A novel simultaneous three-dimensional volumetric morphological imaging and T2-mapping method, multi-interleaved X-prepared turbo-spin echo with intuitive relaxometry provides more accurate quantification of cervical spinal nerves.

PURPOSE: MIXTURE is a simultaneous morphological and quantitative imaging sequence developed by Philips that provides high-resolution T2 maps from the imaged series. We aimed to compare the T2 maps of MIXTURE and SHINKEI-Quant (S-Q) in the cervical spine and to examine their usefulness in the functional diagnosis of cervical radiculopathy. METHODS: Seven healthy male volunteers (mean age: 31 ± 8.0 years) and one patient with cervical disc herniation (44 years old, male) underwent cervical spine magnetic resonance imaging (MRI), and T2-mapping of each was performed simultaneously using MIXTURE and S-Q in consecutive sequences in one imaging session. The standard deviation (SD) of the T2 relaxation times and T2 relaxation times of the bilateral C6 and C7 dorsal root ganglia (DRG) and C5/6 level cervical cord on the same slice in the 3D T2-map of the cervical spine coronal section were measured and compared between MIXTURE and S-Q. RESULTS: T2 relaxation times were significantly shorter in MIXTURE than in S-Q for all C6, C7 DRG, and C5/6 spinal cord measurements. The SD values of the T2 relaxation times were significantly lower for MIXTURE in the C5/6 spinal cord and C7 DRG. In cervical disc herniation, MRI showed multiple intervertebral compression lesions with spinal canal stenosis at C5/6 and disc herniation at C6/7. CONCLUSION: MIXTURE is useful for preoperative functional diagnosis. T2-mapping using MIXTURE can quantify cervical nerve roots more accurately than the S-Q method and is expected to be clinically applicable to cervical radiculopathy.

Establishing a new model of cancer neuropathic pain in rats.

To guide the treatment of malignant neuropathic pain (MNP) in clinical practice, by inoculating MADB-106 breast cancer cells into the right L4 nerve root in Sprague-Dawley rats, a rat model of MNP was established, providing basic conditions for the study of neuropathic pain and development and application of therapeutic drugs. As the tumor grew over time, it pressed the nerve roots, causing nerve damage. The spinal nerve ligation (SNL) model, which is a neuropathic pain model widely used in rats, was compared with the L4 nerve root SNL model, and histologic examination of the nerve tissue of both models was performed by electron microscopy. In addition to the infiltration and erosion of the L4 nerve by tumor cells, the tumor tissue gradually grew and compressed the L4 nerve roots, resulting in hyperalgesia of the rat's posterior foot on the operative side. Some spontaneous pain phenomena were also observed, such as constant lifting or licking of the posterior foot on the operative side under quiet conditions. Electron microscopy images showed that nerve injury was due to progressive compression by the tumor, cells of which were visualized, but the injury was lighter than that in SNL rats. Imaging showed a paravertebral tumor near the L4 nerve root in the carcinomatous neuropathic pain model rat. These results suggest that progressive compression of the nerve by a malignant tumor leads to nerve damage similar to the behavioral changes associated with chronic compression injury resulting from a loose ligature of the nerve. The cancer neuropathologic pain model at the L4 nerve root was successfully established in Sprague-Dawley rats.

Unilateral thoracic spinal nerve resection creates early onset thoracic scoliosis in an immature porcine model.

PURPOSE: To test whether multiple-level unilateral thoracic spinal nerves (TSN) resection can induce the initial thoracic cage deformity to cause early onset thoracic scoliosis in an immature porcine model; and 2) to create an early onset thoracic scoliosis in a large animal model that can be used to evaluate growth-friendly surgical techniques and instruments in growing spine researches. METHODS: Seventeen one-month-old pigs were assigned to 3 groups. In group 1 (n = 6), right TSN were resected from T7 to T14 with the contralateral (left) paraspinal muscle exposing and stripping. In group 2 (n = 5), the animals were treated in the same way except the contralateral (left) side was intact. In group 3 (n = 6), bilateral TSN were resected from T7 to T14. All animals were followed up for 17-weeks. Radiographs were measured and analyzed the correlation between the Cobb angle and thoracic cage deformity. A histological examination of the intercostal muscle (ICM) was performed. RESULTS: In the groups 1 and 2, an average 62 ± 12° and 42 ± 15° right thoracic scoliosis with apical hypokyphosis of a mean - 5.2 ± 16° and - 1.8 ± 9° were created, respectively, during 17-weeks follow up. All curves were located at the operated levels with the convexity toward the TSN resection side. Statistical analysis demonstrated that the thoracic deformities were strongly correlated with the Cobb angle. In group 3, no scoliosis was created in any animal, but an average thoracic lordosis of - 32.3 ± 20.3° was seen. The histological examination showed the ICM denervation on the TSN resection side. CONCLUSION: Unilateral TSN resection induced the initial thoracic deformity toward the TSN resection side resulting in thoracic hypokyphotic scoliosis in an immature pig model. This early onset thoracic scoliosis model could be used to evaluate the growth-friendly surgical techniques and instruments in future growing spine researches.

Correlation between leg pain at rest and spinal nerve edema in symptomatic lumbar foraminal stenosis.

BACKGROUND: Previous studies reported that spinal nerve edema on magnetic resonance myelography (MRM) and leg pain at rest were specifically observed in symptomatic lumbar foraminal stenosis patients. However, the correlation between leg pain at rest and spinal nerve edema in symptomatic foraminal stenosis has not been reported. HYPOTHESIS: The purpose of this prospective study is to reveal a correlation between leg pain at rest and spinal nerve edema focusing on the pathophysiology of symptomatic foraminal stenosis. PATIENTS AND METHODS: Clinical findings and MRM findings were surveyed among 30 patients with symptomatic foraminal stenosis diagnosed by MR imaging (MRI) and selective nerve root block. Comparisons of patient characteristics and clinical findings between the prevalence and absence groups of spinal nerve edema on MRM were analyzed. A correlation between the visual analogue scale (VAS) for leg pain at rest and the spinal edema ratio calculated as maximum intensity value of the affected spinal nerve/maximum intensity value of the asymptomatic side from region of interest (ROI) made on MRM was evaluated. RESULTS: Twenty symptomatic foraminal stenosis cases (67%) showed the affected spinal nerve edema on MRM. The prevalence and VAS of leg pain at rest were significantly higher in the presence of spinal nerve edema group (95% and 67.0±36.4, respectively). The correlation coefficient between the VAS for leg pain at rest (53.0±33.6) and the spinal nerve edema ratio (1.3±0.3) was 0.647 (p<0.01). DISCUSSION: Our study revealed the substantial correlation found between the spinal nerve edema ratio on MRM and the VAS for leg pain at rest in symptomatic foraminal stenosis. The correlation between spinal nerve edema and leg pain at rest has potential to clarify the pathology of symptomatic foraminal stenosis. LEVEL OF EVIDENCE: IV.

Anatomic-Topographic Investigation of the Branches of the Dorsal Ramus of Thoracic Spinal Nerves.

INTRODUCTION: Percutaneous radiofrequency facet denervation (PRFD) by thermocoagulation is a useful treatment for nonspecific thoracic pain syndrome. To guarantee that maximal thermal lesion is applied to the nerve, it is essential to have precise knowledge of the topography of the thoracic dorsal branches of the spinal nerves. This special anatomy was investigated, and the results were compared with the existing technique for PRFD, where the active needle tip is placed in the junction of the superior articular process and the transverse process. METHODS: Twenty thoracic spines of cadavers (10 females and 10 males) embalmed according to Thiel's method were bilaterally dissected. After careful removal of skin and subcutaneous fat tissue, the lateral and medial branches were traced centrally. In addition, the articular branch to the thoracic facet joint was traced peripherally. The distance of the medial branch to the inferior articular process at the level of the nerve passing the superior costotransverse ligament was measured. RESULTS: The dorsal branch bifurcates into lateral and medial branches medial to the superior costotransverse ligament. The medial branch runs laterally first to pass in between two parts of the intertransverse ligament running dorsally and to turn medially superficial to this ligament. The zygapophysial branch always originated from the medial branch passing the inferior articular process laterally by running caudally to turn medially and send branches to the capsule of the zygapophyseal joint. The distance of the medial branch lateral to the inferior articular process was constantly 3 mm. CONCLUSIONS: The current technique of PRFD at the thoracic spine targets the medial branch distal to the separation of the articular branch, rendering the lesion ineffective at denervating the zygapophyseal joint. For selective thermocoagulation of the articular branches of the thoracic zygapophyseal joint, a new technique should be developed. We propose an anatomically informed needle position that can now be confirmed clinically.

Effect of surgical damage to spinal nerve on dorsal-root ganglion gene expressions: Comprehensive analysis of differentially expressed genes.

BACKGROUND: Neuropathic pain can cause significant physical and economic burden, and there are no effective long-term treatments. We conducted a bioinformatics analysis to identify mechanisms to determine strategies for more effective treatments of neuropathic pain. METHOD: GSE24982 and GSE63442 microarray datasets were extracted from the Gene Expression Omnibus database to analyze transcriptome differences of neuropathic pain in the dorsal root ganglions (DRGs). We filtered the differentially expressed genes (DEGs) in the two datasets and conducted Gene Ontology (GO) functional analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of the shared DEGs. The Protein-Protein Interaction network was used to determine the hub genes, which were verified in the GSE30691 dataset. miRDB and miRWalk Databases were used to predict potential miRNA of the selected DEGs. We made the spinal nerve ligation (SNL) rat model and qPCR was used to verify the differential expression of hub genes. RESULTS: A total of 182 overlapped DEGs were found between GSE24982 and GSE63442 datasets. The GO and KEGG analysis showed that the selected DEGs were enriched in infection, transmembrane transport of ion channels, and synaptic transmission. We identified seven hub genes (Atf3, Aif1, Ctss, Gfap, Scg2, Jun, and Vgf). qPCR verified the expression differences of the hub genes in the DRGs after SNL model. Predicted miRNA targeting each selected hub genes were identified. CONCLUSIONS: Seven hub genes related to the pathogenesis of neuropathic pain and potential targeting miRNA were identified, expanding understanding of the mechanism of neuropathic pain and facilitating treatment development.

Anatomical study and clinical significance of rami communicantes of the lumbar spine.

BACKGROUND AND OBJECTIVES: Rami communicantes (RC) infiltration and radiofrequency lesions are new techniques for the treatment of discogenic low back pain (DLBP). Their efficacy is controversial, and the classification of RC remains unclear. We aimed to explore the differences between RC and reclassify RC according to their anatomical characteristics. METHODS: Sixteen sides of the lumbar spine from eight adult male embalmed cadavers were dissected. The presence of RC was noted. The morphology, origin, distribution, course, quantity and spatial orientation of RC on the lumbar spine were examined. The length and width of the RC were measured by a caliper. RESULTS: A total of 213 RC were found in the 8 cadavers in the lumbar region. RC were divided into three types: superficial rami (70, 32.86%), which penetrated the psoas major (PM) and ran above the aponeurosis of the PM; deep rami (125, 58.69%), which ran along the waist of the vertebral body beneath the aponeurosis of the PM; and discal rami, which ran over and adhered to the surface of the intervertebral disc. Superficial rami were divided into two subtypes: oblique rami (45, 21.13%) and parabolic rami (25, 11.74%), which crossed the vertebra and the disc in an oblique and a parabolic course, respectively. CONCLUSIONS: RC should play an important role in the innervation of the lumbar spine. Detailed knowledge of RC in the lumbar region may help surgeons improve the efficacy of infiltration and percutaneous radiofrequency as a supplementary treatment for DLBP.

Plasticity of the Injured Spinal Cord.

Complete spinal cord injury (SCI) leads to permanent motor, sensitive and sensory deficits. In humans, there is currently no therapy to promote recovery and the only available treatments include surgical intervention to prevent further damage and symptomatic relief of pain and infections in the acute and chronic phases, respectively. Basically, the spinal cord is classically viewed as a nonregenerative tissue with limited plasticity. Thereby the establishment of the "glial" scar which appears within the SCI is mainly described as a hermetic barrier for axon regeneration. However, recent discoveries have shed new light on the intrinsic functional plasticity and endogenous recovery potential of the spinal cord. In this review, we will address the different aspects that the spinal cord plasticity can take on. Indeed, different experimental paradigms have demonstrated that axonal regrowth can occur even after complete SCI. Moreover, recent articles have demonstrated too that the "glial" scar is in fact composed of several cellular populations and that each of them exerts specific roles after SCI. These recent discoveries underline the underestimation of the plasticity of the spinal cord at cellular and molecular levels. Finally, we will address the modulation of this endogenous spinal cord plasticity and the perspectives of future therapeutic opportunities which can be offered by modulating the injured spinal cord microenvironment.

Electroacupuncture may alleviate neuropathic pain via suppressing P2X7R expression.

Neuropathic pain is a severe problem that is difficult to treat clinically. Reducing abnormal remodeling of dendritic spines/synapses and increasing the anti-inflammatory effects in the spinal cord dorsal horn are potential methods to treat this disease. Previous studies have reported that electroacupuncture (EA) could increase the pain threshold after peripheral nerve injury. However, the underlying mechanism is unclear. P2X7 receptors (P2X7R) mediate the activation of microglia and participate in the occurrence and development of neuropathic pain. We hypothesized that the effects of EA on relieving pain may be related to the downregulation of the P2X7R. Spinal nerve ligation (SNL) rats were used as a model in this experiment, and 2'(3')-O-(4-benzoyl)benzoyl ATP (BzATP) was used as a P2X7R agonist. We found that EA treatment decreased dendritic spine density, inhibited synaptic reconstruction and reduced inflammatory response, which is consistent with the decrease in P2X7R expression as well as the improved neurobehavioral performance. In contrast to the beneficial effects of EA, BzATP enhanced abnormal remodeling of dendritic spines/synapses and inflammation. Furthermore, the EA-mediated positive effects were reversed by BzATP, which is consistent with the increased P2X7R expression. These findings indicated that EA improves neuropathic pain by reducing abnormal dendritic spine/synaptic reconstruction and inflammation via suppressing P2X7R expression.

Non-SUMOylated CRMP2 decreases NaV1.7 currents via the endocytic proteins Numb, Nedd4-2 and Eps15.

Voltage-gated sodium channels are key players in neuronal excitability and pain signaling. Functional expression of the voltage-gated sodium channel NaV1.7 is under the control of SUMOylated collapsin response mediator protein 2 (CRMP2). When not SUMOylated, CRMP2 forms a complex with the endocytic proteins Numb, the epidermal growth factor receptor pathway substrate 15 (Eps15), and the E3 ubiquitin ligase Nedd4-2 to promote clathrin-mediated endocytosis of NaV1.7. We recently reported that CRMP2 SUMO-null knock-in (CRMP2K374A/K374A) female mice have reduced NaV1.7 membrane localization and currents in their sensory neurons. Preventing CRMP2 SUMOylation was sufficient to reverse mechanical allodynia in CRMP2K374A/K374A female mice with neuropathic pain. Here we report that inhibiting clathrin assembly in nerve-injured male CRMP2K374A/K374A mice precipitated mechanical allodynia in mice otherwise resistant to developing persistent pain. Furthermore, Numb, Nedd4-2 and Eps15 expression was not modified in basal conditions in the dorsal root ganglia (DRG) of male and female CRMP2K374A/K374A mice. Finally, silencing these proteins in DRG neurons from female CRMP2K374A/K374A mice, restored the loss of sodium currents. Our study shows that the endocytic complex composed of Numb, Nedd4-2 and Eps15, is necessary for non-SUMOylated CRMP2-mediated internalization of sodium channels in vivo.

Electroacupuncture effects on the P2X4R pathway in microglia regulating the excitability of neurons in the substantia gelatinosa region of rats with spinal nerve ligation.

Electroacupuncture (EA) has been used to treat neuropathic pain induced by peripheral nerve injury (PNI) by applying an electrical current to acupoints with acupuncture needles. However, the mechanisms by which EA treats pain remain indistinct. High P2X4 receptor (P2X4R) expression levels demonstrate a notable increase in hyperactive microglia in the ipsilateral spinal dorsal horn following PNI. In order to demonstrate the possibility that EA analgesia is mediated in part by P2X4R in hyperactive microglia, the present study performed mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) tests in male Sprague­Dawley rats that had undergone spinal nerve ligation (SNL). The expression levels of spinal P2X4R were determined using reverse transcription­quantitative PCR, western blotting analysis and immunofluorescence staining. Furthermore, spontaneous excitatory postsynaptic currents (sEPSCs) were recorded using whole­cell patch clamp to demonstrate the effect of EA on synaptic transmission in rat spinal substantia gelatinosa (SG) neurons. The results of the present study demonstrated that EA increased the MWT and TWL and decreased overexpression of P2X4R in hyperactive microglia in SNL rats. Moreover, EA attenuated the frequency of sEPSCs in SG neurons in SNL rats. The results of the present study indicate that EA may mediate P2X4R in hyperactive spinal microglia to inhibit nociceptive transmission of SG neurons, thus relieving pain in SNL rats.

Muscle Fascia Changes in Patients with Occipital Neuralgia, Headache, or Migraine.

SUMMARY: In an ongoing effort to understand the pathogenesis of occipital neuralgia/headache/migraine, it is critical to describe the anatomical/tissue changes encountered during surgery. Greater occipital nerve anatomical studies mainly focus on the greater occipital nerve course through muscle/fascial planes and interaction with the occipital vessels. However, structural soft-tissue changes have not been described in detail. Anecdotally, trapezius fascia is thickened at the greater occipital nerve trigger site. This study further investigates this observation. Patients undergoing greater occipital nerve decompression surgery were enrolled prospectively in this observational study (n = 92). Tissue changes were recorded intraoperatively. The resulting data were examined. Trapezius fascia was more than 3 mm thick and appeared fibrotic in 86 patients (94 percent), whereas semispinalis muscle appeared normal in all subjects. The greater occipital nerve was macroscopically abnormal, defined as edematous, flattened, and discolored in 29 cases (32 percent). The occipital artery interacted significantly with the greater occipital nerve in 88 percent of cases. The authors conclude that the tissue structure is abnormal in patients undergoing greater occipital nerve decompression surgery. This is the first study that describes the prevalence of thickened and fibrotic appearing trapezius fascia at the occipital trigger site, a phenomenon encountered in the vast majority of patients (94 percent). This structural anomaly has a resemblance to thickened fascial tissues seen in other nerve compression syndromes, and could be related to microtrauma/overuse or actual trauma in the head and neck region.

LZTR1-related spinal schwannomatosis and 7q11.23 duplication syndrome: A complex phenotype with dual diagnosis.

BACKGROUND: Dual diagnoses in genetics practice are not uncommon and patients with dual diagnosis often present with complex and challenging phenotypes. A combination of meticulous phenotyping and molecular genetic techniques are essential in solving these diagnostic odysseys. METHODS: Clinical features and genetic workup of a patient presenting with incidental schwannomatosis. RESULTS: A 19-year-old male presented with incidental painless schwannomatosis in the background of macrocephaly, distinctive facies, and learning disability. Comprehensive genetic testing with gene panel and chromosomal microarray led to a dual diagnosis of LZTR1-related schwannomatosis and 7q11.23 duplication syndrome. CONCLUSION: We emphasize the need for high index of suspicion and comprehensive genetic testing in complex phenotypes. Interrogation of the interplay between the pathogenic variants in multiple genes could improve our understanding of the pathophysiologic pathways and contribute to therapeutic discoveries.

Fluoroscopy-Guided Blockade of the Greater Occipital Nerve in Cadavers: A Comparison of Spread and Nerve Involvement for Different Injectate Volumes.

Background: Fluoroscopy-guided blockade of the greater occipital nerve (GON) is an accepted method for treating the symptoms of cervicogenic headaches (CGHs). However, the spread patterns among different injectate volumes of fluoroscopy-guided GON blocks are not well defined. Objective: A cadaveric study was established to determine the spread patterns of different volumes of dye injectate within a fluoroscopic GON block. Study Design. Cadaveric study. Setting. Xingtai Institute of Orthopaedics; Orthopaedic Hospital of Xingtai. Methods: 15 formalin-fixed cadavers with intact cervical spines were randomized in a 1 : 1 : 1 ratio to receive a fluoroscopy-guided GON injection of a 2, 3.5, or 5 ml volume of methylene blue. The suboccipital regions were dissected to investigate nerve involvement. Results: The suboccipital triangle regions, including the suboccipital nerves and GONs, were deeply stained in all cadavers. The third occipital nerve (TON) was stained in 7 of 10 administered 2 ml injections and in all the 3.5 ml and 5 ml injections. Compared to the 3 ml injectate group, the 5 mL cohort consistently saw injectate spreading to both superficial and distant muscles. Limitations. Given that cadavers were used in this study, cadaveric soft tissue composition and architecture can potentially become distorted and consequently affect injectate diffusion. Conclusions: A 3.5 or 5 mL fluoroscopy-guided GON injection of methylene blue successfully stains the GON, TON, and suboccipital nerves. This suggests that such an injection would generate blockade of all three nerve groups, which may contribute to the efficacy of the block for CGH. A volume of 3.5 ml may be enough for the performance of a fluoroscopy-guided GON block for therapeutic purposes.

Cav3.2 overexpression in L4 dorsal root ganglion neurons after L5 spinal nerve cutting involves Egr-1, USP5 and HMGB1 in rats: An emerging signaling pathway for neuropathic pain.

Overexpression of Cav3.2 T-type Ca2+ channels in L4 dorsal root ganglion (DRG) participates in neuropathic pain after L5 spinal nerve cutting (L5SNC) in rats. The L5SNC-induced neuropathic pain also involves high mobility group box 1 (HMGB1), a damage-associated molecular pattern protein, and its target, the receptor for advanced glycation end-products (RAGE). We thus studied the molecular mechanisms for the L5SNC-induced Cav3.2 overexpression as well as neuropathic pain in rats by focusing on; 1) possible involvement of early growth response 1 (Egr-1), known to regulate transcriptional expression of Cav3.2, and ubiquitin-specific protease 5 (USP5) that protects Cav3.2 from proteasomal degradation, and 2) possible role of HMGB1/RAGE as an upstream signal. Protein levels of Cav3.2 as well as Egr-1 in L4 DRG significantly increased in the early (day 6) and persistent (day 14) phases of neuropathy after L5SNC, while USP5 protein in L4 DRG did not increase on day 6, but day 14. An anti-HMGB1-neutralizing antibody or a low molecular weight heparin, a RAGE antagonist, prevented the development of neuropathic pain and upregulation of Egr-1 and Cav3.2 in L4 DRG after L5SNC. L5SNC increased macrophages accumulating in the sciatic nerves, and the cytoplasm/nuclear ratio of immunoreactive HMGB1 in those macrophages. Our findings suggest that L5SNC-induced Cav3.2 overexpression in L4 DRG and neuropathic pain involves Egr-1 upregulation downstream of the macrophage-derived HMGB1/RAGE pathway, and that the delayed upregulation of USP5 might contribute to the persistent Cav3.2 overexpression and neuropathy.

Localized sympathectomy reduces peripheral nerve regeneration and pain behaviors in 2 rat neuropathic pain models.

Previous studies have shown that the peripheral nerve regeneration process is linked to pain in several neuropathic pain models. Other studies show that sympathetic blockade may relieve pain in some pain models and clinical conditions. This study examined reduction in peripheral nerve regeneration as one possible mechanism for relief of neuropathic pain by sympathetic blockade. A "microsympathectomy," consisting of cutting the gray rami containing sympathetic postganglionic axons where they enter the L4 and L5 spinal nerves, reduced mechanical hypersensitivity in 2 different rat neuropathic pain models. In the spinal nerve ligation model, in which some functional regeneration and reinnervation of the ligated spinal nerve can be observed, microsympathectomy reduced functional and anatomical measures of regeneration as well as expression of growth-associated protein 43 (GAP43), a regeneration-related protein. In the spared nerve injury model, in which functional reinnervation is not possible and the futile regeneration process results in formation of a neuroma, microsympathectomy reduced neuroma formation and GAP43 expression. In both models, microsympathectomy reduced macrophage density in the sensory ganglia and peripheral nerve. This corroborates previous work showing that sympathetic nerves may locally affect immune function. The results further highlight the challenge of improving pain in neuropathic conditions without inhibiting peripheral nerve regeneration that might otherwise be possible and desired.

CX3CR1-Targeted PLGA Nanoparticles Reduce Microglia Activation and Pain Behavior in Rats with Spinal Nerve Ligation.

Activation of CX3CR1 in microglia plays an important role in the development of neuropathic pain. Here, we investigated whether neuropathic pain could be attenuated in spinal nerve ligation (SNL)-induced rats by reducing microglial activation through the use of poly(D,L-lactic-co-glycolic acid) (PLGA)-encapsulated CX3CR1 small-interfering RNA (siRNA) nanoparticles. After confirming the efficacy and specificity of CX3CR1 siRNA, as evidenced by its anti-inflammatory effects in lipopolysaccharide-stimulated BV2 cells in vitro, PLGA-encapsulated CX3CR1 siRNA nanoparticles were synthesized by sonication using the conventional double emulsion (W/O/W) method and administered intrathecally into SNL rats. CX3CR1 siRNA-treated rats exhibited significant reductions in the activation of microglia in the spinal dorsal horn and a downregulation of proinflammatory mediators, as well as a significant attenuation of mechanical allodynia. These data indicate that the PLGA-encapsulated CX3CR1 siRNA nanoparticles effectively reduce neuropathic pain in SNL-induced rats by reducing microglial activity and the expression of proinflammatory mediators. Therefore, we believe that PLGA-encapsulated CX3CR1 siRNA nanoparticles represent a valuable new treatment option for neuropathic pain.

Spinal paraganglioma as unusual finding in von Hippel-Lindau disease.

A 20-year-old patient with a history of von Hippel-Lindau disease reported on thoracic back pain radiating to the left shoulder for 10 weeks. Magnetic resonance imaging revealed a progressive contrast-enhancing tumor (14 × 21 × 28 mm) compressing the spinal cord and extending into the left neural foramen at T5/6. After embolization of supplying vessels, the tumor was completely resected via hemilaminectomy of T5. The postoperative course was uneventful without surgery related morbidity. The pathological examination disclosed a paraganglioma WHO grade I. We discuss the differential diagnoses and pitfalls of this unexpected finding in this patient with von Hippel-Lindau disease.

Autoimmune polyradiculitis due to combination immunotherapy with ipilimumab and nivolumab for the treatment of metastatic melanoma.

Immune checkpoint inhibitors, also known as immunotherapy, have revolutionised the treatment of metastatic melanoma, but are frequently associated with immune-related adverse events (irAEs) affecting a variety of organ systems. Here, we present a case of a patient with metastatic melanoma, being treated with combination ipilimumab-nivolumab, who developed a foot drop. MRI demonstrated enhancement of the nerve roots of the cauda equina. The patient had other irAEs, which warranted cessation of immunotherapy and the introduction of corticosteroids, and this also resulted in improvement in the patient's lower limb symptoms and MRI appearances. This confirmed an autoimmune polyradiculitis - a rare irAE.

Expanded PCH1D phenotype linked to EXOSC9 mutation.

Pontocerebellar Hypoplasia type 1 is a rare heterogeneous neurodegenerative disorder with multiple subtypes linked to dysfunction of the exosome complex. Patients with mutations in exosome subunits exhibit a generally lethal phenotype characterized by cerebellar and pontine hypoplasia in association with spinal motor neuropathy and multiple systemic and neurologic features. Recently, two variants in the novel PCH1 associated protein EXOSC9 p.(Leu14Pro) and p.(Arg161*) have been identified in 4 unrelated patients exhibiting a severe phenotype involving cerebellar hypoplasia, axonal motor neuropathy, hypotonia, feeding difficulties, and respiratory insufficiency (PCH1D). We report clinical and molecular characterization of 2 unrelated patients exhibiting a relatively milder phenotype involving hypotonia, brachycephaly, cerebellar atrophy, psychomotor delay, as well as lactic acidosis and aberrant CNS myelination, resulting from the recurring homozygous missense mutation NM_001034194.1: c.41T>C; p.(Leu14Pro) in the EXOSC9 gene. We review the clinical picture of the EXOSC9-related PCH disorder.