rating scale (NRS) pain scores improved from 7.0 ± 0.2 to 3.5 ± 0.3 (p < 0.001), Oswestry Disability Index (ODI) scores improved from 46.2 ± 2.2 to 29.2 ± 3.1 (p < 0.001), and health-related quality of life (measured by the EuroQol 5-Dimension 5-Level questionnaire-EQ-5D-5L) improved from 0.426 ± 0.035 to 0.675 ± 0.030 (p < 0.001). Additionally, 57% of patients experienced a greater than 50% reduction in pain, and 51% of patients benefited by a greater than 15-point reduction in ODI, both substantial improvements. CONCLUSION: This real-world sample of patients shows that restorative neurostimulation can provide substantial and durable benefit to a cohort of patients that have traditionally had few reliable treatment options. Our findings support the continued used of this therapy in well-selected patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01985230.

The goal of this study was to examine the effectiveness of restorative neurostimulation for the treatment of patients with chronic mechanical low back pain. This technique has been studied in a clinical trial setting and been shown to be both safe and effective. This study reports on the real-world experience from five sites in the United Kingdom. Patients with a history of severe low back pain that lasted on average for more than 13 years were implanted with a nerve stimulation device that targets the nerves that control important spinal stabilising muscles. All of the patients were asked to perform two stimulation sessions per day for 30 min each. Over the next 2 years, patients reported substantial reductions in pain and disability and an improvement in health-related quality of life. The safety profile of the therapy was excellent when compared to similar minimally invasive therapies for different spine pathologies. In this difficult-to-treat patient population who have few remaining therapeutic options, restorative neurostimulation is a valuable tool in the clinician's armamentarium.

The impact of the COVID-19 pandemic on patients awaiting spinal cord stimulation surgery in the United Kingdom: a multi-centre patient survey.

INTRODUCTION: Spinal cord stimulation (SCS) is a recommended treatment for chronic refractory neuropathic pain. During the COVID-19 pandemic, elective procedures have been postponed indefinitely both to provide capacity to deal with the emergency caseload and to avoid exposure of elective patients to COVID-19. This survey aimed to explore the effect of the pandemic on chronic pain in this group and the views of patients towards undergoing SCS treatment when routine services should resume. METHODS: This was a prospective, multi-centre telephone patient survey that analysed data from 330 patients with chronic pain who were on an SCS waiting list. Questions focussed on severity of pain, effect on mental health, medication consumption and reliance on support networks during the COVID-19 pandemic. Views towards undergoing SCS therapy were also ascertained. Counts and percentages were generated, and chi-square tests of independence explored the impact of COVID-19 risk (very high, high, low) on survey responses. RESULTS: Pain, mental health and patient's ability to self-manage pain deteriorated in around 47%, 50% and 38% of patients, respectively. Some patients reported increases in pain medication consumption (37%) and reliance on support network (41%). Patients showed a willingness to attend for COVID-19 testing (92%), self-isolate prior to SCS (94%) and undergo the procedure as soon as possible (76%). CONCLUSION: Our findings suggest that even during the COVID-19 pandemic, there remains a strong clinical need for patients with chronic pain identified as likely SCS responders to be treated quickly. The current prioritisation of new SCS at category 4 (delayed more than 3 months) is challenged judging by this national survey. These patients are awaiting SCS surgery to relieve severe intractable neuropathic pain. A priority at category 3 (delayed up to 3 months) or in some selected cases, at category 2 are the appropriate priority categories.

Efficacy and Safety of 10 kHz Spinal Cord Stimulation for the Treatment of Chronic Pain: A Systematic Review and Narrative Synthesis of Real-World Retrospective Studies.

10 kHz spinal cord stimulation (SCS) is increasingly utilized globally to treat chronic pain syndromes. Real-world evidence complementing randomized controlled trials supporting its use, has accumulated over the last decade. This systematic review aims to summarize the retrospective literature with reference to the efficacy and safety of 10 kHz SCS. We performed a systematic literature search of PubMed between 1 January 2009 and 21 August 2020 for English-language retrospective studies of ≥3 human subjects implanted with a Senza® 10 kHz SCS system and followed-up for ≥3 months. Two independent reviewers screened titles/abstracts of 327 studies and 46 full-text manuscripts. In total, 16 articles were eligible for inclusion; 15 reported effectiveness outcomes and 11 presented safety outcomes. Follow-up duration ranged from 6-34 months. Mean pain relief was >50% in most studies, regardless of follow-up duration. Responder rates ranged from 67-100% at ≤12 months follow-up, and from 46-76% thereafter. 32-71% of patients decreased opioid or nonopioid analgesia intake. Complication incidence rates were consistent with other published SCS literature. Findings suggest 10 kHz SCS provides safe and durable pain relief in pragmatic populations of chronic pain patients. Furthermore, it may decrease opioid requirements, highlighting the key role 10 kHz SCS can play in the medium-term management of chronic pain.

Comparison of first-time microvascular decompression with percutaneous surgery for trigeminal neuralgia: long-term outcomes and prognostic factors.

OBJECTIVE: Common surgical treatments for trigeminal neuralgia (TN) include microvascular decompression (MVD) and percutaneous procedures (glycerol rhizolysis; thermocoagulation; and balloon compression). Although the efficacy of each procedure has been documented, direct comparisons of their relative efficacies for TN are lacking. We aimed to directly compare long-term outcomes after first-time MVD with percutaneous surgery in primary (idiopathic and classical) TN and identify predictors of outcome. METHODS: We conducted a retrospective analysis of prospectively collected data on 185 patients undergoing MVD and 129 undergoing percutaneous surgery. Procedures were performed by one of two neurosurgeons in a single centre; an independent observer collected long-term follow-up data by interviews, using the same outcome measures for all procedures. RESULTS: MVD patients were younger than those undergoing percutaneous surgery (P <.001). MVD provided superior initial pain relief (P <.001): 87.0% had Barrow Neurological Institute class I or II pain scores after MVD compared with 67.2% after percutaneous surgery. The complication rate for percutaneous procedures was 35.7% and for MVDs was 24.9% (P =.04), including minor and transient complications. Kaplan-Meier analysis demonstrated that MVD provided longer pain relief than percutaneous procedures (P <.001); 25% of patients had recurrence at 96 months following MVD compared with 12 months after percutaneous surgery. Subgroup analysis showed that balloon compression provided more durable relief amongst percutaneous procedures. Multivariate analysis revealed that post-operative numbness and age were prognostic factors for percutaneous procedures (P =.03 and .01, respectively). CONCLUSIONS: MVD provides better initial pain relief and longer durability of relief than percutaneous surgery, although carrying a small risk of major complications. Amongst percutaneous procedures, balloon compression gave the most durable relief from pain. Older age and post-operative numbness were predictors of good outcome from percutaneous surgery. These results can help clinicians to counsel patients with primary TN on neurosurgical treatment selection for pain relief.

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.

High Frequency (HF10) Spinal Cord Stimulation for Chronic Neuropathic Pain.

BACKGROUND AND INTRODUCTION: Spinal cord stimulation (SCS) is well established treatment. In a prospective randomised controlled trial, novel 10-kHz High-frequency Therapy (HF10 Therapy) was superior to traditional low-frequency SCS for the treatment of chronic back and leg pain. OBJECTIVE: To demonstrate the percutaneous SCS implant technique and discuss the operative nuances. SURGICAL TECHNIQUE/PROCEDURE: During the stage 1 procedure (permanent trial), two percutaneous electrodes were placed in the midline posterior epidural space spanning T8-T10 segments straddling the T9-10 disc space. The electrodes were anchored to the fascia, tunnelled into the supragluteal incision and connected to the extensions, which were tunnelled out for the external trial. RESULTS AND CONCLUSIONS: The patient reported 90% pain reduction at follow-up. Thoracic HF10 SCS is effective modality in managing chronic neuropathic pain.

Percutaneous Electrical Nerve Stimulation for Facial Pain.

Percutaneous electrical nerve stimulation (PENS) is a novel, minimally invasive and useful treatment modality. Its use in complex facial pain has been on the rise, and its utility will further increase with the advances in the technology and renewed interest in the field of peripheral neuromodulation. PENS therapy can be used both as diagnostic and therapeutic option. The precise mechanism of action is not known, although a combination of electrical neuromodulation and release of endogenous morphine-like substance in the central nervous system appears as plausible explanation. We analyse the various studies in the literature and discuss the Southampton data regarding facial pain treatment with PENS therapy. We believe that PENS therapy for facial pain and headache is currently underutilised. It is safe, economical and should certainly be part of the armamentarium in the treatment of complex facial pain and headache.

Age-Dependent Changes in Synaptic NMDA Receptor Composition in Adult Human Cortical Neurons.

The molecular processes underlying the aging-related decline in cognitive performance and memory observed in humans are poorly understood. Studies in rodents have shown a decrease in N-methyl-D-aspartate receptors (NMDARs) that contain the GluN2B subunit in aging synapses, and this decrease is correlated with impaired memory functions. However, the age-dependent contribution of GluN2B-containing receptors to synaptic transmission in human cortical synapses has not been previously studied. We investigated the synaptic contribution of GluN2A and GluN2B-containing NMDARs in adult human neurons using fresh nonpathological temporal cortical tissue resected during neurosurgical procedures. The tissue we obtained fulfilled quality criteria by the absence of inflammation markers and proteomic degradation. We show an age-dependent decline in the NMDA/AMPA receptor ratio in adult human temporal cortical synapses. We demonstrate that GluN2B-containing NMDA receptors contribute to synaptic responses in the adult human brain with a reduced contribution in older individuals. With previous evidence demonstrating the critical role of synaptic GluN2B in regulating synaptic strength and memory storage in mice, this progressive reduction of GluN2B in the human brain during aging may underlie a molecular mechanism in the age-related decline in cognitive abilities and memory observed in humans.

A primate-specific short GluN2A-NMDA receptor isoform is expressed in the human brain.

Glutamate receptors of the N-methyl-D-aspartate (NMDA) family are coincident detectors of pre- and postsynaptic activity, allowing Ca2+ influx into neurons. These properties are central to neurological disease mechanisms and are proposed to be the basis of associative learning and memory. In addition to the well-characterised canonical GluN2A NMDAR isoform, large-scale open reading frames in human tissues had suggested the expression of a primate-specific short GluN2A isoform referred to as GluN2A-S. Here, we confirm the expression of both GluN2A transcripts in human and primate but not rodent brain tissue, and show that they are translated to two corresponding GluN2A proteins present in human brain. Furthermore, we demonstrate that recombinant GluN2A-S co-assembles with the obligatory NMDAR subunit GluN1 to form functional NMDA receptors. These findings suggest a more complex NMDAR repertoire in human brain than previously thought.

The Effectiveness of Percutaneous Balloon Compression, Thermocoagulation, and Glycerol Rhizolysis for Trigeminal Neuralgia in Multiple Sclerosis.

BACKGROUND: Balloon compression (BC), thermocoagulation (TC), and glycerol rhizolysis (GR) are percutaneous surgical options for trigeminal neuralgia (TN). Whether the outcomes of these procedures in multiple sclerosis -related TN (MS-TN) are as effective as in idiopathic TN (ITN) is unknown. OBJECTIVE: To retrospectively compare pain relief, complications, and durability achieved by these 3 types of procedures in MS-TN and ITN. METHODS: Two hundred and four patients with typical TN were treated percutaneously: 33 had MS-TN (64 procedures) and 171 had ITN (329 procedures). All were performed by 1 of 2 neurosurgeons; interviews enabled long-term data to be gathered by an independent observer. RESULTS: MS-TN patients (53.1%) had Barrow Neurological Institute pain scores of I or II after a percutaneous procedure, compared with 59.3% in the ITN cohort; there was no difference in initial relief between the 2 groups overall (P = .52). There was a trend toward fewer complications in MS-TN compared with ITN (23.4% vs 33.7%, respectively; P = .058). Kaplan-Meier analysis demonstrated no difference in durability of relief in MS-TN (median 23.0 mo) compared with ITN overall (median 24.0 mo; P = .75). Subgroup analysis demonstrated longer relief from BC and TC compared with GR in MS-TN (P = .013). Multivariate analysis confirmed that although the presence of MS does not predict durability of outcome, postoperative numbness (P = .0046) and undergoing a repeat procedure (P = .037) were significant predictors. CONCLUSION: BC and TC are safe and effective in MS-TN. Postoperative numbness is the strongest prognostic factor in MS-TN.

Abdominal pseudocyst: a rare complication of ventriculoperitoneal shunting.

Abdominal cerebrospinal fluid (CSF) pseudocyst is a rare complication of ventriculoperitoneal shunting. It is well known in children but uncommon in adults. We present a 30-year-old woman with abdominal distension, vomiting and confusion caused by her developing an abdominal CSF pseudocyst, 13 years after her last shunt revision. Adult neurologists need to be aware of this late complication.

Comparing Percutaneous Treatments of Trigeminal Neuralgia: 19 Years of Experience in a Single Centre.

BACKGROUND: Glycerol rhizolysis, thermocoagulation, and balloon compression are well established in the treatment of trigeminal neuralgia. OBJECTIVE: To compare the outcome profile of these 3 percutaneous procedures in a single centre over a long follow-up period. METHODS: Over 19 years, 393 procedures were performed on 210 trigeminal neuralgia patients. Patient records and telephone follow-up were used to determine demographic and operative details and surgical outcomes. The length of follow-up extended to over 17 years. RESULTS: The initial rates of complete pain relief with or without medication were 72% for glycerol, 80% for thermocoagulation, and 86% for balloon compression. Kaplan-Meier analysis of recurrence times showed that balloon compression provides significantly longer relief than the other 2 procedures. Complication rates for glycerol, thermocoagulation, and balloon compression were 30.3, 27.1, and 43.5%, respectively. Analysis of repeat procedures showed no difference in recurrence times for balloon compression or thermocoagulation compared with primary procedures, but repeat glycerol procedures gave shorter recurrence times. CONCLUSION: Balloon compression provides longer pain relief than glycerol and thermocoagulation. Although balloon compression is more likely to give numbness and complications, the complications are largely minor and transitory. Moreover, balloon compression following previous percutaneous procedures remains highly effective.