Intervertebral disc human nucleus pulposus cells associated with back pain trigger neurite outgrowth in vitro and pain behaviors in rats.

Low back pain (LBP) is often associated with the degeneration of human intervertebral discs (IVDs). However, the pain-inducing mechanism in degenerating discs remains to be elucidated. Here, we identified a subtype of locally residing human nucleus pulposus cells (NPCs), generated by certain conditions in degenerating discs, that was associated with the onset of discogenic back pain. Single-cell transcriptomic analysis of human tissues showed a strong correlation between a specific cell subtype and the pain condition associated with the human degenerated disc, suggesting that they are pain-triggering. The application of IVD degeneration-associated exogenous stimuli to healthy NPCs in vitro recreated a pain-associated phenotype. These stimulated NPCs activated functional human iPSC-derived sensory neuron responses in an in vitro organ-chip model. Injection of stimulated NPCs into the healthy rat IVD induced local inflammatory responses and increased cold sensitivity and mechanical hypersensitivity. Our findings reveal a previously uncharacterized pain-inducing mechanism mediated by NPCs in degenerating IVDs. These findings could aid in the development of NPC-targeted therapeutic strategies for the clinically unmet need to attenuate discogenic LBP.

iPSC-derived tenocytes seeded on microgrooved 3D printed scaffolds for Achilles tendon regeneration.

Tendons and ligaments have a poor innate healing capacity, yet account for 50% of musculoskeletal injuries in the United States. Full structure and function restoration postinjury remains an unmet clinical need. This study aimed to assess the application of novel three dimensional (3D) printed scaffolds and induced pluripotent stem cell-derived mesenchymal stem cells (iMSCs) overexpressing the transcription factor Scleraxis (SCX, iMSCSCX+ ) as a new strategy for tendon defect repair. The polycaprolactone (PCL) scaffolds were fabricated by extrusion through a patterned nozzle or conventional round nozzle. Scaffolds were seeded with iMSCSCX+ and outcomes were assessed in vitro via gene expression analysis and immunofluorescence. In vivo, rat Achilles tendon defects were repaired with iMSCSCX+ -seeded microgrooved scaffolds, microgrooved scaffolds only, or suture only and assessed via gait, gene expression, biomechanical testing, histology, and immunofluorescence. iMSCSCX+ -seeded on microgrooved scaffolds showed upregulation of tendon markers and increased organization and linearity of cells compared to non-patterned scaffolds in vitro. In vivo gait analysis showed improvement in the Scaffold + iMSCSCX+ -treated group compared to the controls. Tensile testing of the tendons demonstrated improved biomechanical properties of the Scaffold + iMSCSCX+ group compared with the controls. Histology and immunofluorescence demonstrated more regular tissue formation in the Scaffold + iMSCSCX+ group. This study demonstrates the potential of 3D-printed scaffolds with cell-instructive surface topography seeded with iMSCSCX+ as an approach to tendon defect repair. Further studies of cell-scaffold constructs can potentially revolutionize tendon reconstruction by advancing the application of 3D printing-based technologies toward patient-specific therapies that improve healing and functional outcomes at both the cellular and tissue level.

Primary Human Herpes Virus-6 Causing Recalcitrant Pyrexia after Pilocytic Astrocytoma Resection.

INTRODUCTION: Human herpes virus-6 (HHV-6) is a ubiquitous virus but can lead to deleterious clinical manifestations due to its predilection for the pediatric central nervous system. Despite significant literature describing its common clinical course, it is rarely considered as a causative agent in CSF pleocytosis in the setting of craniotomy and external ventricular drainage device. Identification of a primary HHV-6 infection allowed for timely treatment with an antiviral agent along with earlier discontinuation of antibiotic regimen and expedited placement of a ventriculoperitoneal shunt. CASE PRESENTATION: A two-year-old girl presented with 3 months of progressive gait disturbance and intranuclear ophthalmoplegia. Following craniotomy for removal of 4th ventricular pilocytic astrocytoma and decompression of hydrocephalus, she suffered a prolonged clinical course due to persistent fevers and worsening CSF leukocytosis despite multiple antibiotic regimens. The patient was admitted to the hospital during the COVID-19 pandemic and isolated with her parents in the intensive care unit with strict infection control measures. FilmArray Meningitis/Encephalitis (FAME) panel ultimately detected HHV-6. Clinical confirmation of HHV-6-induced meningitis was proposed given improvement in CSF leukocytosis and fever reduction following the initiation of antiviral medications. Pathologic analysis of brain tumor tissue failed to show HHV-6 genome positivity, suggesting a primary peripheral etiology of infection. CONCLUSION: Here, we present the first known case of HHV-6 infection detected by FAME following intracranial tumor resection. We propose a modified algorithm for persistent fever of unknown origin which may decrease symptomatic sequelae, minimize additional procedures, and shorten length of ICU stay.

Perioperative Complications Following Spine Surgery in Adult Patients with Achondroplasia.

STUDY DESIGN: Retrospective cohort study. OBJECTIVES: To describe the common types of complications and their risk factors during spine surgery in patients with achondroplasia. METHODS: A retrospective review was performed of medical records of adult achondroplasia patients who underwent spine surgery at our institution between 2007 and 2021. Inclusion criteria were achondroplasia and age >16 years. Surgical encounters were evaluated for durotomy, postoperative neurologic deficit, wound compromise, medical complications, and return to the operating room. Statistical analysis included evaluation of relationships across complications and fisher exact test applied to bivariate/categorical variables and t-test/ANOVA for continuous variables. Multivariable analysis using logistic regression was performed to account for patient characteristics. RESULTS: Fifty-five patients with achondroplasia underwent 95 surgeries. Forty-nine percent of the surgeries involved a complication. These included durotomy (33.7%), neurologic deficit (11.6%), wound compromise (6.3%), and other medical complications (6.3%). Thirteen percent of surgeries required return to the operating room. The greatest number of complications occurred in thoracolumbar region (60.0%) compared to cervicothoracic (18.2%) and craniocervical junction (33.3%). Chronologically later surgical encounters had decreased complications and durotomies only occurred in thoracolumbar surgeries (45.7%). CONCLUSIONS: Adult patients with achondroplasia undergoing surgery chronologically later in this set of consecutive patients were at a decreased risk for complications. Thoracolumbar surgeries were at the greatest risk for durotomies. Male sex was a risk factor for durotomy, while age was a risk factor for neurologic deficit. The potential for adverse surgical events should be considered when evaluating patients with achondroplasia for spine surgery. .

Intrathecal Methotrexate Toxicity Resulting in Brain Death due to Generalized Cerebral Edema Case Report.

Intrathecal methotrexate (IT MTX) resulting in severe adverse events including life-threatening cerebral edema is not well described. We report a rare case of death in a 37-year-old BRCA1+ woman with metastatic triple-negative breast cancer status post mastectomy following administration of IT MTX for leptomeningeal carcinomatosis. Within the 24 hours after intraoperative IT MTX delivery, she developed neurologically devastating diffuse cerebral edema leading to uncal and cerebellar tonsillar herniation. This case report highlights a rare but devastating side effect of IT MTX.

Evolution of Bioactive Implants in Lateral Interbody Fusion.

Lateral lumbar interbody fusion (LLIF) is an advantageous approach for spinal arthrodesis for a wide range of spinal disorders including degenerative, genetic, and traumatic conditions. LLIF techniques have evolved over the past 15 years regarding surgical approach, with concomitant improvements in implant material design. Bioactive materials have been a focus in the development of novel methods, which reduce the risk of subsidence and pseudarthrosis. Historically, polyetheretherketone and titanium cages have been selected for their advantageous biomechanical properties; however, both have their limitations, regarding optimal modulus or osseointegrative properties. Recent modifications to these 2 materials have focused on devising bioactive implants, which may enhance the rate of bony fusion in spinal arthrodesis by addressing the shortcomings of each. Specific emphasis has been placed on developing improvements in surface coating, porosity, microroughness, and nanotopography of interbody cages. This has been coupled with advances in additive manufacturing to generate cages with ideal biomechanical properties. Three-dimensional-printed titanium cages may be particularly beneficial in spinal arthrodesis during LLIF and reduce the historical rates of subsidence and pseudarthrosis by combining a number of these putatively beneficial biomaterial properties.

Cost-Effectiveness Analysis of Encephaloduroarteriosynangiosis Surgery for Symptomatic Intracranial Atherosclerotic Disease.

Encephaloduroarteriosynangiosis (EDAS) is a promising treatment for cerebral arterial steno-occlusive disorders, with proven efficacy in moyamoya disease and a growing interest in potential application for patients with symptomatic intracranial atherosclerotic disease, given the early results of intermediate development trials showing reduced rates of recurrence stroke and improved clinical outcomes compared with those patients treated with intense medical management (IMM) alone. Although clinical outcomes are the fundamental goal when considering patient care paradigms, a cost-effective analysis is key to obtaining a comprehensive understanding of the impact EDAS may provide to patients with atherosclerotic disease on a larger scale. Here, we evaluate the EDAS + IMM cost-effectiveness over time in the treatment of intracranial atherosclerotic disease compared with IMM alone.

Placement of Stereotactic Electroencephalography Depth Electrodes Using the Stealth Autoguide Robotic System: Technical Methods and Initial Results.

BACKGROUND: Robotic systems are gaining acceptance as a preferred tool for the placement of electrodes for stereotactic electroencephalography (SEEG) studies. OBJECTIVE: To describe the technical methods for insertion of SEEG using the Medtronic Stealth Autoguide robotic system and detailed outcomes in the initial 9 patients implanted. METHODS: Nine patients underwent placement of electrodes for SEEG studies with the use of the Autoguide system. Patients had at least 10 electrodes placed. Targets were planned on a Stealth S8 planning station, and electrodes were placed under general anesthesia. A technique for placement is described in detail. Patient outcomes and accuracy of electrode placement were evaluated. Methods to improve accuracy were investigated. Comparison of postoperative MRIs with preoperative planning MRIs was performed to determine the accuracy of electrode placement. RESULTS: One hundred two electrodes were placed in 9 patients. Methods for placement and technical nuances are detailed. The distance from the planned target to the actual position of the electrode tip was measured in 8 of the 9 patients. The mean Euclidean distance was 4.67 ± 0.27 mm. There was 1 placement-related hemorrhage deficit in the first patient, and no deaths or infections. Adequate positioning of electrodes for seizure monitoring was obtained in all patients. CONCLUSION: Autoguide can be used for placement of electrodes for SEEG studies with acceptable degrees of patient safety, accuracy, and efficiency. Considering the cost of Autoguide compared with other robotic devices, it may be attractive option.

Encephaloduroarteriosynangiosis Operative Technique and Intraoperative Anesthesia Management: Treatment From Both Sides of the Curtain.

BACKGROUND: Encephaloduroarteriosynangiosis (EDAS) is a form of indirect revascularization for cerebral arterial steno-occlusive disorders. EDAS has gained growing interest as a technique applicable to pediatric and adult populations for several types of ischemic cerebral steno-occlusive conditions. OBJECTIVE: To present a team-oriented, multidisciplinary update of the EDAS technique for application in challenging adult cases of cerebrovascular stenosis/occlusion, successfully implemented in more than 200 cases. METHODS: We describe and demonstrate step-by-step a multidisciplinary-modified EDAS technique, adapted to maintain uninterrupted intensive medical management of patients' stroke risk factors and anesthesia protocols to maintain strict hemodynamic control. RESULTS: A total of 216 EDAS surgeries were performed in 164 adult patients, including 65 surgeries for patients with intracranial atherosclerotic disease and 151 operations in 99 patients with moyamoya disease. Five patients with intracranial atherosclerotic disease had recurrent strokes (3%), and there was one perioperative death. The mean clinical follow-up was 32.9 mo with a standard deviation of 31.1. There was one deviation from the surgical protocol. There were deviations from the anesthesia protocol in 3 patients (0.01%), which were promptly corrected and did not have any clinical impact on the patients' condition. CONCLUSION: The EDAS protocol described here implements a team-oriented, multidisciplinary adaptation of the EDAS technique. This adaptation resides mainly in 3 points: (1) uninterrupted administration of intensive medical management, (2) strict hemodynamic control during anesthesia, and (3) meticulous standardized surgical technique.

RELA Fusion-Positive Ependymoma in a Child with Down Syndrome: A Case Report.

INTRODUCTION: Down syndrome (DS) is the most common multiple malformation syndrome in humans and is associated with an increased risk of childhood malignancy, particularly leukemia. Incidence of brain tumors in patients with DS is limited to sporadic cases. We report the first case of a RELA fusion-positive ependymoma in a 3-year-old boy with DS. CASE PRESENTATION: Imaging prompted by new left-sided hemiparesis demonstrated an 8-cm hemorrhagic right temporal-parietal mass. Subsequent image-complete resection confirmed a RELA fusion-positive anaplastic ependymoma with 90% OLIG2 staining. Postoperatively, the patient, unfortunately, experienced fatal recurrence and drop metastases with leptomeningeal involvement. CONCLUSION: To our knowledge, this is the first reported case of a confirmed RELA fusion-positive ependymoma in a child with DS. We discuss this finding in the context of intracranial tumors in children with DS, as well as the finding of 90% positive OLIG2 expression and its potential as a prognostic marker.

Occipitocervical fusion of traumatic atlanto-occipital dissociation in a patient with autofused cervical facet joints: illustrative case.

BACKGROUND: Patients who survive traumatic atlanto-occipital dissociation (AOD) may present with normal neurological examinations and near-normal-appearing diagnostic images, such as cervical radiographs and computed tomography (CT) scans. OBSERVATIONS: The authors described a neurologically intact 64-year-old female patient with a degenerative autofusion of her right C4-5 facet joints who presented to their center after a motor vehicle collision. Prevertebral soft tissue swelling and craniocervical subarachnoid hemorrhage prompted awareness and consideration for traumatic AOD. An abnormal occipital condyle-C1 interval (4.67 mm) on CT and craniocervical junction ligamentous injury on magnetic resonance imaging (MRI) confirmed the diagnosis of AOD. Her autofused right C4-5 facet joints were incorporated into the occipitocervical fusion construct. LESSONS: Traumatic AOD can be easily overlooked in patients with a normal neurological examination and no associated upper cervical spine fractures. A high index of suspicion is needed when evaluating CT scans because normal values for craniocervical parameters are significantly different from the accepted ranges of normal on radiographs in the adult population. MRI of the cervical spine is helpful to evaluate for atlanto-occipital ligamentous injury and confirm the diagnosis. Occipitocervical fusion construct may need to be extended to incorporate spinal levels with degenerative autofusion to prevent adjacent level degeneration.

Image Guidance-Assisted Decompression and Removal of Heterotopic Ossification Following the Use of Recombinant Human Bone Morphogenetic Protein-2 in Transforaminal Lumbar Interbody Fusion.

Heterotopic ossification (HO) following the use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in the setting of transforaminal lumbar interbody fusion (TLIF) or posterior lumbar interbody fusion (PLIF) is a troublesome and well-described postoperative complication. There is currently no consensus regarding the treatment of this offending pathology. In this report, we present a retrospective single-surgeon review of 14 patients who underwent image-guided decompression of HO. We describe a new technique where navigation demonstrates a safe and thorough decompression compared to that with fluoroscopy or anatomical landmarks alone. To evaluate successful decompression, we reviewed patient self-reported clinical outcomes. Seven patients demonstrated positive results, while three had mixed outcomes and four showed poor outcomes. While more studies are needed to determine the overall efficacy of intraoperative navigation-assisted decompression, findings from this small cohort of patients suggest that it is a useful technique in the setting of the removal of heterotopic bone.

Motion preserving management of unstable traumatic clivus fracture extending through bilateral occipital condyles.

We describe non-operative management a rare traumatic clival fracture extending through the bilateral occipital condyles. Clinical History: A 26-year-old female who was involved in a high-speed motor vehicle crash presented to an outside facility with difficulty speaking. Subsequent CT of the cervical spine demonstrated a fracture of the clivus with extension through the bilateral occipital condyles. She was then transferred to our hospital for further management where complete trauma survey noted multiple other injuries including traumatic subarachnoid hemorrhage, spinal epidural hematoma, bilateral pneumothoraces, liver laceration, bilateral upper extremity injuries, and lumbosacral fractures. Additional spinal imaging was negative for any associated vascular or spinal cord injury. Given her young age, there was a strong interest to preserve craniocervical motion and the decision was made to treat her with non-operatively with halo placement. After 18 weeks of rigid fixation, follow up imaging demonstrated completely healed fractures and at twenty-one weeks post fixation she demonstrated preserved motion of the craniocervical junction. This is a review of the literature and case report regarding this rare entity and its management.

Pituitary apoplexy associated with acute COVID-19 infection and pregnancy.

PURPOSE: We report a case of a pregnant female presenting with pituitary apoplexy and simultaneous SARS-CoV-2 infection with a focus on management decisions. CLINICAL HISTORY: A 28-year-old G5P1 38w1d female presented with 4 days of blurry vision, left dilated pupil, and headache. She tested positive for SARS-CoV-2 on routine nasal swab testing but denied cough or fever. Endocrine testing demonstrated an elevated serum prolactin level, and central hypothyroidism. MRI showed a cystic-solid lesion with a fluid level in the pituitary fossa and expansion of the sella consistent with pituitary apoplexy. Her visual symptoms improved with corticosteroid administration and surgery was delayed to two weeks after her initial COVID-19 infection and to allow for safe delivery of the child. A vaginal delivery under epidural anesthetic occurred at 39 weeks. Two days later, transsphenoidal resection of the mass was performed under strict COVID-19 precautions including use of Powered Air Purifying Respirators (PAPRs) and limited OR personnel given high risk of infection during endonasal procedures. Pathology demonstrated a liquefied hemorrhagic mass suggestive of pituitary apoplexy. She made a full recovery and was discharged home two days after surgery. CONCLUSION: Here we demonstrate the first known case of successful elective induction of vaginal delivery and transsphenoidal intervention in a near full term gravid patient presenting with pituitary apoplexy and acute SARS-CoV-2 infection. Further reports may help determine if there is a causal relationship or if these events are unrelated. Close adherence to guidelines for caregivers can greatly reduce risk of infection.

Symptomatic Cervical Tumoral Calcinosis due to Cosmetic Body Contouring Mineral Oil Injections.

Tumoral calcinosis (TC) is an uncommon disease that has been linked to familial genetic mutations but can often be due to secondary causes such as chronic renal failure and hyperparathyroidism. There are rare instances of tumoral calcinosis induced by foreign body injections, often for cosmetic purposes. Here we describe operative management of spinal cord compression due to mineral oil injection induced tumoral calcinosis. A 54-year-old transgender female presented with signs of myelopathy so severe that she had become wheelchair bound. Labs demonstrated hypercalcemia and imaging of the neuroaxis revealed significant calcification resulting in cervicothoracic and lumbar central canal stenosis. Given symptomatic cervical spinal cord compression, she was taken to the OR for urgent laminectomy and decompression. Postoperatively, she recovered well and was ambulating independently by postoperative day (POD) 9. This is the first reported case of localized mineral oil injections causing distant calcification with subsequent symptomatic cord compression requiring operative intervention.

L5 Osteoid Osteoma Treated with Partial Laminectomy and Cement Augmentation.

Osteoid osteoma is a benign primary bone tumor of unknown etiology that occurs most commonly in males during adolescence and early adulthood. Osteoid osteoma affects the spine in 20% of cases, and may cause spinal deformity, stiffness, and pain that may sometimes be worst at night. We present a novel description of a partial laminectomy with cement augmentation after resection of an osteoid osteoma. A 22-year-old male with a past medical history of Hodgkin's lymphoma status post chemotherapy and radiation to the mediastinum, and right hip osteoblastoma treated with surgery and radiofrequency ablation presented with low back pain for five years with a recent onset of severe radicular symptoms. The pain was described as shooting and radiating laterally down the right leg to the mid-calf without bowel or bladder incontinence. He has a known right L5 laminar sclerotic lesion measuring 11 x 10 mm causing neuroforaminal narrowing and it kept increasing in size despite previous treatment with stereotactic radiosurgery and radiofrequency ablation. This lesion was metabolically active on positron emission tomography-computed tomography (PET-CT) imaging. His pain was worsening and was refractory to physical therapy, non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, and radiation therapy. A right L5 partial laminectomy was performed to resect the abnormality in an en-bloc fashion. The lesion did not involve the inner cortex of the bone. Lamina reconstruction was achieved with bone cement augmentation for the preservation of vertebral column strength. Pathology was consistent with osteoid osteoma with marrow edema. Microscopic findings include bony trabeculae associated with prominent rimming and hypercellular fibroblastic stroma. No nuclear atypia, necrosis or appreciable mitotic activity was observed. The patient remains neurologically intact with significantly improved radicular symptoms and low back pain. Osteoid osteoma of the lamina may be resected using a partial laminectomy and cement augmentation done to preserve the integrity of the posterior ligamentous complex, prevent potential fracture of the pars interarticularis, and avoid the need for lumbar fusion in younger patients in whom this pathology is commonly found.

Mechanical thrombectomy for pediatric stroke arising from an atrial myxoma: case report.

Children experiencing severe neurological deficit due to acute ischemic stroke may benefit from endovascular intervention. The authors describe the use of mechanical thrombectomy in the treatment of embolic occlusion secondary to an atrial myxoma in a pediatric patient. This case involved an 11-year-old boy with a history notable for Raynaud syndrome and a distal extremity rash who presented to the emergency department with dense hemiparesis secondary to thromboembolic occlusion of the M1 segment of the middle cerebral artery. Following mechanical thrombectomy, the patient's pediatric National Institutes of Health Stroke Scale score improved from a 16 to a 7. In the setting of acute pediatric stroke due to atrial myxoma emboli, mechanical thrombectomy may be a first-line therapy.

Time dependent integration of matrix metalloproteinases and their targeted substrates directs axonal sprouting and synaptogenesis following central nervous system injury.

Over the past two decades, many investigators have reported how extracellular matrix molecules act to regulate neuroplasticity. The majority of these studies involve proteins which are targets of matrix metalloproteinases. Importantly, these enzyme/substrate interactions can regulate degenerative and regenerative phases of synaptic plasticity, directing axonal and dendritic reorganization after brain insult. The present review first summarizes literature support for the prominent role of matrix metalloproteinases during neuroregeneration, followed by a discussion of data contrasting adaptive and maladaptive neuroplasticity that reveals time-dependent metalloproteinase/substrate regulation of postinjury synaptic recovery. The potential for these enzymes to serve as therapeutic targets for enhanced neuroplasticity after brain injury is illustrated with experiments demonstrating that metalloproteinase inhibitors can alter adaptive and maladaptive outcome. Finally, the complexity of metalloproteinase role in reactive synaptogenesis is revealed in new studies showing how these enzymes interact with immune molecules to mediate cellular response in the local regenerative environment, and are regulated by novel binding partners in the brain extracellular matrix. Together, these different examples show the complexity with which metalloproteinases are integrated into the process of neuroregeneration, and point to a promising new angle for future studies exploring how to facilitate brain plasticity.