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OBJECTIVE Tethered cord syndrome (TCS) is a clinical and radiographic diagnosis of pathological stretching of the spinal cord leading to progressive loss of neurological function. The gold standard treatment for TCS is a tethered cord release. However, detethering involves significant risks of spinal cord injury and high rates of retethering. To mitigate these risks, the concept of spinal column shortening (SCS) to decrease spinal cord tension has become an alternative to detethering. In this study, the authors applied SCS to a pediatric and emerging adult population affected by secondary TCS. METHODS A retrospective review of a prospective database at the authors’ tertiary pediatric institution was performed. The Pediatric Quality of Life Inventory, patient- and parent-reported outcomes, and urodynamics were used to evaluate the outcomes of TCS treated with SCS. RESULTS A total of 41 patients with secondary TCS were treated with SCS. The average age at the time of surgery was 15.9 years (range 5–55 years). Preoperative symptoms evaluated included pain (33 patients), weakness (30 patients), and bladder/bowel dysfunction (39 patients). The most common level of spinal column osteotomy was T12, with spinal fusion between T10 and L2. The mean follow-up time was 22.6 months (range 8–45 months). For patients with at least 12 months of follow-up, subjective clinical improvements were reported in 21/23 (91.3%) of those with preoperative pain (p < 0.01); in 16/24 (66.7%) of patients with weakness (p < 0.01), and in 15/29 (51.7%) of those with bladder/bowel dysfunction (p < 0.01). The median differences in initial and most recent Pediatric Quality of Life Inventory results were +5 for patient-reported scores (n = 19, p = 0.04) and +5 for parent-reported scores (n = 19, p = 0.08). Formal urodynamics performed at a median of 3.5 months after surgery documented stable to improved bladder function in 16/17 patients, with a median improvement in one classification category (n = 17, p = 0.01). CONCLUSIONS SCS continues to represent a safe and efficacious alternative to traditional spinal cord untethering for TCS in children and emerging adults, as documented by objective formal urodynamics and patient- and parent-reported outcomes.

OBJECTIVE In 2021, several patients across the United States received bone allograft contaminated with Mycobacterium tuberculosis (TB). TB is typically a pulmonary infection with many possible extrapulmonary manifestations, including skeletal tuberculosis. However, TB is a rare causative organism of postoperative surgical site infection. Iatrogenic skeletal TB infections are not widely reported in the medical literature; therefore, treatment and associated outcomes are relatively unknown. In this series, the authors report 6 cases of patients who received a mesenchymal stem cell–enhanced bone graft infected with TB at their institution, including the clinical courses, imaging findings, management plans, and outcomes at 1 year postoperatively. METHODS A retrospective review was performed of 6 consecutive patients who underwent spinal fusion surgery at the authors’ institution and received bone graft from a lot contaminated with TB. Collected data included patient demographic characteristics, indications for surgery, surgical procedures performed, timing of contamination discovery, medical treatment, and follow-up information including reoperation, healing progress, and imaging findings. RESULTS Five of 6 patients (83.3%) eventually tested positive for TB via interferon-gamma release assay or wound culture. They experienced significant complications, including surgical site infections with neck swelling, pain, dysphagia, and wound dehiscence. Extensive soft-tissue infection was common; however, significant bony involvement was not observed. Surgical wound debridement was required in 4 patients, and all patients received medical management with standard RIPE (rifampin, isoniazid pyrazinamide, pyridoxine, and ethambutol) therapy for 8 weeks with extension of rifampin and isoniazid for scheduled 12 months. All patients (excluding 1 patient who died of COVID-19) showed signs of improvement with adequately healing wounds at the most recent follow-up at a median (range) of 12 (6–13) months postoperatively. To date, no patients have developed pulmonary TB. CONCLUSIONS Direct inoculation with TB via contaminated bone grafts resulted in a high rate of severe soft-tissue infection, although extensive skeletal and pulmonary involvement has not been observed at 1 year postoperatively; this review includes the longest reported follow-up period for this TB outbreak. Medical management remains the mainstay of therapy for these patients, with most patients showing recovery with oral antibiotic therapy. The severity of these infections arising from mesenchymal stem cell–containing bone allografts that undergo an alternative sterilization process than standard allografts raises concerns regarding the added risks of infection, which should be weighed against the expected benefits of these grafts.

OBJECTIVE Tethered cord release (TCR) is the gold standard treatment for tethered cord syndrome (TCS); however, there are significant shortcomings including high rates of retethering, especially in complex and recurrent cases. Spinal column shortening (SCS) is an alternative treatment for TCS intended to avoid these shortcomings. Early studies were limited to case reports and smaller case series; however, in recent years, larger case series and small cohort studies have been conducted. Given the increase in available data, a repeat systematic review and meta-analysis is warranted to assess the safety and efficacy of SCS for TCS. METHODS The authors conducted a systematic review using MEDLINE (OVID), Embase (Elsevier), and Web of Science records dating from 1944 to July 2021 to identify all articles investigating SCS for TCS. They performed standard and individual patient data (IPD) meta-analyses, with 2 independent reviewers using PRISMA-IPD guidelines. Primary outcomes were improvement of preoperative clinical symptoms of pain, motor weakness, and bladder and bowel dysfunction, and also surgical complication rate. Secondary outcomes included urodynamic improvement and health-related quality-of-life outcomes determined using patient-reported outcome tools. Individual study quality assessment was performed using a standardized assessment tool for case reports/series, and publication bias was assessed using funnel plot analyses. RESULTS The review yielded 15 studies with 191 cases of TCS treated with SCS. IPD were available in 11 studies with 89 cases. The average age at time of surgery was 28.0 years (range 5–76 years). The average follow-up time was 33.2 months (range 7–132 months). Improvement was observed at last follow-up in 60 of 70 (85.7%) patients with preoperative pain, in 38 of 60 (60.3%) patients with preoperative weakness, and in 36 of 76 (47.4%) patients with preoperative bladder or bowel dysfunction. Complications of CSF leak, new neurological deficit, wound infection, or reoperation occurred in 4 of 89 (4.5%) patients. CONCLUSIONS SCS may be considered a safe and efficacious treatment option for TCS in children and adults (level C evidence; class IIb recommendation), especially for recurrent and complex cases. Current evidence is likely to be affected by selection and publication bias. Prospective comparative studies of SCS and TCR for TCS are recommended to determine long-term duration of outcomes, long-term safety in skeletally immature children, and exact indications of SCS versus traditional TCR.

PURPOSE OF REVIEW: Fractures are painful and disabling injuries that can occur due to trauma, especially when compounded with pathologic conditions, such as osteoporosis in older adults. It is well documented that acute pain management plays an integral role in the treatment of orthopedic patients. There is no current therapy available to completely control post-fracture pain that does not interfere with bone healing or have major adverse effects. In this review, we focus on recent advances in the understanding of pain behaviors post-fracture. RECENT FINDINGS: We review animal models of bone fracture and the assays that have been developed to assess and quantify spontaneous and evoked pain behaviors, including the two most commonly used assays: dynamic weight bearing and von Frey testing to assess withdrawal from a cutaneous (hindpaw) stimulus. Additionally, we discuss the assessment and quantification of fracture pain in the clinical setting, including the use of numeric pain rating scales, satisfaction with pain relief, and other biopsychosocial factor measurements. We review how pain behaviors in animal models and clinical cases can change with the use of current pain management therapies. We conclude by discussing the use of pain behavioral analyses in assessing potential therapeutic treatment options for addressing acute and chronic fracture pain without compromising fracture healing. SUMMARY: There currently is a lack of effective treatment options for fracture pain that reliably relieve pain without potentially interfering with bone healing. Continued development and verification of reliable measurements of fracture pain in both pre-clinical and clinical settings is an essential aspect of continued research into novel analgesic treatments for fracture pain.

Background and Hypothesis: The megakaryocyte (MK) growth factor, thrombopoietin (TPO), improves bone healing in mice, rats, and pigs. Here we explore the role of MK-secreted platelet-derived growth factor-BB (PDGF–BB) in TPO’s mechanism of improving fracture healing. Interestingly, PDGF has neuroprotective effects, and neuronal PDGF receptors (PDGFRs) are primarily stimulated by PDGF–BB. Additionally, fibroblast growth factor 2 (FGF2) is secreted by osteoblasts (OBs), and MKs stimulate OB proliferation; therefore, MKs may regulate FGF2 expression which also promotes nerve regeneration. Importantly, neuropathic pain caused by fractures can be prevented by neuroprotective therapies. We hypothesize that increases in fracture-related neuropathic pain observed with age are due to reductions in: MK-secreted PDGF-BB and MK-stimulated, OBsecreted FGF2. Experimental Design or Project Methods: Dorsal root ganglia (DRG) and MKs from bone marrow and spleens were isolated from 3-4 month-old (young) and 22-24 month-old (old) mice. MKs were also isolated from E13-15 fetal livers of mice and OBs were isolated from the calvaria of neonatal mice. OBs were cultured alone or in the presence of MKs for 4 days. Real-time PCR was completed to examine the expression of PDGF-BB in MKs, FGF2 in OBs, and PDGFR in DRG. Results: Old MKs exhibit a 63% reduction in PDGF–BB expression and old DRG exhibit a 68% reduction in PDGFR expression. OBs cultured with MKs show a 1.78 fold increase in FGF2 expression. Conclusion and Potential Impact: Decreased expression of PDGF-BB in old MKs and PDGFR in old neurons, as well as increased FGF2 expression in OBs cultured with MKs present possible mechanisms for both the reduction in bone healing and increased fracture pain observed with age. TPO improves bone healing and may potentially reduce neuropathic pain directly by increasing MK secreted PDGF-BB and indirectly through MK PDGF-BB stimulating FGF2 secretion from OBs.

Patients with early infantile epileptic encephalopathy (EIEE) are at increased risk for sudden unexpected death in epilepsy (SUDEP). De novo mutations of the sodium channel gene SCN8A, encoding the sodium channel Nav1.6, result in EIEE13 (OMIM 614558), which has a 10% risk of SUDEP. Here, we investigated the cardiac phenotype of a mouse model expressing the gain of function EIEE13 patient mutation p.Asn1768Asp in Scn8a (Nav1.6-N1768D). We tested Scn8aN1768D/+ mice for alterations in cardiac excitability. We observed prolongation of the early stages of action potential (AP) repolarization in mutant myocytes vs. controls. Scn8aN1768D/+ myocytes were hyperexcitable, with a lowered threshold for AP firing, increased incidence of delayed afterdepolarizations, increased calcium transient duration, increased incidence of diastolic calcium release, and ectopic contractility. Calcium transient duration and diastolic calcium release in the mutant myocytes were tetrodotoxin-sensitive. A selective inhibitor of reverse mode Na/Ca exchange blocked the increased incidence of diastolic calcium release in mutant cells. Scn8aN1768D/+ mice exhibited bradycardia compared with controls. This difference in heart rate dissipated after administration of norepinephrine, and there were no differences in heart rate in denervated ex vivo hearts, implicating parasympathetic hyperexcitability in the Scn8aN1768D/+ animals. When challenged with norepinephrine and caffeine to simulate a catecholaminergic surge, Scn8aN1768D/+ mice showed ventricular arrhythmias. Two of three mutant mice under continuous ECG telemetry recording experienced death, with severe bradycardia preceding asystole. Thus, in addition to central neuron hyperexcitability, Scn8aN1768D/+ mice have cardiac myoycte and parasympathetic neuron hyperexcitability. Simultaneous dysfunction in these systems may contribute to SUDEP associated with mutations of Scn8a.

Patients with epileptic encephalopathy have a high risk of sudden unexpected death in epilepsy (SUDEP), an event described as arrhythmia of brain and heart. We investigated the cardiac phenotype of a model of an epileptic encephalopathy caused by mutation of sodium channel SCN8A. We observed that mutant heart cells were hyperexcitable, exhibiting abnormal contraction and action potential wave forms. Mutant mice also had reduced heart rates compared with controls. This difference in heart rate was not observed in isolated hearts, implicating changes in cardiac regulation by the parasympathetic nervous system. When challenged with norepinephrine and caffeine, mutant mice had ventricular arrhythmias. These cardiac and parasympathetic abnormalities are predicted to contribute to the mechanism of SUDEP in patients with SCN8A mutations.