A review of epidural and non-epidural contrast flow patterns during fluoroscopic and CT-guided epidural steroid injections.

Epidural steroid injections are commonly performed using fluoroscopic or CT guidance. With both modalities, the injection of contrast material is necessary before steroid administration to ensure adequate epidural flow and exclude non-epidural flow. While fluoroscopic guidance is conventional, CT is utilized at some centers and can be particularly helpful in the setting of challenging or postoperative anatomy. It is important for proceduralists to be adept at evaluating contrast media flow patterns under both modalities. The goal of this review article is to describe and provide examples of epidural and non-epidural flow patterns on both conventional fluoroscopy and CT. Specific non-epidural patterns discussed include intrathecal flow, intradural/subdural flow, vascular uptake, flow into the retrodural space of Okada, inadvertent facet joint flow, and intradiscal flow.

Spinal region corticosteroid injections are not associated with increased risk for influenza.

BACKGROUND CONTEXT: Spinal region corticosteroid injections (CSI) are intended to act locally to relieve radicular or axial back pain, however some systemic absorption occurs, potentially placing recipients at risk for immunosuppressive effects of corticosteroids. No previous studies examine whether patients undergoing spinal region CSI are at increased risk for viral infections, particularly influenza-a common viral illness with potentially serious consequences, especially for patients with multimorbidity. PURPOSE: To examine odds of influenza in patients who received spinal region CSI compared to matched controls. STUDY DESIGN: Retrospective cohort study. PATIENT SAMPLE: Adults (n=9,196) who received a spinal CSI (epidural, facet, sacroiliac, paravertebral block) during influenza seasons occurring from 2000 to 2020 were 1:1 matched to controls without spinal CSI. OUTCOME MEASURES: The primary outcome was odds of influenza diagnosis in spinal CSI patients compared to matched controls. Predetermined subgroup analyses examined odds of influenza diagnosis based on vaccination status and injection location. METHODS: An institutional database was queried to identify patients that received spinal CSI during influenza season (September 1 to April 30) from 2000 to 2020. Patients were matched by age, sex, and influenza vaccination status to controls without spinal CSI within the specified influenza season. Influenza diagnosis was ascertained using International Classification of Disease codes and data was analyzed using multiple logistic regression adjusted for comorbidities associated with increased risk for influenza. RESULTS: A total of 9,196 adults (mean age 60.8 years, 60.4% female) received a spinal CSI and were matched to a control. There were no increased odds of influenza for spinal CSI patients as compared to matched controls (OR 1.13, [95% CI, 0.86-1.48]). When subgroups were examined, there were also no increased odds of influenza for spinal CSI patients based on immunization status (unvaccinated or vaccinated) or spinal injection location (epidural or non-epidural). CONCLUSIONS: Spinal region CSI was not associated with increased odds of influenza or reduced vaccine efficacy. This is reassuring given the analgesic and functional restoration benefits of these injections. Assessing risk of viral infection associated with spinal CSI is particularly relevant in the era of the COVID-19 pandemic, and further work is needed to address this issue.

Spinal corticosteroid injections are not associated with increased influenza risk.

BACKGROUND CONTEXT: Spinal corticosteroid injections (CSI) are often used to treat radicular and axial pain arising from the spine. Systemic corticosteroids are well known to cause immunosuppression, and locally injected spinal CSI are known to have some systemic absorption. However, it is unknown whether spinal CSI increases the risk of systemic viral infections, such as influenza. PURPOSE: To determine whether spinal CSI causes an increased risk for influenza infection and whether they reduce the protective effect of vaccination STUDY DESIGN/SETTING: A retrospective cohort study was performed at Kaiser Permanente Northern California, a large healthcare system with a diverse population. PATIENT SAMPLE: Adults (n=60,880) who received a spinal CSI during influenza seasons from 2016 to 2019. A comparison was made with 121,760 case-matched individuals who did not receive a spinal CSI. OUTCOME MEASURES: The primary outcome was odds of influenza diagnosis following spinal CSI compared with case-matched controls. Secondary analysis examined odds of influenza diagnosis based on vaccination status, multiple same-day injections, and epidural versus non-epidural route of injection. METHODS: The electronic health record and associated research databases were analyzed to identify patients who received a spinal CSI during three consecutive flu seasons, 2016 through 2019. Injections were stratified into epidural versus non-epidural CSI and single injections versus multiple same-day injections. Additionally, the rate of influenza in vaccinated versus non-vaccinated individuals was examined. Inpatient flu diagnosis was used as a proxy for severe disease. After case matching was completed, odds ratios for flu diagnosis were calculated using a logistical regression model. RESULTS: The odds of flu diagnosis following spinal CSI were not increased compared with controls (OR 0.93 [0.87-1.01, 95% Wald CL]). For epidural CSI the OR was 0.91 (0.83-1.00, 95% Wald CL), and non-epidural it was 1.00 (0.89-1.13, 95% Wald CL). There were similar findings for multiple same-day injections and when looking at inpatient flu diagnosis. For vaccinated individuals, the OR for flu following spinal CSI was 0.86 (0.80-0.92, 95% Wald CL), which indicates a protective effect in these patients. CONCLUSIONS: Spinal CSI did not increase the odds of subsequently receiving a diagnosis of influenza, regardless of vaccination status, location of injection, single versus multiple same-day injection, or co-morbidity. Vaccination had a protective effect against influenza, and this was not adversely affected by receiving spinal CSI during the flu season.

The effectiveness of intradiscal biologic treatments for discogenic low back pain: a systematic review.

BACKGROUND CONTEXT: There are limited treatments for discogenic low back pain. Intradiscal injections of biologic agents such as platelet-rich plasma (PRP) or stem cells (SC) are theorized to have regenerative properties and have gained increasing interest as a possible treatment, but the evidence supporting their use in clinical practice is not yet well-defined. PURPOSE: Determine the effectiveness of intradiscal biologics for treating discogenic low back pain. STUDY DESIGN: PRISMA-compliant systematic review. PATIENT SAMPLE: Patients with discogenic low back pain confirmed by provocation discography or clinical and imaging findings consistent with discogenic pain. OUTCOME MEASURES: The primary outcome was the proportion of individuals with ≥50% pain relief after intradiscal biologic injection at 6 months. Secondary outcomes included ≥2-point pain score reduction on NRS; patient satisfaction; functional improvement; decreased use of other health care, including analgesics and surgery; and structural disc changes on MRI. METHODS: Comprehensive literature search performed in 2018 and updated in 2020. Interventions included were biologic therapies including mesenchymal stem cells, platelet rich plasma, microfragmented fat, amniotic membrane-based injectates, and autologous conditioned serum. Any other treatment (sham or active) was considered for comparative studies. Studies were independently reviewed. RESULTS: The literature search yielded 3,063 results, 37 studies were identified for full-text review, and 12 met established inclusion criteria for review. The quality of evidence on effectiveness of intradiscal biologics was very low. A single randomized controlled trial evaluating platelet-rich plasma reported positive outcomes but had significant methodological flaws. A single trial that evaluated mesenchymal stem cells was negative. Success rates for platelet-rich plasma injectate in aggregate were 54.8% (95% Confidence Interval: 40%-70%). For mesenchymal stem cells, the aggregate success rate at six months was 53.5% (95% Confidence Interval: 38.6%-68.4%), though using worst-case analysis this decreased to 40.7% (95% Confidence Interval: 28.1%-53.2%). Similarly, ≥30% functional improvement was achieved in 74.3% (95% Confidence Interval: 59.8%-88.7%) at six months but using worst-case analysis, this decreased to 44.1% (95% Confidence Interval: 28.1%-53.2%). CONCLUSION: Limited observational data support the use of intradiscal biologic agents for the treatment of discogenic low back pain. According to the Grades of Recommendation, Assessment, Development and Evaluation System, the evidence supporting use of intradiscal mesenchymal stem cells and platelet-rich plasma is very low quality.

Intraosseous Basivertebral Nerve Radiofrequency Ablation for the Treatment of Vertebral Body Endplate Low Back Pain: Current Evidence and Future Directions.

Recently, basivertebral nerve (BVN) radiofrequency ablation has been developed for the treatment of chronic low back pain (CLBP) thought to arise from the vertebral body endplates (VEPs). This review describes the relevant neuroanatomy and pathobiology of VEP degeneration and injury, imaging correlates of presumed VEP pain, randomized controlled trials performed, appropriate patient selection, and safety. Anatomic, histological, and clinical evidence supports the concept of the VEP as a source of CLBP and the nociceptive role of the BVN. BVN radiofrequency ablation appears to be an effective treatment for a subset of patients with CLBP and evidence of Modic change types 1 and 2 in the L3 to S1 VEPs who have failed to respond to conservative treatment. However, all studies performed to date have been industry sponsored, and future non-industry-funded trials will be needed to confirm these results.

The Use of Contrast Agents in Interventional Pain Procedures: A Multispecialty and Multisociety Practice Advisory on Nephrogenic Systemic Fibrosis, Gadolinium Deposition in the Brain, Encephalopathy After Unintentional Intrathecal Gadolinium Injection, and Hypersensitivity Reactions.

This Practice Advisory presents a comprehensive and evidence-based set of position statements and recommendations for the use of contrast media in interventional pain procedures. The advisory was established by an international panel of experts under the auspices of 11 multinational and multispecialty organizations based on a comprehensive review of the literature up to December 31, 2019. The advisory discusses the risks of using gadolinium-based contrast agents. These include nephrogenic systemic fibrosis, gadolinium brain deposition/retention, and encephalopathy and death after an unintentional intrathecal gadolinium injection. The advisory provides recommendations on the selection of a specific gadolinium-based contrast agent in patients with renal insufficiency, those who had multiple gadolinium-enhanced magnetic resonance imaging examinations, and in cases of paraspinal injections. Additionally, recommendations are made for patients who have a history of mild, moderate, or severe hypersensitivity reactions to contrast medium.

Quantitation of Gait and Stance Alterations Due to Monosodium Iodoacetate-induced Knee Osteoarthritis in Yucatan Swine.

Knee osteoarthritis is one of the most common causes of chronic pain worldwide, and several animal models have been developed to investigate disease mechanisms and treatments to combat associated morbidities. Here we describe a novel method for assessment of locomotor pain behavior in Yucatan swine. We used monosodium iodoacetate (MIA) to induce osteoarthritis in the hindlimb knee, and then conducted live observation, quantitative gait analysis, and quantitative weight-bearing stance analysis. We used these methods to test the hypothesis that locomotor pain behaviors after osteoarthritis induction would be detected by multiparameter quantitation for at least 12 wk in a novel large animal model of osteoarthritis. MIA-induced knee osteoarthritis produced lameness quantifiable by all measurement techniques, with onset at 2 to 4 wk and persistence until the conclusion of the study at 12 wk. Both live observation and gait analysis of kinetic parameters identified mild and moderate osteoarthritis phenotypes corresponding to a binary dose relationship. Quantitative stance analysis demonstrated the greatest sensitivity, discriminating between mild osteoarthritis states induced by 1.2 and 4.0 mg MIA, with stability of expression for as long as 12 wk. The multiparameter quantitation used in our study allowed rejection of the null hypothesis. This large animal model of quantitative locomotor pain resulting from MIA-induced osteoarthritis may support the assessment of new analgesic strategies for human knee osteoarthritis.

Synovial Cysts Confounding Access to the Dorsal S1 Neural Foramen in Transforaminal Epidural Steroid Injections.

OBJECTIVES: The S1 dorsal foramen is the route for 30% of lumbar transforaminal epidural injections; it is therefore important to identify structures impeding S1 foraminal access. The study objective was to characterize the imaging findings, prevalence, and anatomic origin of synovial cysts presenting within the S1 neural foramen. METHODS: A case series (N = 14) established imaging characteristics of S1 synovial cysts. Imaging studies of 400 patients undergoing epidural injections were reviewed for lesions compromising S1 foraminal access. Cadaveric dissections defined the relationship of the inferior recess of the L5-S1 facet to the S1 dorsal foramen. RESULTS: Elderly patients (mean age = 76) exhibited S1 synovial cysts. Synovial cysts were typically 1-2 cm in diameter, hyperintense on sagittal T2 weighted magnetic resonance images (MRIs), fluid-density on computed tomography, and dorsal to the S1 spinal nerve. Sixty percent of cysts exhibited complex MRI signal characteristics (thick wall, internal structure). Tarlov cysts, in contrast, were larger, lobular, and exhibited pure fluid intensity. Lesions impeded access to the S1 dorsal foramina in 5% of reviewed imaging studies (16 Tarlov cysts, three synovial cysts, one conjoint S1-S2 nerve root). The multifidus muscle was interposed between the L5-S1 facet inferior recess and the S1 dorsal foramen on dissection specimens; severe atrophy of the ipsilateral multifidus was noted on imaging in 17/18 synovial cysts. CONCLUSIONS: The S1 neural foramina should be inspected on sagittal MRI, when available, for confounding lesions before performing S1 epidural injections. Tarlov cysts are more common than synovial cysts; the latter are seen in elderly patients with severe multifidus atrophy.

Quantitative Knee Arthrography in a Large Animal Model of Osteoarthritis Using Photon-Counting Detector CT.

OBJECTIVE: The aim of this study was to grade cartilage damage in a swine model of osteoarthritis using a whole-body photon-counting detector (PCD) CT. MATERIALS AND METHODS: A multienergy phantom containing gadolinium (Gd) (2, 4, 8, and 16 mg/mL) and hydroxyapatite (200 and 400 mg/cc) was scanned using a PCD-CT system (48 × 0.25 mm collimation, 80 kV, 800 mAs, D50 reconstruction kernel) to serve as calibration for material decomposition and to assess quantification accuracy. Osteoarthritis was induced in Yucatan miniswine (n = 8) using 1.2 mg monoiodoacetate (MIA) injected into a randomized knee, whereas the contralateral control knee received saline. Twenty-one days later, a contrast bolus (gadoterate meglumine, 4 mL/knee) was intra-articularly administered into both knees. The knees were simultaneously scanned on the PCD-CT system (48 × 0.25 mm collimation, 80 kV, 800 mAs). Multienergy images were reconstructed with a sharp "V71" kernel and a quantitative "D50" kernel. Image denoising was applied to the V71 images before grading cartilage damage, and an iterative material decomposition technique was applied to D50 images to generate the Gd maps. Two radiologists blinded to the knee injection status graded the cartilage integrity based on a modified International Cartilage Repair Society scoring system. Histology was performed on excised cartilage using methylene blue/basic fuchsin. Statistical analysis of grade distribution was performed using an exact test of omnibus symmetry with P < 0.05 considered significant. RESULTS: Material decomposed images from the multienergy phantom scan showed delineation and quantification of Gd and hydroxyapatite with a root-mean-squared error of 0.3 mg/mL and 18.4 mg/cc, respectively. In the animal cohort, the radiologists reported chondromalacia in the MIA knees with International Cartilage Repair Society scores ranging from grade 1 (cartilage heterogeneity, n = 4 knees) to grade 3 (up to 100% cartilage loss, n = 4 knees). Grade 1 was characterized by cartilage heterogeneity and increased joint space in the patellofemoral compartment, whereas grade 3 was characterized by cartilage erosion and bone-on-bone articulation in the patellofemoral compartment. All control knees were scored as grade 0 (normal cartilage). Significant difference (P = 0.004) was observed in the grade distribution between the MIA and control knees. Gross examination of the excised knees showed cartilage lesions in the grade 3 MIA knees. The Gd maps from material decomposition showed lower contrast levels in the joint space of the MIA knee compared with the contralateral control knee due to joint effusion. Histology revealed chondrocyte loss in the MIA knee cartilage confirming the chondrotoxic effects of MIA on cartilage matrix. CONCLUSIONS: We demonstrated a high-resolution and quantitative PCD-CT arthrography technique for grading cartilage damage in a large animal model of osteoarthritis. Photon-counting detector CT offers simultaneous high-resolution and multienergy imaging capabilities that allowed morphological assessment of cartilage loss and quantification of contrast levels in the joint as a marker of joint disease. Cartilage damage in the MIA knees was graded using PCD-CT images, and the image-based findings were further confirmed using histology and gross examination of the excised knees.

Low-Pressure Lumbar Provocation Discography According to Spine Intervention Society/International Association for the Study of Pain Standards Does Not Cause Acceleration of Disc Degeneration in Patients With Symptomatic Low Back Pain: A 7-Year Matched Cohort Study.

STUDY DESIGN: Retrospective matched cohort study. OBJECTIVE: To determine if low-pressure lumbar provocation discography (PD) results in long-term accelerated disc degeneration, internal disc disruption, or disc herniation in patients with symptomatic low back pain (LBP). SUMMARY OF BACKGROUND DATA: Study of subjects without clinically-significant LBP suggests that high-pressure PD may accelerate disc degeneration. METHODS: Consecutive patients with symptomatic LBP who underwent magnetic resonance imaging (MRI), PD, and repeat MRI more than 7 years later, but did not undergo subsequent spinal fusion surgery, were included. Punctured discs were matched (1:2 to 1:4) to corresponding discs in a control cohort by age, BMI, Pfirrmann score (±2), and presence of disc herniation; control cohort inclusion required MRIs for symptomatic LBP, separated by more than 7 years. The primary outcome of the study was a progression in Pfirrmann score category (I-II, III-IV, V). MRI disc-to-CSF T2 signal-intensity ratio, disc height, disc herniations, high intensity zones (HIZs), and Modic changes were assessed. RESULTS: Baseline and follow-up MRIs were available for 77 discs exposed to PD, and for 260 discs in the matched control cohort. There was no difference in the proportion of punctured discs that advanced in Pfirrmann score category in the PD group (17%, 95% CI 9-27%) compared with corresponding discs in the Control group (21%, 95% CI 17-27%), P = 0.3578, or in non-punctured discs in the PD group (35%, 95% CI 21-51%) compared with corresponding discs in the Control group (34%, 95% CI 27-42%), P = 0.1169. There were no differences in disc-to-CSF T2 signal-intensity ratio, presence of disc herniations, HIZs, or Modic changes following puncture in the PD versus matched cohort discs or in the non-punctured PD cohort discs versus corresponding control cohort discs (P > 0.05). CONCLUSION: Patients with symptomatic LBP who underwent low-pressure PD, but who did not undergo a subsequent spinal fusion surgery, developed disc degeneration and new disc herniations at a similar rate to corresponding discs in matched control patients. LEVEL OF EVIDENCE: 3.

MRI guidance technology development in a large animal model for hyperlocal analgesics delivery to the epidural space and dorsal root ganglion.

BACKGROUND: Development of new analgesic drugs or gene therapy vectors for spinal delivery will be facilitated by "hyperlocal" targeting of small therapeutic injectate volumes if spine imaging technology can be used that is ready for future clinical translation. NEW METHOD: This study provides methods for MRI-guided drug delivery to the periganglionic epidural space and the dorsal root ganglion (DRG) in the Yucatan swine. RESULTS: Phantom studies showed artifact-corrected needle localization with frequency encoding parallel to the needle shaft, while maximizing bandwidth (125 KHz) minimized needle artifact. A custom constructed 8-12 element surface coil (phased array) wrapped over the spine in conjunction with lateral recumbent positioning achieved diagnostic quality signal to noise ratio at the depth of the DRG and afforded transforaminal access via anterolateral or posterolateral vectors, as well as interlaminar access. Swine epidural anatomy was homologous with human anatomy. Injectate containing 2% gadolinium allowed imaging of injectate volumes in increments as small as 10 microliters and discrimination of epidural flow from intraparenchymal injectate delivery into a DRG. All technical and technological elements of the procedure appear clinically translatable. COMPARISON WITH EXISTING METHODS: Computed tomographic or fluoroscopic guidance cannot directly visualize drug delivery into the DRG due to contrast medium toxicity, nor reliably identify epidural injection volumes of < 50 microliters. CONCLUSIONS: MRI-guided hyperlocal delivery in swine provides a translatable and faithful model of future human spinal novel drug- or gene therapy vector delivery.

Unilateral Epidural Targeting of Resiniferatoxin Induces Bilateral Neurolysis of Spinal Nociceptive Afferents.

OBJECTIVE: This study modeled image-guided epidural drug delivery to test whether intraprocedural distribution of pre-injected contrast reliably predicts the neuroanatomical reach of resiniferatoxin-mediated nociceptive neurolysis. METHODS: Swine (N = 12) received unilateral L4-S2 computed tomography fluoroscopy injections by a blinded neuroradiologist; 0.25 mL of contrast was pre-injected to confirm dorsal periganglionic targeting, followed by a 0.5-mL injection of 5 µg of resiniferatoxin/Tween80 or vehicle control. Epidural contrast distribution was graded according to maximum medial excursion. Spinal cord substance P immunostaining quantified the magnitude and anatomical range of resiniferatoxin activity. RESULTS: Periganglionic injection was well tolerated by all animals without development of neurological deficits or other complications. Swine were a suitable model of human clinical spinal intervention. The transforaminal approach was used at all L4 and 50% of L5 segments; the remaining segments were approached by the interlaminar route. All injections were successful with unilateral contrast distribution for all resiniferatoxin injections (N = 28). Immunohistochemistry showed bilateral ablation of substance P+ fibers entering the spinal cord of all resiniferatoxin-treated segments. The intensity of substance P immunostaining in treated segments fell below the lower 99% confidence interval of controls, defining the knockout phenotype. Substance P knockout occurred over a narrow range and was uncorrelated to the anatomical distribution of pre-injected contrast. CONCLUSIONS: Periganglionic resiniferatoxin/Tween80 induced bilateral ablation of spinal cord substance P despite exclusively unilateral targeting. These data suggest that the location of pre-injected contrast is an imperfect surrogate for the neuroanatomical range of drugs delivered to the dorsal epidural compartment that may fail to predict contralateral drug effects.

Clinical magnetic resonance-enabled characterization of mono-iodoacetate-induced osteoarthritis in a large animal species.

INTRODUCTION: Osteoarthritis (OA) is the most common form of arthritis. Medical and surgical treatments have yet to substantially diminish the global health and economic burden of OA. Due to recent advances in clinical imaging, including magnetic resonance imaging (MRI), a correlation has been established between structural joint damage and OA-related pain and disability. Existing preclinical animal models of OA are useful tools but each suffers specific roadblocks when translating structural MRI data to humans. Intraarticular injection of mono-iodoacetate (MIA) is a reliable, well-studied method to induce OA in small animals but joint size discrepancy precludes the use of clinical grade MRI to study structural disease. The porcine knee is suited for clinical MRI and demonstrates homology with humans. We set out to establish the first large animal model of MIA-induced knee OA in swine characterized by structural MRI. MATERIALS AND METHODS: Yucatan swine (n = 27) underwent ultrasound-guided injection of knees with 1.2, 4, 12, or 40 mg MIA. MRI was performed at several time points over 12 weeks (n = 54 knees) and images were assessed according to a modified clinical grading scheme. Knees were harvested and graded up to 35 weeks after injection. RESULTS: MIA-injected knees (n = 25) but not control knees (n = 29) developed gross degeneration. A total of n = 6,000 MRI measurements were recorded by two radiologists. MRI revealed progressive cartilage damage, bone marrow edema, erosions, and effusions in MIA-injected knees. Lesion severity and progression was influenced by time, dose, and inter-individual variability. CONCLUSIONS: Intraarticular injection of MIA produced structural knee degradation that was reliably characterized using clinical MRI in swine. Destruction was progressive and, similar to human OA, lesion severity was heterogeneous between and within treatment groups.

Human interleukin-10 delivered intrathecally by self-complementary adeno-associated virus 8 induces xenogeneic transgene immunity without clinical neurotoxicity in swine.

INTRODUCTION: Intrathecal interleukin (IL)-10 delivered by plasmid or viral gene vectors has been proposed for clinical testing because it is effective for chronic pain in rodents, is a potential therapeutic for various human diseases, and was found to be nontoxic in dogs, when the human IL-10 ortholog was tested. However, recent studies in swine testing porcine IL-10 demonstrated fatal neurotoxicity. The present study aimed to deliver vector-encoded human IL-10 in swine, measure expression of the transgene in cerebrospinal fluid and monitor animals for signs of neurotoxicity. RESULTS: Human IL-10 levels peaked 2 weeks after vector administration followed by a rapid decline that occurred concomitant with the emergence of anti-human IL-10 antibodies in the cerebrospinal fluid and serum. Animals remained neurologically healthy throughout the study period. CONCLUSIONS: The findings of the present study suggest that swine are not idiosyncratically sensitive to intrathecal IL-10 because, recapitulating previous reports in dogs, they suffered no clinical neurotoxicity from the human ortholog. These results strongly infer that toxicity of intrathecal IL-10 in large animal models was previously overlooked because of a species mismatch between transgene and host. The present study further suggests that swine were protected from interleukin-10 by a humoral immune response against the xenogeneic cytokine. Future safety studies of IL-10 or related therapeutics may require syngeneic large animal models.

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.

Laminotomy for Lumbar Dorsal Root Ganglion Access and Injection in Swine.

Dorsal root ganglia (DRG) are anatomically well defined structures that contain all primary sensory neurons below the head. This fact makes DRG attractive targets for injection of novel therapeutics aimed at treating chronic pain. In small animal models, laminectomy has been used to facilitate DRG injection because it involves surgical removal of the vertebral bone surrounding each DRG. We demonstrate a technique for intraganglionic injection of lumbar DRG in a large animal species, namely, swine. Laminotomy is performed to allow direct access to DRG using standard neurosurgical techniques, instruments, and materials. Compared with more extensive bone removal via laminectomy, we implement laminotomy to conserve spinal anatomy while achieving sufficient DRG access. Intraoperative progress of DRG injection is monitored using a non-toxic dye. Following euthanasia on post-operative day 21, the success of injection is determined by histology for intraganglionic distribution of 4',6-diamidino-2-phenylindole (DAPI). We inject a biologically inactive solution to demonstrate the protocol. This method could be applied in future preclinical studies to target therapeutic solutions to DRG. Our methodology should facilitate testing the translatability of intraganglionic small animal paradigms in a large animal species. Additionally, this protocol may serve as a key resource for those planning preclinical studies of DRG injection in swine.

Fatal Meningitis in Swine after Intrathecal Administration of Adeno-associated Virus Expressing Syngeneic Interleukin-10.

Interleukin-10 (IL-10) delivered by intrathecal (i.t.) gene vectors is a candidate investigational new drug (IND) for several chronic neurological disorders such as neuropathic pain. We performed a preclinical safety study of IL-10. A syngeneic large animal model was used delivering porcine IL-10 (pIL-10) to the i.t. space in swine by adeno-associated virus serotype 8 (AAV8), a gene vector that was previously found to be nontoxic in the i.t. space. Unexpectedly, animals became ill, developing ataxia, seizures, and an inability to feed and drink, and required euthanasia. Necropsy demonstrated lymphocytic meningitis without evidence of infection in the presence of normal laboratory findings for body fluids and normal histopathology of peripheral organs. Results were replicated in a second animal cohort by a team of independent experimenters. An extensive infectious disease and neuropathology workup consisting of comprehensive testing of tissues and body fluids in a specialized research veterinary pathology environment did not identify a pathogen. These observations raise the concern that i.t. IL-10 therapy may not be benign, that previously used xenogeneic models testing the human homolog of IL-10 may not have been sensitive enough to detect toxicity, and that additional preclinical studies may be needed before clinical testing of IL-10 can be considered.