Impact of temperature on the magnitude and duration of relief after lumbar facets medial branch nerves radiofrequency ablation: a randomized double-blinded study.

INTRODUCTION: There are numerous studies appraising the variables that may influence the clinical outcomes after lumbar thermal radiofrequency ablation (RFA). Expanding the lesion size may increase the likelihood of capturing the target nerves in the lesion, thereby increasing the technical success rate of RFA. However, our literature search has failed to identify a consensus on the optimal target temperature. A retrospective study demonstrated that there seems to be significant functional improvement associated with the temperature of 90°C compared with 80°C. The authors prospectively studied the subject in a double-blinded randomized fashion. METHODS: Patients undergoing RFA for lumbar facetogenic pain were randomized in two cohorts (80°C and 90°C). Physicians and patients were blinded to the temperature used. The primary outcome was self-reported pain scores up to 12 months. Secondary outcomes included: self-reported functional improvement, duration of relief as measured by the time before repeat ablation of the same medial branches nerves, opioids' consumption, and patient satisfaction. RESULTS: Both groups reported pain improvement in all follow-up time points. Overall, both groups achieved statistically significant pain reduction (p<0.05). The median time to repeat RFA in the 80°C group was 112 (49-252) days, while it was 217 (198-348) days in the 90°C group (p<0.04). The univariate analysis emphasized that the RFA temperature is a statistically significant factor for pain improvement of more than 50%, OR 2.7 (1.1 to 6.6) p value=0.031. CONCLUSION: RFA has been demonstrated as an effective therapeutic modality for lumbar facetogenic back pain. Yet, the several factors involved in determining a favorable outcome of this procedure require further research and optimization. This prospective double-blinded randomized trial demonstrated that RFA at both temperatures (80°C, 90°C) provided significance at all the time periods examined. However, RFA at 90°C was superior to 80°C in regard to the duration of relief.

Patient and physician radiation exposure during minimally invasive lumbar decompression: A prospective assessment of X-ray exposure risks.

INTRODUCTION: Minimally invasive lumbar decompression (mild®) is becoming a popular procedure for treating lumbar spinal stenosis (LSS) secondary to hypertrophic ligamentum flavum (LF). The mild® procedure is commonly performed under live fluoroscopic guidance and carries a risk of radiation exposure to the patient and healthcare. METHODS: One physician performed mild® on 41 patients at the Cleveland Clinic Department of Pain Management from October 2019 to December 2021, while wearing a radiation exposure monitor (Mirion Technologies). Mean fluoroscopy time, mean exposure per case, and mean exposure per unilateral level decompressed were the primary outcomes measured. The secondary outcome was to provide a comparison of radiation exposure during similar fluoroscopically guided procedures. RESULTS: Mean patient fluoroscopy exposure time was 2.1 min ±0.9 (range: 1.1-5.6) fluoroscopy time per unilateral level decompressed. The mean patient radiation skin exposure from mild® was 1.1 ± 0.9 mGym2, and the mean total dose was 142.3 ± 108.6 mGy per procedure. On average, the physician was exposed to an average deep tissue exposure of 4.1 ± 3.2 mRem, 2.9 ± 2.2 mRem estimated eye exposure, and 14.7 ± 11.0 mRem shallow tissue exposure per unilateral level decompressed. An individual physician would exceed the annual exposure limit of 5 Rem after approximately 610 mild® procedures per year. CONCLUSIONS: This study is an attempt to quantify the radiation exposure to the physician and patient during the mild® procedure. Compared with other fluoroscopically guided pain management procedures, patient and physician radiation exposure during mild® was low.

The Choice of Spinal Cord Stimulation Versus Targeted Drug Delivery in the Management of Chronic Pain: Validation of an Outcomes Predictive Formula.

OBJECTIVE: In 2020, Mekhail et al published a formula that predicted the likelihood of a successful outcome for those who undergo spinal cord stimulation (SCS) for long-term pain management, based on retrospectively collected clinical and demographic data from one major medical center. The aim of this study is to validate such a predictive formula, prospectively, in a cohort of patients from multiple medical practices that are more representative of real-life clinical practice. MATERIALS AND METHODS: For the study, 939 patients who underwent successful SCS or targeted drug delivery (TDD) trials at multiple independent medical centers in the USA were enrolled into the Medtronic product surveillance registry data base before they underwent SCS or TDD device implantation, from 2018 to 2020. The registry data were collected prospectively but not specifically for this study. The data examined included demographic information, pain diagnosis, pain scores (visual analog scale [VAS]), Oswestry Disability Index scores, and quality-of-life scores at baseline and six months after implant. Because our goal is to validate the previously published predictive formula, in addition to the outcomes data previously mentioned, we collected the variables necessary for such a task: sex, age, depression, the presence of neuropathic pain, spine-related pain diagnosis, and persistent spinal pain syndrome "post laminectomy syndrome." Spine-related pain diagnosis included subjects with chronic spine pain who never had back surgery and whose pain was not radicular nor neuropathic. RESULTS: Of 619 patients with SCS, 138 (22%) achieved ≥ 50% reductions of the baseline VAS at six months. The logistic model predicts SCS success with an area under the receiver operating characteristic curve (AUC) of 80% in the current validation data set. Of 320 patients with TDD, 147 (46%) achieved ≥ 50% reduction of the baseline VAS at six months. The logistic model predicts TDD success with an AUC of 78% in the current validation data set. CONCLUSION: The study provides real life validation of the previously published predictive formula(4).

Association Between Oral Pain Medications and Intrathecal Opioid Dose Escalation: A Retrospective Analysis.

OBJECTIVES: Patients treated with intrathecal therapy frequently require opioid dose increases to maintain analgesia. The kinetics of intrathecal opioid dose escalation are poorly understood. We hypothesized that antidepressant use, antiepileptic use, and lower baseline oral opioid intake prior to intrathecal pump implantation will be protective against intrathecal opioid dose escalation. MATERIALS AND METHODS: Targeted drug delivery medication doses were collected from patients who had an intrathecal pump implanted between 2007 and 2016. From a sample size of 136 patients, the association between antidepressant, antiepileptic, and oral opioid use with intrathecal dose escalation was assessed using statistical models. RESULTS: Individuals using an antiepileptic had an estimated ratio of means (97.5% CI) of opioid consumption of 0.91 (97.5% CI: [0.48, 1.73], p = 0.74) at six months, 0.83 ([0.43, 1.58], p = 0.51) at 12 months, and 0.77 ([0.40, 1.45], p = 0.36) at 24 months. Patients prescribed antidepressants had an estimated ratio of means (97.5% CI) of 1.43 ([0.77, 2.65], p = 0.19) at six months, 1.41 ([0.76, 2.63], p = 0.22) at 12 months, and 1.33 ([0.70, 2.51], p = 0.31) at 24 months. In our secondary analysis of pre-implant oral opioid use, patients treated with high oral opioid doses had a similar pattern of intrathecal dose escalation when compared to patients using low doses of oral opioids. CONCLUSIONS: Use of antiepileptics, antidepressants, or low oral opioid doses was not associated with attenuation of intrathecal dose escalation. Intrathecal opioid dose escalation was observed to occur similarly, regardless of baseline oral analgesics concomitantly employed.

Sorsby Fundus Dystrophy Mutation in Tissue Inhibitor of Metalloproteinase 3 (TIMP3) promotes Choroidal Neovascularization via a Fibroblast Growth Factor-dependent Mechanism.

Choroidal neovascularization (CNV) leads to loss of vision in patients with Sorsby Fundus Dystrophy (SFD), an inherited, macular degenerative disorder, caused by mutations in the Tissue Inhibitor of Metalloproteinase-3 (TIMP3) gene. SFD closely resembles age-related macular degeneration (AMD), which is the leading cause of blindness in the elderly population of the Western hemisphere. Variants in TIMP3 gene have recently been identified in patients with AMD. A majority of patients with AMD also lose vision as a consequence of choroidal neovascularization (CNV). Thus, understanding the molecular mechanisms that contribute to CNV as a consequence of TIMP-3 mutations will provide insight into the pathophysiology in SFD and likely the neovascular component of the more commonly seen AMD. While the role of VEGF in CNV has been studied extensively, it is becoming increasingly clear that other factors likely play a significant role. The objective of this study was to test the hypothesis that basic Fibroblast Growth Factor (bFGF) regulates SFD-related CNV. In this study we demonstrate that mice expressing mutant TIMP3 (Timp3S179C/S179C) showed reduced MMP inhibitory activity with an increase in MMP2 activity and bFGF levels, as well as accentuated CNV leakage when subjected to laser injury. S179C mutant-TIMP3 in retinal pigment epithelial (RPE) cells showed increased secretion of bFGF and conditioned medium from these cells induced increased angiogenesis in endothelial cells. These studies suggest that S179C-TIMP3 may promote angiogenesis and CNV via a FGFR-1-dependent pathway by increasing bFGF release and activity.

Low-velocity Gunshot Injuries to the Femur: What Is the Utility of Stabilizing Incomplete Fractures?

INTRODUCTION: Extremity involvement is common among nonfatal gunshot injuries. Most of these injuries are low energy in nature and may be associated with fractures. Although displaced fractures of lower extremity long bones are often treated surgically, the purpose of this study was to review our experience in managing incomplete femur fractures caused by gunshot penetration and to develop treatment recommendations. METHODS: We retrospectively reviewed clinical and radiographic data for 46 consecutive patients with incomplete femur fractures secondary to low-energy gunshot wounds. Fracture patterns included OTA/AO 31 (n = 7), 32 (n = 20), and 33 (n = 19). All fractures were nondisplaced and extra-articular. Type of treatment, clinical and radiographic healing, and related complications were recorded. RESULTS: Thirty-two patients (70%) were managed nonsurgically with progressive weight bearing from toe touch to full weight bearing by 6 weeks of follow-up, whereas 14 patients (30%) underwent prophylactic fixation of the femur. No differences in treatment were seen based on age, body mass index, fracture pattern, or the presence of other fractures or systemic injuries. Two of the 32 patients (6.2%) treated nonsurgically for femoral shaft fractures fell subacutely after the original injury and displaced their fractures. Both underwent reduction and fixation. All other fractures maintained alignment until union. No infections or nonunions were seen. Among patients who underwent prophylactic fixation, two underwent removal of prominent implants after union. DISCUSSION: Only 6% of incomplete femur fractures treated at our hospital required later surgery for fracture displacement. Although incomplete fractures occur infrequently, nonsurgical management with limited weight bearing seems to be successful and cost-effective for most patients. We propose initial nonsurgical management of nondisplaced femoral fractures secondary to cortical penetration from low-energy gunshot wounds.

Infection Rates and Treatment of Low-Velocity Extremity Gunshot Injuries.

OBJECTIVES: To determine the rates of infection in low-energy gunshot wounds (GSWs) to the extremity. DESIGN: Retrospective review. SETTING: Level I trauma center. PATIENTS/PARTICIPANTS: Patients (N = 140) with at least 90-day follow-up for extremity-only low-energy GSW injuries from 2010-2014 were retrospectively reviewed. Treatment was recorded, including type and duration of antibiotics and details of nonoperative and operative managements. MAIN OUTCOME MEASURES: The rates of superficial and deep infections. RESULTS: The overall infection rate was 15.7% (22 patients), and the deep infection rate was 3.6% (5 patients). Age, sex, and injury location were similar between the groups that did and did not receive antibiotic prophylaxis. Injury Severity Scores were higher in the group that did receive antibiotics. Regarding soft tissue-only injuries, antibiotic prophylaxis trended toward a lower rate of overall infection versus no antibiotic prophylaxis (6.1% vs. 25.9%, respectively, P = 0.07). Multiple doses of antibiotics did not reduce the rate of infection when compared with a single dose (14.6% vs. 12.5%, respectively, P = 1.00). No deep infections occurred in patients with nonoperatively treated fractures, regardless of antibiotic administration. All operatively treated fractures received antibiotic prophylaxis and demonstrated superficial and deep infection rates of 15.1% and 5.7%, respectively. CONCLUSIONS: Infections after low-energy extremity GSWs are infrequent. For soft tissue injuries without fracture, a single dose of intravenous antibiotics in the emergency department was associated with a lower rate of infection compared with no antibiotics. Operatively treated low-energy GSW fractures should receive standard perioperative antibiotics. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Infection and Complications After Low-velocity Intra-articular Gunshot Injuries.

OBJECTIVES: The purpose of this study is to characterize the demographics, interventions, infection rates, and other complications after intra-articular (IA) gunshot wounds. DESIGN: Retrospective review. SETTING: Level I trauma center. PATIENTS/PARTICIPANTS: Fifty-three patients with 55 civilian low-velocity IA gunshot injuries with a minimum of 4 weeks follow-up were included in the study. Seven patients had associated vascular injuries. INTERVENTIONS: Most patients (84.9%) received antibiotic prophylaxis, consisting most often of cefazolin (93.3%). Based on injury pattern and surgeon preference, joint injuries were either treated nonoperatively (43.6%), with surgical debridement only (20.0%), with surgical debridement plus fracture fixation and/or neurovascular repair (32.7%), or with percutaneous fracture fixation without debridement (3.6%). MAIN OUTCOME MEASURES: Incidence of deep infection. RESULTS: Two joints (3.6%) developed deep infections. Both had associated vascular injuries. Patients with vascular injuries were at higher risk of infection compared with those without vascular injury (28.6% vs. 0.0%, P = 0.02). Two of 24 (8.3%) injuries that were originally managed nonoperatively required delayed surgical procedures, 1 for bullet removal and 1 for ulnar nerve allograft. No patient treated nonoperatively developed an infection. CONCLUSIONS: The incidence of infection after IA gunshot injuries is low with the routine use of antibiotic prophylaxis. In the absence of IA pathology, IA gunshot injuries do not appear to necessitate surgical debridement to decrease the risk of infection. Patients with vascular injury deserve special attention, as they are at higher risk of infection. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for authors for a complete description of levels of evidence.

Tissue inhibitor of metalloproteinases-3 peptides inhibit angiogenesis and choroidal neovascularization in mice.

Tissue inhibitors of metalloproteinases (TIMPs) while originally characterized as inhibitors of matrix metalloproteinases (MMPs) have recently been shown to have a wide range of functions that are independent of their MMP inhibitory properties. Tissue inhibitor of metalloproteinases-3 (TIMP-3) is a potent inhibitor of VEGF-mediated angiogenesis and neovascularization through its ability to block the binding of VEGF to its receptor VEGFR-2. To identify and characterize the anti-angiogenic domain of TIMP-3, structure function analyses and synthetic peptide studies were performed using VEGF-mediated receptor binding, signaling, migration and proliferation. In addition, the ability of TIMP-3 peptides to inhibit CNV in a mouse model was evaluated. We demonstrate that the anti-angiogenic property resides in the COOH-terminal domain of TIMP-3 protein which can block the binding of VEGF specifically to its receptor VEGFR-2, but not to VEGFR-1 similar to the full-length wild-type protein. Synthetic peptides corresponding to putative loop 6 and tail region of TIMP-3 have anti-angiogenic properties as determined by inhibition of VEGF binding to VEGFR-2, VEGF-induced phosphorylation of VEGFR-2 and downstream signaling pathways as well as endothelial cell proliferation and migration in response to VEGF. In addition, we show that intravitreal administration of TIMP-3 peptide could inhibit the size of laser-induced choroidal neovascularization lesions in mice. Thus, we have identified TIMP-3 peptides to be efficient inhibitors of angiogenesis and have a potential to be used therapeutically in diseases with increased neovascularization.

Microscopic thrombi in anaplastic astrocytoma predict worse survival?

The purpose of this study is to determine whether anaplastic astrocytoma patients with intratumoral vascular thrombi have a worse survival than anaplastic astrocytoma patients without thrombi. A retrospective review of 101 patients (60 males; mean age, 53.3 years) with anaplastic astrocytoma (World Health Organization grade III) was conducted. Thrombi were counted relative to the number of involved blood vessels in the initially resected tumor (69 biopsies, 32 subtotal resections) and were correlated with survival and development of postoperative deep venous thrombosis (DVT). Of tumors with thrombi (n = 17), the percentage of blood vessels with thrombi ranged from 1.5% to 20% (mean, 5.6%). Of these patients, 16 died of tumor (mean survival, 15.4 months), and 1 patient was alive with tumor at 180 months. Eighty-four patients with anaplastic astrocytoma had no intravascular tumor thrombi; 75 of these patients died of tumor (mean survival, 26.5 months), 4 patients were alive, and 5 patients were lost to follow-up. Evidence of DVT was found in 2 (18.2%) of 11 tested patients with thrombi vs 10 (18.5%) of 54 patients without thrombi. Patients with microscopic intratumoral thrombi (17% of anaplastic astrocytoma) had a worse survival compared with patients without thrombi; the difference did not reach statistical significance. There was no correlation between the presence of intratumoral thrombi and the development of DVT.

Microscopic thrombi in glioblastoma multiforme do not predict the development of deep venous thrombosis.

Patients with glioblastoma multiforme (GBM) are known to be at risk for hypercoagulable events. Tumoral intravascular thrombi likely contribute to the development of hypoxia and necrosis. The purpose of this study was to assess whether there is a relationship between the number of thrombi identified microscopically at the time of tumor resection and the subsequent development of extremity deep venous thrombosis (DVT). A retrospective review of 96 patients (53 men and 43 women; age range, 21-92 years; mean age, 60.2 years) with GBM (World Health Organization grade IV) was carried out. Thrombi were counted (number of thrombi/blood vessels evaluated/10 high-power fields) in nonnecrotic areas of the resected tumor and correlated with a variety of clinical and pathological parameters, including the development of postoperative DVT, as detected by extremity ultrasound. Thrombi were identified in the resected GBM in 66 (69%) patients. Of the tumors with thrombi, the percentage of blood vessels with thrombi ranged from 1.1% to 42.9% (mean, 10.7%). Deep venous thrombosis was discovered in 30 (31.3%) patients. There was no correlation between the number of microscopic thrombi and the development of DVT. Eighty-one patients died of tumor (survival, 1-66 months; mean, 11.0 months), 12 patients were alive at last known follow-up (mean, 23 months), and 3 patients were lost to follow-up. Of patients with DVT, 27 patients died of tumor (survival, 1-47 months; mean, 11.0 months), 3 patients were alive (18, 20, and 21 months), and 1 patient was lost to follow-up. There was no correlation between the number of microscopic thrombi and the percentage of resected tumor that was necrotic (range, <5%-90%), presence of palisaded necrosis (36.8% of tumors), presurgical (mean, 78.3) or postsurgical (mean, 75.5) Karnofsky performance scores, or survival (mean, 8.9 months in patients with no microscopic thrombi vs 11.5 months in patients with thrombi). Microscopic thrombi were identified in about two thirds (69%) of patients with GBM, and DVT developed in about one third (31.3%) of patients with GBM. There was no correlation between the number of microscopic thrombi and the subsequent development of DVT in patients with GBM. Patients who developed DVT did not appear to have a worse survival.