Jmjd3 Mediates Neuropathic Pain by Inducing Macrophage Infiltration and Activation in Lumbar Spinal Stenosis Animal Model

Lumbar spinal stenosis (LSS) is a major cause of chronic neuropathic back and/or leg pain. Recently, we demonstrated that a significant number of macrophages infiltrated into the cauda equina after compression injury, causing neuroinflammation, and consequently mediating neuropathic pain development and/or maintenance. However, the molecular mechanisms underlying macrophage infiltration and activation have not been elucidated. Here, we demonstrated the critical role of histone H3K27 demethylase Jmjd3 in blood-nerve barrier dysfunction following macrophage infiltration and activation in LSS rats. The LSS rat model was induced by cauda equina compression using a silicone block within the epidural spaces of the L5-L6 vertebrae with neuropathic pain developing 4 weeks after compression. We found that Jmjd3 was induced in the blood vessels and infiltrated macrophages in a rat model of neuropathic pain. The blood-nerve barrier permeability in the cauda equina was increased after compression and significantly attenuated by the Jmjd3 demethylase inhibitor, GSK-J4. GSK-J4 also inhibited the expression and activation of MMP-2 and MMP-9 and significantly alleviated the loss of tight junction proteins and macrophage infiltration. Furthermore, the activation of a macrophage cell line, RAW 264.7, by LPS was significantly alleviated by GSK-J4. Finally, GSK-J4 and a potential Jmjd3 inhibitor, gallic acid, significantly inhibited mechanical allodynia in LSS rats. Thus, our findings suggest that Jmjd3 mediates neuropathic pain development and maintenance by inducing macrophage infiltration and activation after cauda equina compression and thus may serve as a potential therapeutic target for LSS-induced neuropathic pain.

Determination of potential risk characteristics for cauda equina compression in emergency department patients presenting with atraumatic back pain: a 4-year retrospective cohort analysis within a tertiary referral neurosciences centre

ObjectiveAtraumatic back pain is an increasingly common presentation to the ED. A minority of these cases will have significant structural pathology, resulting in acute cauda equina compression (CEC). Although clinicians often look for ‘red flags’ to identify potential CEC, the prognostic accuracy of these presenting symptoms and clinical examination findings is unclear. We sought to evaluate the accuracy of individual clinical features in a large cohort of ED patients with atraumatic backpain and reference standard imaging, for the diagnosis of CEC.MethodsA retrospective case note review from 2014 to 2018 within an established ED atraumatic back pain pathway, undertaken at the largest tertiary spinal referral centre in the UK. We analysed routine data, collected prospectively by treating clinicians within a structured electronic health record clinical proforma. Data on signs and symptoms in 996 patients with suspected CEC referred for definitive MRI over a 4-year study period were extracted and compared against a final reference standard diagnosis.ResultsWe identified 111 patients with radiological evidence of CEC within the cohort referred for definitive imaging (111/996, 11.1%), of whom 109 (98.2%) underwent operative intervention. Patients with CEC were more likely to present with bilateral leg pain (OR=2.2), dermatomal sensory loss (OR 1.8) and bilateral absent ankle or ankle and knee jerks (OR=2.9). Subjective weakness was found to be associated with CEC on univariate but not multivariate analysis. We found no relationship between digital rectal examination findings and the diagnosis of CEC.ConclusionsIn our cohort, factors independently associated with CEC diagnosis on MRI included bilateral leg pain, dermatomal sensory loss. Loss of lower limb reflexes was strongly suggestive of CES (likelihood ratio 3.4 on multivariate logistic regression). Our findings raise questions about the diagnostic utility of invasive digital rectal examination.

A Polyostotic Paget’s Disease Involving Lumbar Spine Presenting with Cauda Equina Syndrome: An Unusual Entity

Introduction:Paget’s disease of bone (PDB) is a metabolic bone disease presenting as polyostotic or monostotic lesions of the spine. Although common in the Anglo-Saxon population, it is rare on the Indian subcontinent. Neurological complications though infrequent can be severe in pagetic spine. Case Report:We report a case of a polyostotic variant of PDB involving lumbar spine (L2 vertebrae), iliac bones, and femur presenting as chronic low back pain and neurological deficit, i.e., cauda equina syndrome. On initial workup, a diagnosis of PDB was made and given cauda equina compression with neurological deficit, posterior spinal decompression, and biopsy was performed. The histopathological evaluation confirmed the diagnosis and the patient was treated with bisphosphonates for 6 months, along with serial monitoring of alkaline phosphatase levels. Conclusion:Through this case report, we hope to emphasize that PDB should be considered as a possible cause of neurological symptoms at presentation, especially in elderly patients. Also furthermore, early surgical intervention followed by bisphosphonates therapy can lead to favorable outcomes in such patients. Keywords:Polyostotic, Paget’s disease, cauda equine syndrome, lumbar spine.

Transdural reduction of a bone fragment protruding into the spinal canal during surgical treatment of lumbar burst fracture: A case report

Background: There have been many reports on the clinical, radiographic, and surgical management of thoracolumbar burst fractures attributed to high-energy trauma. Interestingly, few reports have described how to extract bone fragments associated with these injuries protruding into the spinal canal contributing to significant neurological deficits. Methods: An 18-year-old male presented with a severe L3-level paraparesis (i.e., loss of motor/sensory function below L3 lower extremity hyporeflexia, and sphincter dysfunction: American Spinal Injury Association [ASIA] Impairment Scale B) following a high-speed crash. The computed tomography and magnetic resonance studies revealed a L3 burst fracture with bone fragments protruding into the spinal canal causing marked cauda equina compression. Following a L3-L4 laminectomy, and opening of the dorsal dura, the bone fragments were ventrally impacted into the fractured L3 vertebral body a pedicle/screw L1-L5 fusion was then completed. Results: One month later, the patient recovered to an ASIA Scale of C, (i.e., residual proximal 3/5 and distal 2/5 motor deficits, with partial sensory sparing). Conclusion: Transdural ventral impaction of protruded bone fragments attributed to high speed lumbar burst fractures contributing to significant cauda equina compression can be safely/effectively accomplished.

‘Scan-negative’ cauda equina syndrome: what to do when there is no neurosurgical cause

Suspected cauda equina syndrome is a common presentation in emergency departments, but most patients (≥70%) have no cauda equina compression on imaging. As neurologists become more involved with ‘front door’ neurology, referral rates of patients with these symptoms are increasing. A small proportion of patients without structural pathology have other neurological causes: we discuss the differential diagnosis and how to recognise these. New data on the clinical features of patients with ‘scan-negative’ cauda equina syndrome suggest that the symptoms are usually triggered by acute pain (with or without root impingement) causing changes in brain–bladder feedback in vulnerable individuals, exacerbated by medication and anxiety, and commonly presenting with features of functional neurological disorder.

Epidural lipomatosis in elderly patient: A rare cause of cauda equina compression

Background: The most common cause of cauda equina compression in the elderly is lumbar spinal stenosis. Epidural lipomatosis is an additional known but rare cause of cauda equina compression readily diagnosed on MR studies. Notably, spinal canal decompression and direct excision of the epidural fat effectively manage this combined pathology. Case Description: A 70-year-old male presented with progressive truncal obesity associated with refractory lumbar neurogenic claudication. The lumbar magnetic resonance imaging (MRI) showed excessive epidural fat extending from L4 to S2 resulting in thecal sac compression; this was confirmed on the MRI myelogram study. Following a decompressive laminectomy, the patient’s cauda equina syndrome resolved. Conclusion: Recent weight gain with increased neurogenic claudication and the onset of a cauda equina syndrome may herald the presence of significant lumbar epidural lipomatosis. Here, laminectomy for excision of the excessive epidural fat resolved the patient’s symptomatic spinal stenosis.

Dorsal migration of lumbar disc fragments causing cauda equina syndromes: A three case series and literature review

Background: Dorsal migration of an intervertebral lumbar disc fragment is exceedingly rare and may result in spinal cord or cauda equina compression. Radiologically, these lesions may be misdiagnosed as extradural masses or epidural hematomas. Case Description: We present three cases involving dorsal migration of sequestered lumbar disc fragments resulting in cauda equina syndromes. A 31-year-old male, 79-year-old female, and 47-year-old female presented with cauda equina syndromes attributed to the migration of dorsal sequestered lumbar disc fragments. Prompt surgical decompression resulted in adequate outcomes. Here, we review the three cases and the current literature for such lesions. Conclusion: Dorsal migration of sequestered lumbar disc fragments is exceedingly rare, and these lesions are frequently misdiagnosed as extradural masses of other origin or epidural hematomas. Here and in the literature, prompt epidural decompression both confirmed the correct diagnosis and resulted in excellent outcomes.