Normality Analysis of Numeric Rating Scale Scores in Patients with Chronic Axial Spine Pain Before and After Medial Branch Blocks: a Multicenter Study.

OBJECTIVE: The statistical analysis typically employed to compare pain both before and after interventions assumes scores are normally distributed. The present study evaluates whether Numeric Rating Scale (NRS), specifically the NRS-11, scores are indeed normally distributed in a clinically-relevant cohort of adults with chronic axial spine pain pre- and post-analgesic intervention. METHODS: Retrospective review from four academic medical centers of prospectively collected data from a uniform pain diary administered to consecutive patients after undergoing medial branch blocks. The pain diary assessed NRS-11 scores immediately pre-injection and at 12 different time points post-injection up to 48 hours. D'Agostino-Pearson tests were used to test normality at all time points. RESULTS: One hundred fifty pain diaries were reviewed and despite normally distributed pre-injection NRS-11 scores (K2 = 0.655, p = 0.72), all post-injection NRS-11 data was not normally distributed (K2 = 9.70- 17.62, p = 0.0001-0.008). CONCLUSIONS: Although the results of parametric analyses of NRS-11 scores are commonly reported in pain research, some properties of NRS-11 do not satisfy the assumptions required for these analyses. The data demonstrate non-normal distributions in post-intervention NRS-11 scores, thereby violating a key requisite for parametric analysis. We urge pain researchers to consider appropriate statistical analysis and reporting for non-normally distributed NRS-11 scores to ensure accurate interpretation and communication of these data. Practicing pain physicians should similarly recognize that parametric post-intervention pain score statistics may not accurately describe the data and should expect manuscripts to utilize measures of normality to justify the selected statistical methods.

The Association Between Well-Being and Empathy in Medical Residents: A Cross-Sectional Survey.

Objective: To evaluate the extent to which personal well-being may be associated with empathy, while controlling for potential confounders. Settings/Location: Residency programs throughout the United States. Subjects: A total of 407 medical residents from residencies including general medicine, surgery, specialized and diagnostic medicine participated in this study. Outcome Measures: Well-being was measured using the modified existential well-being subscale of the spiritual well-being scale. Empathy was measured using the Jefferson Scale of Empathy. Results: Well-being was found to be positively correlated with empathy when adjusted for possible confounders (p < 0.001). In addition to well-being, other factors noted to be statistically significant contributors to higher empathy scores while controlling for the others included age, gender, year in residency, specialty, and work-hours (p < 0.05 for each). After controlling for these factors, a resident's year in residency was not found to be a statistically significant contributor to empathy score. Conclusions: In this study, well-being was associated with empathy in medical and surgical residents. Empathy is a fundamental component of physician competency, and its development is an essential aspect of medical training. These findings suggest that efforts to increase well-being may promote empathy among medical residents.

Electrophysiological Analyses of Human Dorsal Root Ganglia and Human Induced Pluripotent Stem Cell-derived Sensory Neurons From Male and Female Donors.

Human induced pluripotent stem cell-derived sensory neurons (hiPSC-SNs) and human dorsal root ganglia neurons (hDRG-N) are popular tools in the field of pain research; however, few groups make use of both approaches. For screening and analgesic validation purposes, important characterizations can be determined of the similarities and differences between hDRG-N and hiPSC-SNs. This study focuses specifically on the electrophysiology properties of hDRG-N in comparison to hiPSC-SNs. We also compared hDRG-N and hiPSC-SNs from both male and female donors to evaluate potential sex differences. We recorded neuronal size, rheobase, resting membrane potential, input resistance, and action potential waveform properties from 83 hiPSCs-SNs (2 donors) and 108 hDRG-N neurons (8 donors). We observed several statistically significant electrophysiological differences between hDRG-N and hiPSC-SNs, such as size, rheobase, input resistance, and several action potential waveform properties. Correlation analysis also revealed many properties that were positively or negatively correlated, some of which were differentially correlated between hDRG-N and hiPSC-SNs. This study shows several differences between hDRG-N and hiPSC-SNs and allows a better understanding of the advantages and disadvantages of both for use in pain research. We hope this study will be a valuable resource for pain researchers considering the use of these human in vitro systems for mechanistic studies and/or drug development projects. PERSPECTIVE: hiPSC-SNs and hDRG-N are popular tools in the field of pain research. This study allows for a better functional understanding of the pros and cons of both tools.

Electrophysiological analyses of human dorsal root ganglia and human induced pluripotent stem cell-derived sensory neurons from male and female donors.

Human induced pluripotent stem cell-derived sensory neurons (hiPSC-SNs) and human dorsal root ganglia (hDRG) neurons are popular tools in the field of pain research; however, few groups make use of both approaches. For screening and analgesic validation purposes, important characterizations can be determined of the similarities and differences between hDRG and hiPSC-SNs. This study focuses specifically on electrophysiology properties of hDRG in comparison to hiPSC-SNs. We also compared hDRG and hiPSC-SNs from both male and female donors to evaluate potential sex differences. We recorded neuronal size, rheobase, resting membrane potential, input resistance, and action potential waveform properties from 83 hiPSCs-SNs (2 donors) and 108 hDRG neurons (9 donors). We observed several statistically significant electrophysiological differences between hDRG and hiPSC-SNs, such as size, rheobase, input resistance, and several actional potential (AP) waveform properties. Correlation analysis also revealed many properties that were positively or negatively correlated, some of which were differentially correlated between hDRG and hiPSC-SNs. This study shows several differences between hDRG and hiPSC-SNs and allows better understanding of the advantages and disadvantages of both for use in pain research. We hope this study will be a valuable resource for pain researchers considering the use of these human in vitro systems for mechanistic studies and/or drug development projects.

A phase 1/2a dose-escalation study of oligodendrocyte progenitor cells in individuals with subacute cervical spinal cord injury.

OBJECTIVE: The primary objective of this study was to evaluate the safety of 3 escalating doses of oligodendrocyte progenitor cells (LCTOPC1; previously known as GRNOPC1 and AST-OPC1) administered at a single time point between 21 and 42 days postinjury to participants with subacute cervical spinal cord injuries (SCIs). The secondary objective was to evaluate changes in neurological function following administration of LCTOPC1. METHODS: This study was designed as an open-label, dose-escalation, multicenter clinical trial. Twenty-five participants with C4-7 American Spinal Injury Association Impairment Scale grade A or B injuries received a single dose of either 2 × 106, 1 × 107, or 2 × 107 LCTOPC1 delivered via intraparenchymal injection into the spinal cord at the site of injury using a custom-designed syringe positioning device. Low-dose tacrolimus was administered until day 60. Outcome measures included adverse event (AE) monitoring and neurological function as measured by the International Standards for Neurological Classification of Spinal Cord Injury. RESULTS: All 25 participants experienced at least one AE, with a total of 534 AEs (32 study-related vs 502 study-unrelated anticipated complications of SCI) reported at the completion of 1-year follow-up. There were 29 serious AEs reported. Two grade 3 serious AEs (CSF leak in one participant and a bacterial infection in another) were considered related to the injection procedure and to immunosuppression with tacrolimus, respectively. The CSF leakage resolved with sequelae, including self-limited altered mental status, and the infection resolved with antibiotic therapy. For all participants, MRI scans demonstrated no evidence of an enlarging mass, spinal cord damage related to the injection procedure, inflammatory lesions in the spinal cord, or masses in the ventricular system. At 1-year follow-up, 21/22 (96%) of the intention-to-treat group recovered one or more levels of neurological function on at least one side of their body, and 7/22 (32%) recovered two or more levels of neurological function on at least one side of their body. CONCLUSIONS: LCTOPC1 can be safely administered to participants in the subacute period after cervical SCI. The injection procedure, low-dose temporary immunosuppression regimen, and LCTOPC1 were well tolerated. The safety and neurological function data support further investigation to determine the efficacy of LCTOPC1 in the treatment of SCI. Clinical trial registration no.: NCT02302157 (ClinicalTrials.gov).

Ten-year safety of pluripotent stem cell transplantation in acute thoracic spinal cord injury.

OBJECTIVE: The purpose of this study was to evaluate the safety of oligodendrocyte progenitor cells (LCTOPC1) derived from human pluripotent stem cells administered between 7 and 14 days postinjury to patients with T3 to T11 neurologically complete spinal cord injury (SCI). The rationale for this first-in-human trial was based on evidence that administration of LCTOPC1 supports survival and potential repair of key cellular components and architecture at the SCI site. METHODS: This study was a multisite, open-label, single-arm interventional clinical trial. Participants (n = 5) received a single intraparenchymal injection of 2 × 106 LCTOPC1 caudal to the epicenter of injury using a syringe positioning device. Immunosuppression with tacrolimus was administered for a total of 60 days. Participants were followed with annual in-person examinations and MRI for 5 years at the time of this report and will be followed with annual telephone questionnaires for 6 to 15 years postinjection. The primary endpoint was safety, as measured by the frequency and severity of adverse events related to the LCTOPC1 injection, the injection procedure, and/or the concomitant immunosuppression administered. The secondary endpoint was neurological function as measured by sensory scores and lower-extremity motor scores as measured by the International Standards for Neurological Classification of Spinal Cord Injury examinations. RESULTS: No unanticipated serious adverse events related to LCTOPC1 have been reported with 98% follow-up of participants (49 of 50 annual visits) through the first 10 years of the clinical trial. There was no evidence of neurological decline, enlarging masses, further spinal cord damage, or syrinx formation. MRI results during the long-term follow-up period in patients administered LCTOPC1 cells showed that 80% of patients demonstrated T2 signal changes consistent with the formation of a tissue matrix at the injury site. CONCLUSIONS: This study provides crucial first-in-human safety data supporting the pursuit of future human embryonic stem cell-derived therapies. While we cannot exclude the possibility of future adverse events, the experience in this trial provides evidence that this cell type can be well tolerated by patients, with an event-free period of up to 10 years. Based on the safety profile of LCTOPC1 obtained in this study, a cervical dose escalation trial was initiated (NCT02302157).

Anterior cervical pseudomeningocele causing syncope after spinal surgery: A case report.

INTRODUCTION AND IMPORTANCE: Pseudomeningocele formation from incidental durotomy is a known risk in spine surgery. We present a case of incidental durotomy leading to anterior neck pseudomeningocele, compressing the carotid body (CB) resulting in syncopal episodes. To our knowledge, this is the first case report implicating syncopal episodes to CB compression via a pseudomeningocele. CASE PRESENTATION: A mid sixty-year-old patient with history of obesity, hypertension, and diabetes presented with gait impairment and hand weakness. Ossification of posterior longitudinal ligament (OPLL) was diagnosed with computed tomography imaging (CT) and magnetic resonance imaging (MRI). Elective surgery was completed with an anterior and posterior approach for decompression and fusion. Hospital course (San Jose, CA, USA) was complicated by respiratory depression and incomplete tetraplegia. On post-operative day (POD) six, CT revealed anterolateral soft tissue neck swelling; subsequent CT and MRI showed fluid collection expansion, with associated syncopal episodes on POD thirty-nine. Despite interventional radiology drainage, the fluid collection and symptoms returned five days later. The patient ultimately underwent durotomy revision and repair with muscle patch. CLINICAL DISCUSSION: This case highlights the challenges in managing anterior cervical dural tears resulting in pseudomeningocele. Risk factors include anterior cervical corpectomy and decompression, as well as an underlying diagnosis of OPLL. Untreated dural tears may develop into pseudomeningoceles which can contribute to life-threatening outcomes. CONCLUSION: This case report presents the serious consequences of incidental durotomy, the unique post-surgical complication of syncope due to compression of the CB from a pseudomeningocele, and the challenges of managing a persistent pseudomeningocele.

A Single-Center Retrospective Analysis Investigating the Effect of Timing of Vertebral Augmentation on Pain Outcomes.

BACKGROUND: Approximately 700,000 individuals experience osteoporotic vertebral compression fractures (OVCF) every year in the United States. Chronic complications from patients and increasing economic burdens continue to be major problems with OVCFs. Multiple treatment options for OVCF are available, including conservative management, surgical intervention, and minimally invasive vertebral augmentation. Prior studies have investigated the utility of vertebral augmentation techniques such as percutaneous vertebroplasty (PVP), balloon vertebroplasty (BVP), and vertebral augmentation with the KivaTM implant on patient mortality with favorable results. The optimal time from OVCF occurrence to vertebral augmentation continues to be a topic of investigation. OBJECTIVES: To further investigate the effect of the timing of vertebral augmentation on pain outcomes. STUDY DESIGN: A retrospective cohort chart review study. SETTING: A single academic center in Albuquerque, New Mexico. METHODS: One hundred twenty-six consecutive patient encounters with OVCF diagnosed on imaging and treated with PVP, BVP, or vertebral augmentation with a KivaTM implant between 01/01/2004 and 11/28/2016 were analyzed. The time between fracture and intervention was categorized into < 6 weeks, 6-12 weeks, and >= 12 weeks. Pain scores were measured before and after treatment using the numeric pain rating scale. Statistical analysis using Wilcoxon-Mann-Whitney and Kruskal-Wallis tests were used as appropriate, and effect sizes were described with the Hodges-Lehmann estimates of difference. RESULTS: The 3 vertebral augmentation procedures compared in this study did not demonstrate statistically significant differences in pain score reduction (P = 0.949). The < 12 weeks group had a median and interquartile range (IQR) pain improvement of 3 (IQR 1,6) versus 1 (IQR 0,4) in the >= 12 weeks group (P = 0.018). Further analysis showed that the median and IQR pain improvement for the < 6 weeks group was 3 (IQR 1,7), for the 6-12 weeks group was 3 (IQR 1,4), and for the >= 12 weeks group was 1 (IQR 0,4). The overall effect of the time category on pain improvement was statistically significant for these groups (P = 0.040). Comparisons between groups only showed differences between the < 6 weeks and >= 12 weeks groups (P = 0.013), with an estimated median difference of 2 (95% CI 0,3). There was no statistically significant relationship between fill percentage and pain relief (P = 0.291). LIMITATIONS: This is a retrospective cohort study from a single academic center with a limited sample size that lacked a control group and procedural blinding. There was also substantial heterogeneity among patients, fractures, operators, and techniques. Pain relief outcomes are subjective and can be biased by patients as well as physician reporting. CONCLUSIONS: Early intervention (< 12 weeks) with vertebral augmentation in patients with OVCF is associated with improved pain scores when compared to later intervention (> 12 weeks). Very early intervention (< 6 weeks) confers a greater advantage when compared to later intervention (> 12 weeks).

Topological network analysis of patient similarity for precision management of acute blood pressure in spinal cord injury.

Background: Predicting neurological recovery after spinal cord injury (SCI) is challenging. Using topological data analysis, we have previously shown that mean arterial pressure (MAP) during SCI surgery predicts long-term functional recovery in rodent models, motivating the present multicenter study in patients. Methods: Intra-operative monitoring records and neurological outcome data were extracted (n = 118 patients). We built a similarity network of patients from a low-dimensional space embedded using a non-linear algorithm, Isomap, and ensured topological extraction using persistent homology metrics. Confirmatory analysis was conducted through regression methods. Results: Network analysis suggested that time outside of an optimum MAP range (hypotension or hypertension) during surgery was associated with lower likelihood of neurological recovery at hospital discharge. Logistic and LASSO (least absolute shrinkage and selection operator) regression confirmed these findings, revealing an optimal MAP range of 76-[104-117] mmHg associated with neurological recovery. Conclusions: We show that deviation from this optimal MAP range during SCI surgery predicts lower probability of neurological recovery and suggest new targets for therapeutic intervention. Funding: NIH/NINDS: R01NS088475 (ARF); R01NS122888 (ARF); UH3NS106899 (ARF); Department of Veterans Affairs: 1I01RX002245 (ARF), I01RX002787 (ARF); Wings for Life Foundation (ATE, ARF); Craig H. Neilsen Foundation (ARF); and DOD: SC150198 (MSB); SC190233 (MSB).

Spinal cord injury is a devastating condition that involves damage to the nerve fibers connecting the brain with the spinal cord, often leading to permanent changes in strength, sensation and body functions, and in severe cases paralysis. Scientists around the world work hard to find ways to treat or even repair spinal cord injuries but few patients with complete immediate paralysis recover fully. Immediate paralysis is caused by direct damage to neurons and their extension in the spinal cord. Previous research has shown that blood pressure regulation may be key in saving these damaged neurons, as spinal cord injuries can break the communication between nerves that is involved in controlling blood pressure. This can lead to a vicious cycle of dysregulation of blood pressure and limit the supply of blood and oxygen to the damaged spinal cord tissue, exacerbating the death of spinal neurons. Management of blood pressure is therefore a key target for spinal cord injury care, but so far, the precise thresholds to enable neurons to recover are poorly understood. To find out more, Torres-Espin, Haefeli et al. used machine learning software to analyze previously recorded blood pressure and heart rate data obtained from 118 patients that underwent spinal cord surgery after acute spinal cord injury. The analyses revealed that patients who suffered from either low or high blood pressure during surgery had poorer prospects of recovery. Statistical models confirming these findings showed that the optimal blood pressure range to ensure recovery lies between 76 to 104-117 mmHg. Any deviation from this narrow window would dramatically worsen the ability to recover. These findings suggests that dysregulated blood pressure during surgery affects to odds of recovery in patients with a spinal cord injury. Torres-Espin, Haefeli et al. provide specific information that could improve current clinical practice in trauma centers. In the future, such machine learning tools and models could help develop real-time models that could predict the likelihood of a patient's recovery following spinal cord injury and related neurological conditions.

Pre- and Post-Interventional Changes in Physiological Profiles in a Patient Presenting With Opioid Withdrawal After Intrathecal Drug Delivery System Failure Related to Assumed Catheter Microfracture.

The intrathecal drug delivery system (IDDS) is successfully utilized for the treatment of chronic pain conditions; however, they are associated with complications related to human error and system failure. A case report is presented of a patient with opioid withdrawal (OW) secondary to assumed catheter microfracture. Interrogation of the IDDS allowed for the collection of pre- and post-treatment/stabilization cerebrospinal fluid (CSF), which is used to investigate the possible physiological determinants of OW. A 46-year-old female with a history of low back pain after traumatic low back injury status post-IDDS placement for failed back surgery syndrome presented with signs and symptoms concerning for OW. After every other possible explanation was ruled out, it was hypothesized that there may be IDDS catheter microfracture(s), and catheter replacement led to symptom resolution. There were no significant differences in cytokine levels tested in pre-CSF versus post-CSF samples. Whole-cell patch-clamp electrophysiology analysis of human-induced pluripotent stem cell-derived nociceptors after treatment with pre- and post-CSF samples demonstrated modulation of action potential waveform. In patients presenting with acute OW attribution IDDS malfunction, catheter microfracture must be in the differential, and non-conventional interrogation of the IDDS catheter should be considered. The possible differences in pre-CSF and post-CSF may be more complicated than previously postulated, as there were no significant differences in cytokine profiles; however, treatment of in vitro neurons with pre- and post-CSF resulted in differential neuronal excitability, which may account for some of the symptoms of OW.

Ultrasound-guided cervical selective nerve root injections: a narrative review of literature.

BACKGROUND/IMPORTANCE: Ultrasound (US)-guided cervical selective nerve root injections (CSNRI) have been proposed as an alternative to fluoroscopic (FL) -guided injections. When choosing US guidance, the proceduralist should be aware of potential issues confirming vertebral level, be clear regarding terminology, and up to date regarding the advantages and disadvantages of US-guided CSNRI. OBJECTIVE: Review the accuracy and effectiveness of US guidance in avoiding vascular puncture (VP) and/or intravascular injection (IVI) during CSNRI. EVIDENCE REVIEW: Queries included PubMed, CINAHL and Embase databases from 2005 to 2019. Three authors reviewed references for eligibility, abstracted data, and appraised quality. FINDINGS: The literature demonstrates distinct safety considerations and limited evidence of the effectiveness of US guidance in detecting VP and/or IVI. As vascular flow and desired injectate spread cannot be visualized with US, the use of real-time fluoroscopy, and if needed digitial subraction imaging, is indicated in cervical transforaminal epidural injections (CTFEIs). Given the risk of VP and/or IVI, the ability to perform and to retain FL images to document that the procedure was safely conducted is valuable in CTFEIs. CONCLUSION: US guidance remains to be proven as a non-inferior alternative to FL guidance or other imaging modalities in the prevention of VP and/or IVI with CTFEIs or cervical selective nerve root blocks. There is a paucity of adequately powered clinical studies evaluating the accuracy and effectiveness of US guidance in avoiding VP and/or IVI. US-guided procedures to treat cervical radicular pain has limitations in visualization of anatomy, and currently with the evidence available is best used in a combined approach with FL guidance.

Lumbar Annular High-Intensity Zone as a Precursor to Disc Extrusion.

Low back pain (LBP) is a common affliction with numerous causes. Some individuals experience LBP attributed to disc pathology. Disc pathology has been implicated in a plurality of cases of LBP, and some cases are associated with annular fissures (AFs). AFs are weaknesses in the structure that contains the nucleus pulposus and is the site of possible disc herniations. On magnetic resonance imaging (MRI), some AFs manifest as the high-intensity zone (HIZ), otherwise known as an annular enhancement region. In this report, we present three patients with LBP, mild radiculitis, and HIZ who later developed herniated nucleus pulposus (HNP) with extrusion through the HIZ. These cases suggest that HIZ indicates a propensity for the future development of disc extrusion through the weakened tissue at the AF visualized as HIZ on MRI. With a better understanding of the association between AFs and disc herniations with HIZ, clinicians may be able to predict and prevent the pain and disability associated with disc extrusion.

Correction: Exploration of surgical blood pressure management and expected motor recovery in individuals with traumatic spinal cord injury.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Antiplatelet and Anticoagulant Risk for Select Spine Interventions: A Retrospective Cohort.

OBJECTIVES: To identify significant bleeding complications following spinal interventions in patients taking medications with antiplatelet or anticoagulation effect. DESIGN: Retrospective chart review of a 12-month period. SETTING: Outpatient academic medical practice. INTERVENTIONS: Injections during outpatient interventional spine clinical encounters, including 14 cervical transforaminal epidural steroid injections, 26 cervical medial branch blocks, seven cervical radiofrequency neurotomies, three cervical facet joint injections, 88 lumbar transforaminal epidural steroid injections, 66 lumbosacral medial branch blocks, 18 lumbosacral radiofrequency neurotomies, 13 lumbar facet joint injections, one caudal epidural steroid injection, 11 sacral transforaminal epidural steroid injections, and 32 sacroiliac joint injections. MAIN OUTCOME MEASURE: Epidural hematoma or other serious bleeding. RESULTS: In this cohort of 275 consecutive encounters with available records in which patients underwent a spinal injection while continuing medications with antiplatelet or anticoagulant effect, zero of the 275 clinical encounters (0%, 95% confidence interval = 0-1.4%) resulted in epidural hematoma or other serious bleeding. For antiplatelet medication, nonsteroidal anti-inflammatory drugs were continued in 102 procedures, aspirin in 142, clopidogrel in 21, and meloxicam and/or Celebrex in 81; for anticoagulation medication, warfarin was continued in four procedures, apixaban in six, dabigatran in one, and fondaparinux in two. Of note, one patient suffered a deep vein thrombosis, which was identified at two-week follow-up despite continuing aspirin therapy. CONCLUSIONS: This cohort adds to the growing evidence that the risk of serious bleeding complications from select spine interventions while continuing medications with antiplatelet or anticoagulant effect appears low.

Prevalence of Low Plasma Vitamin B1 in the Stroke Population Admitted to Acute Inpatient Rehabilitation.

OBJECTIVE: To determine the prevalence of vitamin B1 (VitB1) deficiency in the stroke population admitted to acute inpatient rehabilitation. DESIGN: Retrospective cohort study. SETTING: Acute inpatient rehabilitation facility at an academic medical center. PARTICIPANTS: 119 consecutive stroke patients admitted to stroke service from 1 January 2018 to 31 December 2018. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Plasma VitB1 level. RESULTS: There were 17 patients (14%; 95% CI 9-22%) with low VitB1 with a range of 2-3 nmol/L, an additional 58 (49%; CI 40-58%) patients had normal low VitB1 with a range of 4-9 nmol/L, twenty-five patients (21%; CI 15-29%) had normal high VitB1 with a range of 10-15 nmol/L, and nineteen patients (16%; CI 10-24%) had high VitB1 with a range of 16-43 nmol/L. CONCLUSIONS: In this cohort of patients admitted to the stroke service at an acute rehabilitation facility, there is evidence of thiamine deficiency. Moreover, the data suggest that there is inadequate acute intake of VitB1. Given the role of thiamine deficiency in neurologic function, further study of the role of thiamine optimization in the acute stroke rehabilitation population is warranted.