Alterations in the spinal cord, trigeminal nerve ganglion, and infraorbital nerve through inducing compression of the dorsal horn region at the upper cervical cord in trigeminal neuralgia.

BACKGROUND: Idiopathic trigeminal neuralgia (TN) cases encountered frequently in daily practice indicate significant gaps that still need to be illuminated in the etiopathogenesis. In this study, a novel TN animal model was developed by compressing the dorsal horn (DH) of the upper cervical spinal cord. METHODS: Eighteen rabbits were equally divided into three groups, namely control (CG), sham (SG), and spinal cord compression (SCC) groups. External pressure was applied to the left side at the C3 level in the SCC group. Dorsal hemilaminectomy was performed in the SG, and the operative side was closed without compression. No procedure was implemented in the control group. Samples from the SC, TG, and ION were taken after seven days. For the histochemical staining, damage and axons with myelin were scored using Hematoxylin and Eosin and Toluidine Blue, respectively. Immunohistochemistry, nuclei, apoptotic index, astrocyte activity, microglial labeling, and CD11b were evaluated. RESULTS: Mechanical allodynia was observed on the ipsilateral side in the SCC group. In addition, both the TG and ION were partially damaged from SC compression, which resulted in significant histopathological changes and increased the expression of all markers in both the SG and SCC groups compared to that in the CG. There was a notable increase in tissue damage, an increase in the number of apoptotic nuclei, an increase in the apoptotic index, an indication of astrocytic gliosis, and an upsurge in microglial cells. Significant increases were noted in the SG group, whereas more pronounced significant increases were observed in the SCC group. Transmission electron microscopy revealed myelin damage, mitochondrial disruption, and increased anchoring particles. Similar changes were observed to a lesser extent in the contralateral spinal cord. CONCLUSION: Ipsilateral trigeminal neuropathic pain was developed due to upper cervical SCC. The clinical finding is supported by immunohistochemical and ultrastructural changes. Thus, alterations in the DH due to compression of the upper cervical region should be considered as a potential cause of idiopathic TN.

The CSF1-CSF1R pathway in the trigeminal ganglion mediates trigeminal neuralgia via inflammatory responses in mice.

BACKGROUND: Trigeminal neuralgia (TN) is the most severe type of neuropathic pain. The trigeminal ganglion (TG) is a crucial target for the pathogenesis and treatment of TN. The colony-stimulating factor 1 (CSF1) - colony-stimulating factor 1 receptor (CSF1R) pathway regulates lower limb pain development. However, the effect and mechanism of the CSF1-CSF1R pathway in TG on TN are unclear. METHODS: Partial transection of the infraorbital nerve (pT-ION) model was used to generate a mouse TN model. Mechanical and cold allodynia were used to measure pain behaviors. Pro-inflammatory factors (IL-6, TNF-a) were used to measure inflammatory responses in TG. PLX3397, an inhibitor of CSF1R, was applied to inhibit the CSF1-CSF1R pathway in TG. This pathway was activated in naïve mice by stereotactic injection of CSF1 into the TG. RESULTS: The TN model activated the CSF1-CSF1R pathway in the TG, leading to exacerbated mechanical and cold allodynia. TN activated inflammatory responses in the TG manifested as a significant increase in IL-6 and TNF-a levels. After using PLX3397 to inhibit CSF1R, CSF1R expression in the TG declined significantly. Inhibiting the CSF1-CSF1R pathway in the TG downregulated the expression of IL-6 and TNF-α to reduce allodynia-related behaviors. Finally, mechanical allodynia behaviors were exacerbated in naïve mice after activating the CSF1-CSF1R pathway in the TG. CONCLUSIONS: The CSF1-CSF1R pathway in the TG modulates TN by regulating neuroimmune responses. Our findings provide a theoretical basis for the development of treatments for TN in the TG.

Application of Sequential Thresholding-Based Automated Reconstruction of the Trigeminal Nerve in Trigeminal Neuralgia.

OBJECTIVE: High-resolution magnetic resonance imaging (MRI) of the trigeminal nerve is indispensable for workup of trigeminal neuralgia (TN) before microvascular decompression; however, the evaluation is often subjective and prone to variability. We aim to develop and assess sequential thresholding-based automated reconstruction of the trigeminal nerve (STAR-TN) as an algorithm for segmenting the trigeminal nerve and contacting structures that will allow for a structured method for assessing neurovascular conflict. METHODS: A total of 42 patients with TN who underwent high-resolution MRI before microvascular decompression in 2022 were included in our study. Segmentation of the trigeminal nerve and contacting structures was performed on preoperative MRI scans using STAR-TN. The segmentations were then evaluated for neurovascular conflict and compared to the preoperative radiology and operative notes. Geometric features, including the area of contact and distance to conflict, were extracted. RESULTS: Of the 42 patients, 32 (76.2%) were found to show neurovascular conflict based solely on their STAR-TN segmentations and 10 (23.8%) were found to not show neurovascular conflict. Compared with the intraoperative findings, this resulted in a sensitivity of 78.0% and specificity of 100%. In contrast, assessments of neurovascular conflict by radiologists using only 2-dimensional MRI views had a sensitivity of 68.3% and specificity of 100%. Of the 32 patients with neurovascular conflict, 29 (90.9%) had conflict within the root entry zone. Overall, the patients had a median area of contact of 10.66 mm2. CONCLUSIONS: STAR-TN allows for 3-dimensional visualization and identification of neurovascular conflict with improved sensitivity compared with neuroradiologist assessments from MRI slices.

Sixth cranial nerve palsy and trigeminal neuropathic pain due to a space-occupying lesion.

Various neuropathies of the cranil nerves can accompany trigeminal neuropathic pain attributed to space-occupying lesions. In this case report, the patient presented with persistent intraoral pain and numbness on the right side of the face. Cranial nerve examination revealed dysfunctional eye movements, diplopia, and mechanical hyposensitivity in the mandibular region. The patient was diagnosed with neuropathy due to intracranial lesions and referred to the Department of Neurosurgery and Otorhinolaryngology. The patient was suspected of having malignant lymphoma and is currently undergoing neurosurgical intervention. This article discusses the importance of the examination of the cranial nerve for patients with persistent pain in the trigeminal nerve distribution.

Progress in animal models of trigeminal neuralgia.

OBJECTIVE: This review aims to systematically summarize the methods of establishing various models of trigeminal neuralgia (TN), the scope of application, and current animals used in TN research and the corresponding pain measurements, hoping to provide valuable reference for researchers to select appropriate TN animal models and make contributions to the research of pathophysiology and management of the disease. DESIGN: The related literatures of TN were searched through PubMed database using different combinations of the following terms and keywords including but not limited: animal models, trigeminal neuralgia, orofacial neuropathic pain. To find the maximum number of eligible articles, no filters were used in the search. The references of eligible studies were analyzed and reviewed comprehensively. RESULTS: This study summarized the current animal models of TN, categorized them into the following groups: chemical induction, photochemical induction, surgery and genetic engineering, and introduced various measurement methods to evaluate animal pain behaviors. CONCLUSIONS: Although a variety of methods are used to establish disease models, there is no ideal TN model that can reflect all the characteristics of the disease. Therefore, there is still a need to develop more novel animal models in order to further study the etiology, pathological mechanism and potential treatment of TN.

Establishment of a Rat Model of Infraorbital Neuroinflammation Under CT Guidance.

INTRODUCTION: The aim is to establish a rat model of infraorbital neuroinflammation with less trauma, stable pain, and a long duration of pain. The pathogenesis of TN is not fully clear. There are various models of TN in rats with different disadvantages, such as damaging the surrounding structures and inaccuracy of location for infraorbital nerve (ION). We aim to establish a rat model of infraorbital neuroinflammation with minimal trauma, a simple operation, and accurate positioning under CT guidance to help us study the pathogenesis of trigeminal neuralgia. METHODS: Thirty-six adult male Sprague Dawley rats (180-220 g) were randomly divided into 2 groups and injected with talc suspension or saline through the infraorbital foramen (IOF) under CT guidance. Mechanical thresholds were measured in the right ION innervation region of 24 rats over 12 postoperative weeks. At 4 weeks, 8 weeks, and 12 weeks after the operation, the inflammatory involvement of the surgical area was evaluated by MRI, and neuropathy was observed using a transmission electron microscope (TEM). RESULTS: The talc group had a significant decrease in the mechanical threshold at 3 days after surgery that continued until 12 weeks post-operation, and the talc group had a significantly lower mechanical threshold than the saline group 10 weeks post-operation. The talc group had significantly impaired trigeminal nerve (TGN) myelin after 8 weeks post-operation. CONCLUSION: The rat model of infraorbital neuroinflammation established by CT-guided injection of talc into the IOF is a simple operation that results in less trauma, stable pain, and a long duration of pain. Moreover, infraorbital neuroinflammation in peripheral branches of the TGN can cause demyelination of the TGN in the intracranial segment.

Should trigeminal neuralgia be considered a clinically isolated syndrome?

The association between trigeminal neuralgia (TN) and multiple sclerosis (MS) is well established. Many MS patients with TN have magnetic resonance imaging (MRI) evidence of a symptomatic demyelinating lesion. Although infratentorial presentations are included in the diagnostic criteria for MS, there remains confusion in clinical practice as to whether TN should be considered a clinically isolated syndrome for the application of McDonald criteria. In this case series, we discuss this diagnostic quandary in patients presenting with TN and additional MRI findings suggestive of MS and highlight the unmet need for data in such patients to optimally guide their care.

Asymmetric activation of microglia in the hippocampus drives anxiodepressive consequences of trigeminal neuralgia in rodents.

BACKGROUND AND PURPOSE: Patients suffering from trigeminal neuralgia are often accompanied by anxiety and depression. Microglia-mediated neuroinflammation is involved in the development of neuropathic pain and anxiodepression pathogenesis. Whether and how microglia are involved in trigeminal neuralgia-induced anxiodepression remains unclear. EXPERIMENTAL APPROACH: Unilateral constriction of the infraorbital nerve (CION) was performed to establish trigeminal neuralgia in rat and mouse models. Mechanical allodynia and anxiodepressive-like behaviours were measured. Optogenetic and pharmacological manipulations were employed to investigate the role of hippocampal microglia in anxiety and depression caused by trigeminal neuralgia. KEY RESULTS: Trigeminal neuralgia activated ipsilateral but not contralateral hippocampal microglia, up-regulated ipsilateral hippocampal ATP and interleukin-1ß (IL-1ß) levels, impaired ipsilateral hippocampal long-term potentiation (LTP) and induced anxiodepressive-like behaviours in a time-dependent manner in rodents. Pharmacological or optogenetic inhibition of ipsilateral hippocampal microglia completely blocked trigeminal neuralgia-induced anxiodepressive-like behaviours. Activation of unilateral hippocampal microglia directly elicited an anxiodepressive state and impaired hippocampal LTP. Knockdown of ipsilateral hippocampal P2X7 receptors prevented trigeminal neuralgia-induced microglial activation and anxiodepressive-like behaviours. Furthermore, we demonstrated that microglia-derived IL-1ß mediated microglial activation-induced anxiodepressive-like behaviours and LTP impairment. CONCLUSION AND IMPLICATIONS: These findings suggest that priming of microglia with ATP/P2X7 receptors in the ipsilateral hippocampus drives pain-related anxiodepressive-like behaviours via IL-1ß. An asymmetric role of the bilateral hippocampus in trigeminal neuralgia-induced anxiety and depression was uncovered. The approaches targeting microglia and P2X7 signalling might offer novel therapies for trigeminal neuralgia-related anxiety and depressive disorder.

Magnetic resonance imaging evaluation of masticatory muscle changes in patients with primary trigeminal neuralgia before microvascular decompression.

Primary trigeminal neuralgia (PTN) is characterized by chronic neuropathic pain. There are few studies exploring masticatory muscle changes in patients with PTN. This study evaluated the changes in the masticatory muscles using magnetic resonance imaging (MRI) and the predictive factors of masticatory muscle changes in patients with PTN. The radiologic outcomes of 52 patients with PTN and 58 healthy adults were evaluated. The temporalis, lateral pterygoid, medial pterygoid, and masseter muscles were assessed using MRI. Atrophy and edema of the masticatory muscles were noted. Multivariate analyses were conducted to identify factors associated with masticatory muscle atrophy. Among the PTN group, the right side (61.5%) and mandibular branch (53.9%) were the most affected. Muscle atrophy of the temporalis (P < .001), medial pterygoid (P = .016), lateral pterygoid (P = .031), and masseter (P = .001) were significantly higher in the PTN group than in the control group. Lateral pterygoid edema was significantly higher in the PTN group (P < .001). However, no significant difference was found in the temporalis and masseter edema between the two groups. Logistic regression analysis demonstrated that neurovascular conflict (NVC) significantly predicted mastication muscle atrophy (P = .037). Patients with PTN had higher rates of masticatory muscle atrophy and edema. The assessment of NVC may be a preoperative imaging biomarker to predict atrophy in PTN.

The Role of Preoperative Magnetic Resonance Imaging in Assessing Neurovascular Compression Before Microvascular Decompression in Trigeminal Neuralgia.

BACKGROUND: Preoperative magnetic resonance imaging (MRI) is a standard component of the preoperative clinical workup for patients before microvascular decompression (MVD). However, its ability to accurately exclude neurovascular compression of the trigeminal nerve is not well understood. METHODS: We retrospectively reviewed 1020 patients with available preoperative MRI data before microvascular decompression. General patient demographics and clinical characteristics were collected for each case. We recorded both evidence of neurovascular conflict on preoperative MRI radiology notes and intraoperative compression from operative notes. Sensitivity, specificity, positive predictive value, and negative predictive value were determined for general MRI, high-resolution MRI, and non-high resolution. RESULTS: Overall, preoperative MRI before MVD showed a sensitivity of 75.8%, specificity of 65.8%, positive predictive value of 92.4%, and negative predictive value of 33.3% in predicting neurovascular compression of the trigeminal nerve. In particular, MRI was unable to identify 21.0% cases of sole arterial compression, 42.5% cases of sole venous compression, and combined arterial and venous compression in 18.5% of cases. A total of 958 patients (93.9%) underwent high-resolution preoperative MRI with skull base sequences. This imaging showed a sensitivity of 75.6%, specificity of 66.9%, positive predictive value of 92.5% and a negative predictive value of 33.4% in predicting trigeminal nerve neurovascular compression. Non-high-resolution MRI showed a sensitivity of 78.8%, specificity of 50.0%, positive predictive value of 89.1%, and negative predictive value of 31.3%. The negative predictive values of general, high-resolution, and non-high-resolution MRIs were all <50%. CONCLUSIONS: Preoperative MRI may offer a high predictive value for neurovascular conflict and should be part of the standard preoperative care workup for patients with trigeminal neuralgia. However, lack of neurovascular conflict on preoperative imaging is not sufficient to exclude patients from undergoing MVD.

Direct Mechanical Stimulation Mediates Cell-to-Cell Interactions in Cultured Trigeminal Ganglion Cells.

Trigeminal neuralgia occurs in the orofacial region, characteristically causing pain that feels like a transient electric shock. Some histopathological studies have reported that trigeminal neuralgia is caused by mechanical compression of the demyelinated trigeminal nerve; the pathophysiological mechanism behind this phenomenon remains to be clarified, however. Cell-cell interactions have also been reported to be involved in the development and modulation of some types of neuropathic pain. The purpose of this study was to investigate the potential contribution of cell-cell interactions to trigeminal neuralgia by measuring intracellular free Ca2+ concentrations ([Ca2+]i) in primary cultured trigeminal ganglion (TG) cells. Direct mechanical stimulation of TG cells induced an increase in [Ca2+]i in both neuronal and non-neuronal cells, such as glial cells. Moreover, this increase was stimulus intensity-dependent and non-desensitizing. Direct mechanical stimulation increased [Ca2+]i in neighboring cells as well, and this increase was inhibited by application of carbamazepine. These results indicate that direct mechanical stimulation affects Ca2+ signaling. Trigeminal ganglion cells establish intercellular networks between themselves, suggesting that this is involved in the development and generation of trigeminal neuralgia.

[The peak latency prolongation of the blink reflex in a patient with trigeminal neuralgia of Meckel's cave mass]. / A pislogási reflexcsúcs latenciájának megnyúlása egy Meckel-barlang-terime következtében kialakuló trigeminusneuralgia esetben.

The blink reflex test of the trigeminal nerve can provide valuable information about lesions site. However it may not find small compressive lesions. We observed peak latency prolongation of the blink reflex test in a patient with trigeminal neuralgia caused by a small Meckel's cave mass, in whom the onset latency was normal. Conclusion - We suggest peak latency of the blink reflex might be a valuable aid for discerning small mass in patients with trigeminal neuralgia. This is the first case report of compressive trigeminal neuralgia showing peak latency prolongation of the blink reflex test.

Anatomy of the Trigeminal Nerve and Its Clinical Significance Via Fusion of Computed Tomography and Magnetic Resonance Imagery.

BACKGROUND: The Gasserian ganglion (GG) is the primary neuronal aggregation area of the trigeminal nervous system and the epidural structure outside the central nervous system, thus, it has become the most commonly used target for minimally invasive treatment of trigeminal neuralgia (TN). Whether it is the classic trigeminal radiofrequency treatment or GG balloon compression therapy, the intervention target is the GG. The anatomy and imaging anatomy of the GG of the trigeminal nerve is of great importance in the minimally invasive treatment of TN. OBJECTIVE: To study the anatomy of the trigeminal nerve and multimodal image fusion, and to provide a basis for a clinical minimally invasive interventional treatment forTN. STUDY DESIGN: Review, clinical research study. SETTING: Department of Anesthesiology and Pain Medical Center, Jiaxing, China. METHODS: Dissect the general structure of the trigeminal nerve and its positional relationship with adjacent structures, and use computed tomography (CT) and magnetic resonance imaging (MRI) to observe the trigeminal nerve, and then, perform a fusion of the CT/MR images. RESULTS: The GG of the trigeminal nerve is located in Meckel's cave of the middle cranial fossa, and the 3 branches of the nerve fibers are intertwined. CT could only clearly show the bony structures adjacent to the GG, rather than the GG in the body, which was inconsistent with MR images. The bony structure was blurred, while the Meckel's cave and nerve roots, where the trigeminal nerve is located, could be clearly distinguished. Fusing the CT/MR images could provide 2 complementary advantages. LIMITATIONS: It does not prove the the balloon position thought to be a "dumbbell" shape is adequate for the successful treatment. CONCLUSION: Based on the anatomical structure and position of the trigeminal nerve, it is difficult to achieve highly selective branch treatment of TN with radiofrequency in the GG. For the treatment of TN with percutaneous microballoon compression on the GG, the balloon catheter should be placed in Meckel's cave. While it is not easy to insert into Meckel's cave, the depth of the balloon catheter should be that the distal end is flush with the top of the temporal bone petrous cone.

Longitudinal alterations of the cisternal segment of trigeminal nerve and brain pain-matrix regions in patients with trigeminal neuralgia before and after treatment.

BACKGROUND: Trigeminal neuralgia (TN) is the most common type of chronic neuropathic facial pain, but the etiology and pathophysiological mechanisms after treatment are still not well understood. The purpose of this study was to investigate the longitudinal changes of the cisternal segment of the trigeminal nerve and brain pain-related regions in patients with TN before and after treatment using readout segmentation of long variable echo-train (RESOLVE) diffusion tensor imaging (DTI) and transverse relaxation (T2)-weighted sampling perfection with application-optimized contrast at different flip angle evolutions (T2-SPACE). METHODS: Twelve patients with TN and four healthy controls were enrolled in this study. All patients underwent assessment of the visual analog scale (VAS), and acquisition of RESOLVE DTI and T2-SPACE images before and at 1, 6, and 12 months after treatments. Regions-of-interest were placed on the bilateral anterior, middle, and posterior parts of the cisternal segment of the trigeminal nerve, the bilateral root entry zone (REZ), bilateral nuclear zone, and the center of pontocerebellar tracts, respectively. Voxel-based morphometry (VBM) analysis was conducted with T2-SPACE images, and gray matter volumes (GMV) were measured from brain pain-matrix regions. RESULTS: The results demonstrated that the VAS scores, the axial diffusivity of the middle part of the affected cisternal trigeminal nerve, the fractional anisotropy of the bilateral nuclear zones, and the mean diffusivity of the center of pontocerebellar tract significantly changed over time before and after treatment. The changes of GMV in the pain-matrix regions exhibited similar trends to the VAS before and after treatment. CONCLUSION: We conclude that magnetic resonance imaging with RESOLVE DTI and VBM with T2-SPACE images were helpful in the understanding of the pathophysiological mechanisms in patients with TN before and after treatment.

Flow cytometry analysis of immune and glial cells in a trigeminal neuralgia rat model.

Microvascular compression of the trigeminal root entry zone (TREZ) is the main cause of most primary trigeminal neuralgia (TN), change of glial plasticity was previously studied in the TREZ of TN rat model induced by chronic compression. To better understand the role of astrocytes and immune cells in the TREZ, different cell markers including glial fibrillary acidic protein (GFAP), complement C3, S100A10, CD45, CD11b, glutamate-aspartate transporter (GLAST), Iba-1 and TMEM119 were used in the TN rat model by immunohistochemistry and flow cytometry. On the post operation day 28, GFAP/C3-positive A1 astrocytes and GFAP/S100A10-positive A2 astrocytes were activated in the TREZ after compression injury, there were no statistical differences in the ratios of A1/A2 astrocytes between the sham and TN groups. There was no significant difference in Iba-1-positive cells between the two groups. The ratios of infiltrating lymphocytes (CD45+CD11b-) (p = 0.0075) and infiltrating macrophages (CD45highCD11b+) (p = 0.0388) were significantly higher than those of the sham group. In conclusion, different subtypes A1/A2 astrocytes in the TREZ were activated after compression injury, infiltrating macrophages and lymphocytes increased, these neuroimmune cells in the TREZ may participate in the pathogenesis of TN rat model.

Recent Advances of Magnetic Resonance Neuroimaging in Trigeminal Neuralgia.

Trigeminal neuralgia (TN) is a disease of unclear pathogenesis. It has a low incidence and is not fatal, but it can cause afflicted patients' depression or suicide. In the past, neurovascular compression was considered to be the main cause of TN, but recent studies have found that neurovascular contact is also common in asymptomatic patients and the asymptomatic side in symptomatic patients. This indicates that the neurovascular contact is not, or is only to a lesser extent, a factor in the development of TN. Thus, the study of the peripheral branches of the trigeminal nerve is necessary to understand the etiology of TN. With the development of imaging technology and the emergence of various imaging modalities, it is possible to study the etiology of TN and the pathological changes of related structures by magnetic resonance neuroimaging. This article reviews the recent advances in magnetic resonance neuroimaging of the trigeminal nerve.

Gain-of-function mutation Met136Val in SCN8A may not be a common cause of trigeminal neuralgia.

BACKGROUND: The Met136Val mutation in SCN8A was described in a case of trigeminal neuralgia but no frequency among affected individuals was provided. METHODS: Direct sequencing of 123 individuals diagnosed with classic trigeminal neuralgia was performed aimed to detect the Met136Val change. RESULTS: No cases of classical trigeminal neuralgia studied had the Met136Val mutation in SCN8A. CONCLUSION: Met136Val mutation in SCN8A is not a frequent cause of classical trigeminal neuralgia.

Three-dimensional morphology of the superior cerebellar artery running in trigeminal neuralgia.

The superior cerebellar artery (SCA) is the most frequent offending vessel in trigeminal neuralgia. This study aims to elucidate the patterns of the SCA running in 34 patients with typical trigeminal neuralgia using three-dimensional computer graphics. The SCA which runs in the medial aspect of the trigeminal nerve compressed predominantly the root entry zone at the distal segment of the caudal loop. Meanwhile, the SCA which runs in the cranial or lateral aspect of the trigeminal nerve compressed predominantly the mid-third portion at the proximal segment of the caudal loop. The site of neurovascular compression differed depending on the shape of the initial segment of SCA. Transposition methods could not be performed in several patients with arch-shaped SCA. Three-dimensional computer graphics revealed different characteristics of the SCA running in trigeminal neuralgia depending on the site of neurovascular compression and shape of the SCA. These differences might affect procedures for microvascular decompression.