Intrathecal delivery of adipose-derived mesenchymal stem cells in traumatic spinal cord injury: Phase I trial.

Intrathecal delivery of autologous culture-expanded adipose tissue-derived mesenchymal stem cells (AD-MSC) could be utilized to treat traumatic spinal cord injury (SCI). This Phase I trial (ClinicalTrials.gov: NCT03308565) included 10 patients with American Spinal Injury Association Impairment Scale (AIS) grade A or B at the time of injury. The study's primary outcome was the safety profile, as captured by the nature and frequency of adverse events. Secondary outcomes included changes in sensory and motor scores, imaging, cerebrospinal fluid markers, and somatosensory evoked potentials. The manufacturing and delivery of the regimen were successful for all patients. The most commonly reported adverse events were headache and musculoskeletal pain, observed in 8 patients. No serious AEs were observed. At final follow-up, seven patients demonstrated improvement in AIS grade from the time of injection. In conclusion, the study met the primary endpoint, demonstrating that AD-MSC harvesting and administration were well-tolerated in patients with traumatic SCI.

Persistent chest pain following COVID-19 infection - A scoping review.

Persistent chest pain (PCP) following acute COVID-19 infection is a commonly reported symptom with an unclear etiology, making its management challenging. This scoping review aims to address the knowledge gap surrounding the characteristics of PCP following COVID-19, its causes, and potential treatments. This is a scoping review of 64 studies, including observational (prospective, retrospective, cross-sectional, case series, and case-control) and one quasi-experimental study, from databases including Embase, PubMed/MEDLINE, Cochrane CENTRAL, Google Scholar, Cochrane Database of Systematic Reviews, and Scopus. Studies on patients with PCP following mild, moderate, and severe COVID-19 infection were included. Studies with patients of any age, with chest pain that persisted following acute COVID-19 disease, irrespective of etiology or duration were included. A total of 35 studies reported PCP symptoms following COVID-19 (0.24%-76.6%) at an average follow-up of 3 months or longer, 12 studies at 1-3 months and 17 studies at less than 1-month follow-up or not specified. PCP was common following mild-severe COVID-19 infection, and etiology was mostly not reported. Fourteen studies proposed potential etiologies including endothelial dysfunction, cardiac ischemia, vasospasm, myocarditis, cardiac arrhythmia, pneumonia, pulmonary embolism, postural tachycardia syndrome, or noted cardiac MRI (cMRI) changes. Evaluation methods included common cardiopulmonary tests, as well as less common tests such as flow-mediated dilatation, cMRI, single-photon emission computed tomography myocardial perfusion imaging, and cardiopulmonary exercise testing. Only one study reported a specific treatment (sulodexide). PCP is a prevalent symptom following COVID-19 infection, with various proposed etiologies. Further research is needed to establish a better understanding of the causes and to develop targeted treatments for PCP following COVID-19.

Pain Associated With Monkeypox Virus: A Rapid Review.

International concerns for another pandemic arose after emerging reports of an ongoing outbreak of the monkeypox virus (MPXV) in Europe and the United States in 2022. Severe pain is one of the most distressing complications for patients in the current outbreak, but there is a general paucity of relevant peer-reviewed medical literature from which to draw clear recommendations on appropriate pain therapies. The Centers for Disease Control recently published a letter in July 2022 urging providers to conduct further studies concerning pain management. Thus, a rapid literature search was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive search of several databases from inception until August 19, 2022, was conducted. All published studies describing pain in patients who tested positive for MPXV with original data and written in English were included. Sixty-nine studies were initially identified for screening. After initial screening, 27 papers were considered for full-text review, and 15 papers met the inclusion criteria. A total of 1043 positive cases were included in this study. Most patients were men. Treatment options proposed by the authors include acetaminophen, ibuprofen, opioids, lidocaine gel, metamizole, and rectal suppositories containing emollients or steroids with oral laxatives for severe anal pain. Although most cases were mild requiring outpatient treatment, a considerable number of patients were admitted due to serious complications. Severe pain was often the reason to seek medical attention and hospital admission for pain control. Analgesic plans included oral and topical analgesia. In severe cases, pain was managed with opioids. To our knowledge, this rapid review is the first study to comprehensively summarize proposed treatments for pain associated with MPXV. Guidelines may be needed to help direct the best management to avoid morbidity in patients, particularly as adjuvants may play a key role but are not commonly utilized in published reports.

Ultrasound-guided percutaneous peripheral nerve stimulation for chronic refractory neuropathic pain: a unique series.

During the last two decades, with the advent of recent technology, peripheral nerve stimulation has become an appealing modality at the forefront of pain management. In this case series, we document the clinical rationale and technical considerations on three of the most challenging cases, refractory to previous interventions, that were treated by our team with an ultrasound-guided percutaneous peripheral nerve stimulator targeting the musculocutaneous, bilateral greater occipital and subcostal nerves. At the 6-month follow-up, all patients experienced greater than 50% relief of baseline pain, with a near-complete resolution of pain exacerbations. Furthermore, to our knowledge, this is the first report of an ultrasound-guided percutaneous technique of a peripheral nerve stimulator targeting the musculocutaneous and subcostal nerves.

Peripheral nerve stimulation is a new tool used in the treatment of peripheral nerve pain. In this study, we share our experience using this technology in three unusual, difficult-to-treat chronic nerve pain presentations, targeting the musculocutaneous, bilateral greater occipital and subcostal nerves. All patients were asked about how pain levels had changed since the peripheral nerve stimulation device had been implanted. In every case, patients reported a decline in their pain level from day one. After 6 months of peripheral nerve stimulator use, all patients reported a greater than 50% pain relief.

Chemogenetic and Optogenetic Manipulations of Microglia in Chronic Pain.

Chronic pain relief remains an unmet medical need. Current research points to a substantial contribution of glia-neuron interaction in its pathogenesis. Particularly, microglia play a crucial role in the development of chronic pain. To better understand the microglial contribution to chronic pain, specific regional and temporal manipulations of microglia are necessary. Recently, two new approaches have emerged that meet these demands. Chemogenetic tools allow the expression of designer receptors exclusively activated by designer drugs (DREADDs) specifically in microglia. Similarly, optogenetic tools allow for microglial manipulation via the activation of artificially expressed, light-sensitive proteins. Chemo- and optogenetic manipulations of microglia in vivo are powerful in interrogating microglial function in chronic pain. This review summarizes these emerging tools in studying the role of microglia in chronic pain and highlights their potential applications in microglia-related neurological disorders.

Spinal microglia contribute to sustained inflammatory pain via amplifying neuronal activity.

Microglia are highly dynamic immune cells of the central nervous system (CNS). Microglial processes interact with neuronal elements constantly on the order of minutes. The functional significance of this acute microglia-neuron interaction and its potential role in the context of pain is still largely unknown. Here, we found that spinal microglia increased their process motility and electrophysiological reactivity within an hour after the insult in a mouse model of formalin-induced acute, sustained, inflammatory pain. Using an ablation strategy to specifically deplete resident microglia in the CNS, we demonstrate that microglia participate in formalin-induced acute sustained pain behaviors by amplifying neuronal activity in the spinal dorsal horn. Moreover, we identified that the P2Y12 receptor, which is specifically expressed in microglia in the CNS, was required for microglial function in formalin-induced pain. Taken together, our study provides a novel insight into the contribution of microglia and the P2Y12 receptor in inflammatory pain that could be used for potential therapeutic strategies.

Rescue therapy with novel waveform spinal cord stimulation for patients with failed back surgery syndrome refractory to conventional stimulation: a systematic review and meta-analysis.

OBJECTIVE: Conventional spinal cord stimulators (SCSs) have demonstrated efficacy in individuals with failed back surgery syndrome (FBSS). However, a subgroup of patients may become refractory to the effects of conventional waveforms over time. The objective of this study was to systematically review and evaluate the current literature on the use of novel waveform spinal cord stimulation for the management of FBSS refractory to conventional SCSs. METHODS: A comprehensive electronic search of the literature published in electronic databases, including Ovid MEDLINE and Epub Ahead of Print, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus, was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The outcomes of interest were reduction in back pain and/or leg pain after conversion from conventional to novel SCSs. Risk of bias was assessed with the Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) tool. The strength of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) criteria. RESULTS: A total of 6 studies with 137 patients with FBSS were identified. Studies were published between 2013 and 2021. The mean ± SD age of the pooled patient sample was 55 ± 10.5 years. All patients who underwent treatment with conventional SCSs were identified. Two studies evaluated the efficacy of high-density spinal cord stimulation, 3 studies evaluated burst spinal cord stimulation, and 1 study assessed multimodal waveforms. The mean difference in back pain scores after conversion from a standard SCS to a novel waveform SCS was 2.55 (95% CI 1.59-4.08), demonstrating a significant reduction in back pain after conversion to novel stimulation. The authors also performed a subgroup analysis to compare burst stimulation to tonic waveforms. In this analysis, the authors found no significant difference in the average reductions in back pain between the 2 groups (p = 0.534).The authors found an I2 statistic equivalent to 98.47% in the meta-regression model used to assess the effect of follow-up duration on study outcome; this value implied that the variability in the data can be attributed to the remaining between-study heterogeneity. The overall certainty was moderate, with a high risk of bias across studies. CONCLUSIONS: Rescue therapy with novel waveform spinal cord stimulation is a potential option for pain reduction in patients who become refractory to conventional SCSs. Conversion to novel waveform SCSs may potentially mitigate expenses and complications.

A case for ultrasound-guided peripheral nerve stimulation in intractable anterior cutaneous nerve entrapment syndrome.

Aim: This case report documents the use of peripheral nerve stimulation in the setting of entrapment of the anterior cutaneous branches of the intercostal nerves, with pain rated by the patient as severe during exacerbation episodes. Materials & methods: Under ultrasound guidance, two permanent leads were implanted caudad to cephalad, along and superficial to the lateral aspect of the rectus abdominis, distal to the umbilicus (1 lead per side). Results: At the 6 month follow-up, the patient reported near complete resolution of baseline pain, as well as fewer, sporadic pain exacerbation episodes, rated as mild-to-moderate. Conclusion: This case report suggests that peripheral nerve stimulation might be a valuable treatment option for previously intractable abdominal pain due to entrapment of the anterior cutaneous branches.

Anterior cutaneous nerve entrapment syndrome is a peculiar, a largely disregarded pain condition. Current management algorithms rely mostly on local injections followed by surgical anterior neurectomy. This case report presents a case of longstanding, anterior cutaneous nerve entrapment syndrome, unresponsive to first-line treatment, that was successfully treated with peripheral nerve stimulation technology targeting the anterior cutaneous branches.

Ultrasound-guided lumbar medial branch blocks and intra-articular facet joint injections: a systematic review and meta-analysis.

There is great interest in expanding the use of ultrasound (US), but new challenges exist with its application to lumbar facet-targeted procedures. The primary aim of this systematic review and meta-analysis was to determine the risk of incorrect needle placement associated with US-guided lumbar medial branch blocks (MBB) and facet joint injections (FJI) as confirmed by fluoroscopy or computerized tomography (CT). An a priori protocol was registered, and a database search was conducted. Inclusion criteria included all study types. Risk of bias was assessed using the Cochrane risk of bias tool for randomized controlled trials and the National Heart, Lung, and Blood tool for assessing risk bias for observational cohort studies. Pooled analysis of the risk difference (RD) of incorrect needle placement was calculated. Pooled analysis of 7 studies demonstrated an 11% RD (P < 0.0009) of incorrect needle placement for US-guided MBB confirmed using fluoroscopy with and without contrast. Pooled analysis of 3 studies demonstrated a 13% RD (P < 0.0001) of incorrect needle placement for US-guided FJI confirmed using CT. The time to complete a single-level MBB ranged from 2.6 to 5.0 minutes. The certainty of evidence was low to very low. Ultrasound-guided lumbar MBB and FJI are associated with a significant risk of incorrect needle placement when confirmed by fluoroscopy or CT. The technical limitations of US and individual patient factors could contribute to the risk of incorrect needle placement.

Characteristics of completed clinical trials for spinal cord injury from 1999 to 2020.

Numerous clinical trials are being conducted in the field of spinal cord injury (SCI). These trials are typically registered on ClinicalTrials.gov. The objective of this study was to identify the characteristics of the completed SCI trials and characterize the potential factors associated with publication. ClinicalTrials.gov database was queried for all the completed trials on patients with SCI. Baseline characteristics of the completed trials were assessed. The publication status of these trials was identified using PubMed or Google Scholar. The secondary and primary outcomes reported in the publication were then compared to the outcomes registered in ClinicalTrial.gov. Multivariable logistic regression analysis was performed to determine the characteristics associated with publication status and time to publication. A total of 457 of 1,061 trials on SCI were completed. Of those, 60% were ultimately published. Trials that had received funding from sources besides the NIH, private industries, or the federal government were more likely to remain unpublished. The median time to publish was three years, with larger trials taking a longer time. The median sample size for completed trials was 30. Assessment of mismatch rates in primary outcomes of published data to registered outcomes was 8.9%. In SCI trials, outcomes registered on ClinicalTrial.gov often matched published results. Additionally, sample size and funding source play a significant role in the publication rate of these trials. Published data represents a reliable source for clinicians, researchers, and patients; efforts to curb publication bias and reporting bias are paramount for implementing evidence-based practices and ensure proper scientific conduct.

Current Perspectives on Spinal Cord Stimulation for the Treatment of Cancer Pain.

Cancer and cancer treatment-related chronic pain affect a significant number of patients. The etiology of this pain is diverse and may include nociceptive and/or neuropathic characteristics. Treatment is often multifactorial and may require advanced interventional techniques, such as spinal cord stimulation (SCS). This narrative review provides a thorough overview of cancer-related pain mechanisms and the use of SCS for cancer-related pain. Additionally, a review of the precautions that should be considered when caring for this patient population is provided with recommendations for safe care when utilizing these techniques.

Beyond Revision Surgery: Work-Up and Interventional Treatments for the Painful Total Knee Arthroplasty.

Total knee arthroplasty is a common and successful treatment modality for knee arthritis that is refractory to conservative management strategies. Over 600,000 arthroplasties are performed per year in the United States, and this number is expected to increase in the coming years. Unfortunately, 8% to 34% of patients experience chronic pain after having a total knee arthroplasty. These patients should undergo an appropriate work-up by the orthopedic surgeon, but many times a surgical problem is not uncovered. In these situations, a thorough and specific plan for pain management should be sought. In this article, we outline the work-up of a painful total knee arthroplasty. Then we provide a thorough review of interventional pain management strategies and highlight the pertinent literature. Lastly, we hypothesize future developments in the field that may provide better outcomes for patients suffering from painful total knee arthroplasty.

Injectable Biologics: What Is the Evidence?

Injectable biologics have attracted considerable interest in the field of musculoskeletal medicine. Biologics encompass a broad and diverse group of human tissue-derived therapeutics. The most commonly reported biologics for use in musculoskeletal conditions include platelet-rich plasma, bone marrow aspirate concentrate, mesenchymal stem cells, microfragmented fat, stromal vascular fraction, amniotic membrane-based products, and autologous conditioned serum. The benefits of biologics in tissue healing and regeneration are thought to be derived from their trophic, paracrine, and immunomodulatory functions. The purpose of this review is to define commonly used injectable biologics and to appraise current evidence on its efficacy in the treatment of musculoskeletal disease.

Current Evidence Lacking to Guide Clinical Practice for Spinal Cord Stimulation in the Treatment of Neuropathic Pain in Spinal Cord Injury: A Review of the Literature and a Proposal for Future Study.

BACKGROUND/OBJECTIVE: Chronic pain is commonly reported in individuals with spinal cord injuries (SCIs), with recent prevalence reported as high as 80%. Uncontrolled pain is known to decrease quality of life, attenuate mood, and impact sleep. Spinal cord stimulation (SCS) for the treatment of refractory pain was first used in the SCI population in 1972. To date there have been no randomized controlled trials examining the effect of SCS on neuropathic pain post-SCI. A literature review in 2009 identified 27 studies, the majority prior to 2000, that included at least 1 patient with SCI. Given the significant advancements in the field of SCS, this review examines the updated evidence of SCS for the treatment of neuropathic pain in individuals with SCI and provides guidance on future investigations. METHODS: MEDLINE and EMBASE databases were searched. All published reports, case series, and clinical trials reviewing SCS for neuropathic pain that included at least 1 individual with SCI were included. RESULTS: The initial search identified 376 reports, of which 22 met inclusion criteria, for a total of 69 patients. All reports were of very low quality. A majority of the reported patients were male, underwent tonic stimulation, and reportedly experienced improvement in pain and spasticity, with decreased use of pain medication. CONCLUSIONS: The synthesized findings from primarily case studies support the safety of SCS in SCI with the suggestion of potential pain relief benefit; however, data from low-quality studies are insufficient for informing clinical practice. A well-designed, prospective clinical trial is proposed to further investigate this indication.

CELLTOP Clinical Trial: First Report From a Phase 1 Trial of Autologous Adipose Tissue-Derived Mesenchymal Stem Cells in the Treatment of Paralysis Due to Traumatic Spinal Cord Injury.

Spinal cord injury (SCI) is a devastating condition with limited pharmacological treatment options to restore function. Regenerative approaches have recently attracted interest as an adjuvant to current standard of care. Adipose tissue-derived (AD) mesenchymal stem cells (MSCs) represent a readily accessible cell source with high proliferative capacity. The CELLTOP study, an ongoing multidisciplinary phase 1 clinical trial conducted at Mayo Clinic (ClinicalTrials.gov Identifier: NCT03308565), is investigating the safety and efficacy of intrathecal autologous AD-MSCs in patients with blunt, traumatic SCI. In this initial report, we describe the outcome of the first treated patient, a 53-year-old survivor of a surfing accident who sustained a high cervical American Spinal Injury Association Impairment Scale grade A SCI with subsequent neurologic improvement that plateaued within 6 months following injury. Although he improved to an American Spinal Injury Association grade C impairement classification, the individual continued to be wheelchair bound and severely debilitated. After study enrollment, an adipose tissue biopsy was performed and MSCs were isolated, expanded, and cryopreserved. Per protocol, the patient received an intrathecal injection of 100 million autologous AD-MSCs infused after a standard lumbar puncture at the L3-4 level 11 months after the injury. The patient tolerated the procedure well and did not experience any severe adverse events. Clinical signs of efficacy were observed at 3, 6, 12, and 18 months following the injection in both motor and sensory scores based on International Standards for Neurological Classification of Spinal Cord Injury. Thus, in this treated individual with SCI, intrathecal administration of AD-MSCs was feasible and safe and suggested meaningful signs of improved, rather than stabilized, neurologic status warranting further clinical evaluation.

Office-Based Mesenchymal Stem Cell Therapy for the Treatment of Musculoskeletal Disease: A Systematic Review of Recent Human Studies.

BACKGROUND: The use of mesenchymal stem cells (MSCs) in clinical applications for the treatment of musculoskeletal disease is steadily increasing in office-based practice. The so-called "first generation" of MSCs is defined as autologous stem cells that have undergone minimal manipulation and are used for a homologous purpose. Systematic reviews of the clinical trials completed to date of such MSCs enable practitioners to better understand what is currently known about the outcomes and side effects of such treatments. STUDY DESIGN: A systematic review of human clinical studies of office-based MSC therapy for the treatment of painful degenerative musculoskeletal conditions. METHODS: A search of the Ovid MEDLINE, EMBASE, and Scopus databases was conducted from 2006 through September 2016. Seven hundred sixty-one records were identified from database searching, and two records from reference review of included papers. Studies with human subjects that evaluated treatment of musculoskeletal disease with minimally manipulated MSCs were included. RESULTS: Eight studies were included in this review based on selection criteria. A total of 941 patients were included, 841 of whom received cellular products, and no significant adverse events were reported. Symptomatology generally improved, though no differences were seen over controls where present. CONCLUSION: Support in the literature is strongest for the use of bone marrow aspirate concentrate (BMAC) injections for the treatment of knee pain, but applications of the use of BMAC and peripheral blood-derived MSCs for the treatment of hip pain, tendon pain, and disc pain have all been reported. Further research is required, with large randomized controlled trials.

The Effect of Epidural Steroid Injections on Bone Mineral Density and Vertebral Fracture Risk: A Systematic Review and Critical Appraisal of Current Literature.

Objective: The aim of this paper is to review the available literature investigating the effect of epidural steroid injections (ESIs) on bone mineral density (BMD) and vertebral fracture risk. Study design: Systematic review of current literature. Methods: The sources of the data were PubMed, Embase, Cochrane, and Scopus. Papers included in the review were original research articles in peer-reviewed journals. Results: A total of 7,233 patients (eight studies) with a mean age ranging between 49 and 74 years and an average follow-up between six and 60 months were studied. Steroids that were used included triamcinolone, dexamethasone, and methylprednisolone (MP), with a mean number of injections ranging from one to 14.7 and an average cumulative dose in MP equivalents between 80 and 8,130 mg. Epidural steroids were associated with significantly decreased BMD in four out of six included studies, and with increased risk of vertebral fracture in one out of two included studies. Significant reductions in BMD were associated with a cumulative MP dose of 200 mg over a one-year period and 400 mg over three years, but not in doses of less than 200 mg of MP equivalents for postmenopausal women and at least 3 g for healthy men. The risk of osteopenia and osteoporosis was lower in patients who were receiving anti-osteoporotic medication during the treatment course. Conclusions: ESIs should be recommended with caution, especially in patients at risk for osteoporotic fractures, such as women of postmenopausal age. Anti-osteoporotic medication might be considered prior to ESI.