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.

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.

Pain and Functional Outcomes After Sacroiliac Joint Injection with Anesthetic and Corticosteroid at Six Months, Stratified by Anesthetic Response and Physical Exam Maneuvers.

OBJECTIVE: To evaluate sacroiliac joint (SIJ) injection outcomes with local anesthetic and corticosteroid. DESIGN: Prospective cohort. SETTING: Single academic medical center. METHODS: Thirty-four patients referred for SIJ injection with a clinical diagnosis of SIJ pain underwent injections with 1:1 mixture of 2% lidocaine and triamcinolone 40 mg/mL. Pain provocation physical exam (PE) maneuvers were recorded immediately before and after injection. Outcome measures at two to four weeks and six months included pain numeric rating scale (NRS) and Oswestry Disability Index (ODI). RESULTS: For the analysis of outcomes by the overall group (not stratified by PE and/or anesthetic block), a 58.8% (95% confidence interval [CI] = +/-16.5%) ≥2 NRS reduction, a 32.4% (95% CI = +/-15.7%) ≥50% NRS reduction, and a 38.2% (95% CI = +/-16.3%) ≥30% ODI reduction were observed at two to four weeks, with similar improvements at six months. Outcomes stratified based on pre-injection PE did not reveal significant differences at either time point. The stratification based on the presence of 100% postinjection anesthetic response demonstrated a significant difference at two to four weeks for ≥50% NRS improvement. The true positive/true negative group (TP/TN) stratification demonstrated a significant difference for ≥50% NRS improvement at two to four weeks, whereas six-month outcomes for TP/TN demonstrated significant differences for ≥50% NRS and ≥30% ODI improvement. An increased injection response was observed with stratification of patients more likely to have true SIJ pain (i.e., TP), with TP/TN stratification demonstrating a 75% (95% CI = +/-30.0%) ≥2 NRS improvement and a 62.5% (95% CI = +/-33.5%) improvement of ≥50% NRS and ≥30% ODI for the TP group at two to four weeks, with similar results at six months. CONCLUSIONS: SIJ steroid injection based on referral clinical diagnosis is unlikely to demonstrate true injection efficacy, and more specific selection criteria are warranted.

Validity of Physical Exam Maneuvers in the Diagnosis of Sacroiliac Joint Pathology.

BACKGROUND: A combination of physical examination maneuvers is currently considered necessary to help predict who will respond to injections in the sacroiliac joint. However, the literature on this topic currently consists of conflicting studies, with one showing the value of a combination of exam maneuvers and the other showing no real value. OBJECTIVE: To determine the diagnostic validity of sacroiliac joint (SIJ) physical exam maneuvers using anesthetic intra-articular injection as a reference standard. DESIGN: A single institution prospective study. PARTICIPANTS: Patients with the clinical diagnosis of SIJ pain and referred for SIJ injection were enrolled. MAIN OUTCOME MEASURE: Numeric rating scale (NRS) to assess pain intensity. RESULTS: Participants underwent fluoroscopically guided SIJ intra-articular injection with 1 cc of 2% lidocaine and 1 cc of triamcinolone 40 mg. Patients' pain was assessed via 0-10 NRS pre-injection and immediately postinjection to determine positive anesthetic response to the injection. Six physical exam maneuvers (thigh thrust, Geanslen's test, FABER test, distraction test, compression test, and sacral thrust) were performed pre-injection and 15 minutes postinjection. The results of these SIJ physical exam maneuvers were evaluated singly and in combinations for diagnostic power in relation to a positive anesthetic response (>80% relief) to the injection. No association was found between a single SIJ physical exam maneuver or combination of maneuvers and anesthetic response to the injection. CONCLUSIONS: In this cohort, patient physical exam maneuvers to identify intra-articular SIJ pain did not demonstrate diagnostic value when compared with the reference standard of an intra-articular anesthetic block.

Smoking Is Associated with Pain in All Body Regions, with Greatest Influence on Spinal Pain.

OBJECTIVE: Examine the interrelationship between smoking and pain in the US population. DESIGN: A cross-sectional population-based study. SETTING: Nationwide survey. METHODS: Comprehensive pain reports categorically defined as head, spine, trunk, and limb pain; smoking history; demographics; medical history from a total of 2,307 subjects from the 2003-2004 National Health and Nutrition Examination Survey obtained from the Centers for Disease Control were analyzed. Unpaired t tests were used to analyze independent continuous variables, and chi-square tests were used to analyze categorical variables between smoker and nonsmoker groups. Weighted multivariate logistic regression analyses determined the association of current smoking with the presence of pain in various body regions. RESULTS: Smoking is most strongly associated with spine pain (odds ratio [OR] = 2.89, 95% confidence interval [CI] = 2.21-3.77), followed by headache (OR = 2.47, 95% CI = 1.73-3.53), trunk pain (OR = 2.17, 95% CI = 1.45-2.74), and limb pain (OR = 1.99, 95% CI = 1.45-2.73). CONCLUSIONS: Current smoking is associated with pain in every region of the body. This association is strongest for spine and head pain. Given that pain is a strong motivator and that current smoking was associated with pain in all body regions, we recommend that these results be used to further raise public awareness about the potential harms of smoking.

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.

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

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

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

STUDY DESIGN: Retrospective analysis. OBJECTIVE: To assess the impact of mean arterial blood pressure (MAP) during surgical intervention for spinal cord injury (SCI) on motor recovery. SETTING: Level-one Trauma Hospital and Acute Rehabilitation Hospital in San Jose, CA, USA. METHODS: Twenty-five individuals with traumatic SCI who received surgical and acute rehabilitation care at a level-one trauma center were included in this study. The Surgical Information System captured intraoperative MAPs on a minute-by-minute basis and exposure was quantified at sequential thresholds from 50 to 104 mmHg. Change in International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) motor score was calculated based on physiatry evaluations at the earliest postoperative time and at discharge from acute rehabilitation. Linear regression models were used to estimate the rate of recovery across the entire MAP range. RESULTS: An exploratory analysis revealed that increased time within an intraoperative MAP range (70-94 mmHg) was associated with ISNCSCI motor score improvement. A significant regression equation was found for the MAP range 70-94 mmHg (F[1, 23] = 5.07, r2 = 0.181, p = 0.034). ISNCSCI motor scores increased 0.039 for each minute of exposure to the MAP range 70-94 mmHg during the operative procedure; this represents a significant correlation between intraoperative time with MAP 70-94 and subsequent motor recovery. Blood pressure exposures above or below this range did not display a positive association with motor recovery. CONCLUSIONS: Hypertension as well as hypotension during surgery may impact the trajectory of recovery in individuals with SCI, and there may be a direct relationship between intraoperative MAP and motor recovery.

Contrast enhancing epidural fluid accumulation after percutaneous endoscopic lumbar discectomy: A case report of recurrent disc herniation within pseudocyst secondary to irrigation fluid.

INTRODUCTION: Percutaneous endoscopic lumbar discectomy (PELD) is increasingly being utilized to treat patients with lumbar disc herniation. PELD is unique in that it uses a single working port endoscope with constant irrigation of the surgical field to visualize pathology. The current report is of a case of postoperative epidural irrigation fluid accumulation presenting as peripherally enhancing epidural lesions, masking an underlying re-herniation. PRESENTATION OF CASE: A patient with a Lumbar 5-Sacral 1 level disc herniation presenting with radiculopathy was treated using PELD. Following the operation, the patient experienced recurrent pain, prompting a repeat MRI of the lumbar spine. Multiple ring-enhancing lesions within the epidural space were observed, creating diagnostic dilemmas. The differential diagnoses included epidural abscess, pseudomeningocele from unintended durotomy, epidural hematoma, or trapped epidural fluid collection presenting as a pseudocyst with or without recurrent disc herniation. A repeat endoscopic discectomy was performed to confirm the diagnosis of pseudocyst, revealing a recurrent disc herniation. DISCUSSION: Pseudocysts are not an uncommon complication of PELD, typically believed to be due to an inflammatory response to disc fragments. However, in this case, the epidural fluid collection was likely the result of trapped irrigation fluid from continuous irrigation during the procedure, which masked an underlying re-herniation on imaging. CONCLUSION: With the increasing utilization of PELD, it is important to acknowledge unique complications such as fluid accumulation from irrigation within the epidural space. Fluid accumulation can lead to contrast-enhancing pseudocyst formation, which can theoretically lead to mass effect or increased intracranial and intraspinal pressure and may mask additional underlying pathology.

Improvement of the rapid response system at an acute rehabilitation hospital in New Mexico.

Aim: Enhance the Rapid Response System (RRS) in a free-standing acute rehabilitation hospital (ARH) by improving announcements, crash cart standardization and role assignments. Materials & methods: Pre-intervention (PreIQ) and post-intervention questionnaires (PostIQ), conducted in English and utilizing a Likert scale, were distributed in-person to clinical staff, yielding a 100% response rate. The questionnaire underwent no prior testing. The PreIQ were disseminated in February 2021, and PostIQ in December 2022. Results: PostIQ illustrated the improvement of audibility and improved the clarity of roles. The training positively impacted the RRS in the ARH. Conclusion: This study highlights the value of continuous RRS improvement in ARHs. Interventions led to notable enhancements, emphasizing the need for sustained efforts and future research on broader implementation.

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.

Machine learning elucidates electrophysiological properties predictive of multi- and single-firing human and mouse dorsal root ganglia neurons.

Human and mouse dorsal root ganglia (hDRG and mDRG) neurons are important tools in understanding the molecular and electrophysiological mechanisms that underlie nociception and drive pain behaviors. One of the simplest differences in firing phenotypes is that neurons are single-firing (exhibit only one action potential) or multi-firing (exhibit 2 or more action potentials). To determine if single- and multi-firing hDRG exhibit differences in intrinsic properties, firing phenotypes, and AP waveform properties, and if these properties could be used to predict multi-firing, we measured 22 electrophysiological properties by whole-cell patch-clamp electrophysiology of 94 hDRG neurons from 6 male and 4 female donors. We then analyzed the data using several machine learning models to determine if these properties could be used to predict multi-firing. We used 1000 iterations of Monte Carlo Cross Validation to split the data into different train and test sets and tested the Logistic Regression, k-Nearest Neighbors, Random Forest, Supported Vector Classification, and XGBoost machine learning models. All models tested had a greater than 80% accuracy on average, with Supported Vector Classification and XGBoost performing the best. We found that several properties correlated with multi-firing hDRG neurons and together could be used to predict multi-firing neurons in hDRG including a long decay time, a low rheobase, and long first spike latency. We also found that the hDRG models were able to predict multi-firing with 90% accuracy in mDRG. Targeting the neuronal properties that lead to multi-firing could elucidate better targets for treatment of chronic pain.

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.

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).

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).

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).