Pathogenesis Of Trigeminal Neuralgia Research Articles

Foxg1 Modulation of the Prkcd Gene in the Lateral Habenula Mediates Trigeminal Neuralgia-Associated Anxiety-Like Behaviors in Mice.

Trigeminal Neuralgia (TN) is a debilitating disorder frequently accompanied by mood complications such as depression and anxiety. The current study sought to elucidate the molecular underpinnings that contribute to the pathogenesis of TN and its associated anxiety. Employing a partial transection of the infraorbital nerve (pT-ION) in a murine model, we successfully induced sustained primary and secondary orofacial allodynia alongside anxiety-like behavioral manifestations. Transcriptome-wide gene microarray analyses revealed a marked upregulation of Foxg1 subsequent to pT-ION. Targeted knockdown of Foxg1, achieved through bilateral microinjection of adeno-associated virus harboring Foxg1-specific shRNA into the lateral habenula (LHb), resulted in a significant attenuation of both orofacial pain and anxiety-like behaviors. Subsequent RNA sequencing implicated Prkcd as a downstream effector gene modulated by Foxg1. Pharmacological inhibition of protein kinase C delta, encoded by Prkcd, within the LHb markedly ameliorated pT-ION-induced symptomatology. The dual luciferase assay revealed that Foxg1 substantially enhances the transcriptional activity of the Prkcd gene. Collectively, these findings indicate that trigeminal nerve injury leads to Foxg1 upregulation in the LHb, which in turn elevates the expression of Prkcd, culminating in the manifestation of orofacial pain and anxiety-like behaviors. This work offers promising therapeutic targets and a conceptual framework for the clinical management of TN and its psychological comorbidities.

Novel insights into STIM1's role in store-operated calcium entry and its implications for T-cell mediated inflammation in trigeminal neuralgia.

This investigation aims to elucidate the novel role of Stromal Interaction Molecule 1 (STIM1) in modulating store-operated calcium entry (SOCE) and its subsequent impact on inflammatory cytokine release in T lymphocytes, thereby advancing our understanding of trigeminal neuralgia (TN) pathogenesis. Employing the Gene Expression Omnibus (GEO) database, we extracted microarray data pertinent to TN to identify differentially expressed genes (DEGs). A subsequent comparison with SOCE-related genes from the Genecards database helped pinpoint potential target genes. The STRING database facilitated protein-protein interaction (PPI) analysis to spotlight STIM1 as a gene of interest in TN. Through histological staining, transmission electron microscopy (TEM), and behavioral assessments, we probed STIM1's pathological effects on TN in rat models. Additionally, we examined STIM1's influence on the SOCE pathway in trigeminal ganglion cells using techniques like calcium content measurement, patch clamp electrophysiology, and STIM1- ORAI1 co-localization studies. Changes in the expression of inflammatory markers (TNF-α, IL-1β, IL-6) in T cells were quantified using Western blot (WB) and enzyme-linked immunosorbent assay (ELISA) in vitro, while immunohistochemistry and flow cytometry were applied in vivo to assess these cytokines and T cell count alterations. Our bioinformatic approach highlighted STIM1's significant overexpression in TN patients, underscoring its pivotal role in TN's etiology and progression. Experimental findings from both in vitro and in vivo studies corroborated STIM1's regulatory influence on the SOCE pathway. Furthermore, STIM1 was shown to mediate SOCE-induced inflammatory cytokine release in T lymphocytes, a critical factor in TN development. Supportive evidence from histological, ultrastructural, and behavioral analyses reinforced the link between STIM1-mediated SOCE and T lymphocyte-driven inflammation in TN pathogenesis. This study presents novel evidence that STIM1 is a key regulator of SOCE and inflammatory cytokine release in T lymphocytes, contributing significantly to the pathogenesis of trigeminal neuralgia. Our findings not only deepen the understanding of TN's molecular underpinnings but also potentially open new avenues for targeted therapeutic strategies.

Trigeminal neuralgia at the present stage: Pathophysiology, classification, diagnosis and treatment (literature review)

The incidence of trigeminal neuralgia (TN) is 4–5 cases per 100,000 population per year, and the prevalence is about 20–50 cases per 100,000 population. According to the modern classification, the following types of TN are distinguished: classical, symptomatic and idiopathic. The cause of classical TN is a neurovascular conflict, of symptomatic TN – neoplasms in the petroclival area, vascular anomalies, multiple sclerosis, etc. In the absence of a reliable etiological factor, TN is considered idiopathic. TN pathogenesis remains one of the most challenging topics in neuroscience. Today, there are many theories and hypotheses regarding the peripheral and central mechanisms of trigeminal neuralgia. The most popular theory is the neurovascular conflict that occurs between the trigeminal nerve and the cerebral vessels, but this theory is not the only one. It is known that even after microvascular decompression, patients may continue to experience facial pain. Therefore, other pathogenetic mechanisms are discussed: short circuit theory, multineuronal mechanism, allergic and immune hypothesis, gate theory, bioresonance hypothesis, trigeminal convergence projection theory, “ignition” hypothesis and ion channel pathology. TN is a clinical diagnosis, and its establishing requires certain criteria proposed by the International Headache Society. Using instrumental research methods, namely magnetic resonance imaging of the brain, is necessary for the differential diagnosis of classical and symptomatic TN, and imaging results should always be interpreted in combination with clinical data to make correct decisions on further treatment tactics.

Role of Magnetic Resonance Imaging in the Evaluation of Trigeminal Neuralgia Using Steady-State Imaging.

Trigeminal neuralgia (TN) poses diagnostic challenges due to its complex origins, often associated with neurovascular compression. Advanced imaging techniques, particularly magnetic resonance imaging (MRI) with thefast imaging employing steady-state acquisition (FIESTA) sequence, offer crucial insights into TN pathophysiology. This prospective cross-sectional observational study aimed to elucidate MRI's utility in diagnosing TN and correlating imaging findings with clinical manifestations and treatment outcomes. A cohort of 41 patients clinically suspected of TN underwent MRI evaluation at Acharya Vinoba Bhave Rural Hospital, Sawangi (Meghe), Wardha, utilizing various sequences including FIESTA. Analysis revealed a higher incidence among females, predominant unilateral presentation, and a higher prevalence of abnormal MRI findings, with neurovascular compression as the leading etiology. Correlation analysis demonstrated significant associations between facial pain localized to the trigeminal nerve distribution, triggering factors, and abnormal MRI findings. Gender distribution did not significantly influence MRI findings. Treatment outcomes favored microvascular surgery over conservative management in cases of neurovascular compression. This study underscores MRI's pivotal role, particularly FIESTA, in TN evaluation, guiding personalized treatment strategies and emphasizing the importance of integrated clinical and imaging approaches. Further research is warranted to validate these findings and explore additional imaging modalities for a deeper understanding of TN pathogenesis.

The role of artificial intelligence in the management of trigeminal neuralgia.

Trigeminal neuralgia (TN) is the most frequent facial pain. It is difficult to treat pharmacologically and a significant amount of patients can become drug-resistant requiring surgical intervention. From an etiologically point of view TN can be distinguished in a classic form, usually due to a neurovascular conflict, a secondary form (for example related to multiple sclerosis or a cerebello-pontine angle tumor) and an idiopathic form in which no anatomical cause is identifiable. Despite numerous efforts to treat TN, many patients experience recurrence after multiple operations. This fact reflects our incomplete understanding of TN pathogenesis. Artificial intelligence (AI) uses computer technology to develop systems for extension of human intelligence. In the last few years, it has been a widespread of AI in different areas of medicine to implement diagnostic accuracy, treatment selection and even drug production. The aim of this mini-review is to provide an up to date of the state-of-art of AI applications in TN diagnosis and management.

The cerebellopontine angle cistern volumetric differences in trigeminal neuralgia patients with and without vertebrobasilar compression: a case-matched study.

Previous studies have indicated that the small cerebellopontine angle (CPA) cistern plays a role in the pathogenesis of trigeminal neuralgia (TN), but they are likely not involved in TN associated with vertebrobasilar artery (VBA) compression because of its rarity. Forty-four patients with VBA-associated TN and 44 age-, sex-, and hypertension-matched TN patients without VBA compression (non-VBA-associated) were included. All patients underwent high-resolution MRI. The CPA cistern volumes were measured bilaterally. The presence of vertebrobasilar dolichoectasia (VBD) and laterality of the vertebrobasilar junction (VBJ) were observed. The CPA cistern volume on the affected side was smaller than the unaffected side (714.4 ± 372.8 vs 890.2 ± 462.2 mm3, p < 0.001) in non-VBA-associated TN patients, while VBA-associated TN patients show a larger CPA cistern on the affected side than the unffected side (1107.0 ± 500.5 vs 845.3 ± 314.8 mm3, p < 0.001). The prevalence of VBD was higher in patients with VBA-associated TN than in matched non-VBA-associated TN patients (90.9% vs 4.5%, p < 0.001). A positive correlation between the laterality of VBJ and the affected side was found in the VBA-associated TN group (p < 0.0001). Large CPA cistern may be a neuroradiological feature of VBA-associated TN, and most of the VBA-associated TN is accompanied by VBD. The presence of VBD and the lateral shift of VBJ may expand the CPA cistern by squeezing the surrounding tissue on the affected side and also increase the chance of VBA compression on the trigeminal nerve, resulting in the genesis of VBA-associated TN.

Amelioration of nerve demyelination by hydrogen-producing silicon-based agent in neuropathic pain rats

Trigeminal neuralgia (TN) is a complex orofacial neuropathic pain. The crippling condition's underlying mechanism is still not completely understood. The main cause of lightning-like pain in patients with TN may be chronic inflammation that causes nerve demyelination. Nano-silicon (Si) can safely and continuously produce hydrogen in the alkaline environment of the intestine to exert systemic anti-inflammatory effects. Hydrogen has a promising anti-neuroinflammatory impact. The study aimed to determine how intra-intestinal application of a hydrogen-producing Si-based agent affected the demyelination of the trigeminal ganglion in TN rats. We discovered that increased expression of the NLRP3 inflammasome and inflammatory cell infiltration occurred concurrently with demyelination of the trigeminal ganglion in TN rats. We could determine that the neural effect of the hydrogen-producing Si-based agent was connected to the inhibition of microglial pyroptosis by using transmission electron microscopy. The results demonstrated that the Si-based agent reduced the infiltration of inflammatory cells and the degree of neural demyelination. In a subsequent study, it was discovered that hydrogen produced by a Si-based agent regulates the pyroptosis of microglia may through the NLRP3-caspase-1-GSDMD pathway, preventing the development of chronic neuroinflammation and consequently lowering the incidence of nerve demyelination. This study offers a novel strategy for elucidating the pathogenesis of TN and developing potential therapeutic drugs.

Fluorescence visualization of the neuropathic pain triad in trigeminal neuralgia.

Trigeminal neuralgia (TN), an exemplary condition of neuropathic facial pain, seriously affects the physical and mental health of patients, becoming a major medical and social problem. So far, the mechanism of TN and its relation to neuronal activity remain unclear, largely limited by the spatial resolution of visualization methods. In the meanwhile, current therapeutic strategies targeting neurons have not achieved satisfactory outcome. Here, we investigate the neuropathic pain triad in TN by establishing an animal model of TN by chronic constriction injury of the unilateral infraorbital nerve (ION-CCI) and leveraging the single-cell resolution of confocal microscopy, including neuronal hyperexcitability, glial activation, and macrophage polarization. These results can broaden the understanding of TN pathogenesis from neurons to the neuropathic pain triad, and suggest that optical microscopy can provide new opportunities for understanding the complex pathogenesis of TN at single-cell resolution, potentially contributing to the identification of more precise therapeutic targets and the development of more effective treatment modalities.

Effect of lidocaine on expression of P2X7, p-p38 and IL-Iβ in the thalamus of rats with trigeminal neuralgia

ABSTRACT We investigated whether lidocaine can increase the pain threshold of rats with trigeminal neuralgia by affecting the expression of P2X7, p-p38 and IL-Iβ proteins in the thalamus. Thirty-three male Sprague–Dawley (SD) rats were randomly divided into three groups (n = 11): Sham group, Ion-CCI (infraorbital nerve chronic constriction injury) group and Ion-CCI+L group(Ion-CCI+lidocaine 10 mg/kg/day, i.p.). The mechanical pain threshold of rats was measured preoperatively and at 1, 3, 5, 7, 9, 11 and 14days after operation with the von Frey filament sensor tester. Fourteen days after operation, the rats were dissected to collect their whole brain, thalamus and trigeminal ganglion to detect IL-1β, P2X7, p38, and p-p38 protein expression. The pain threshold of rats in Ion-CCI+L group was lower than that in Sham group (p < 0.01) and higher than that in Ion-CCI group (p < 0.01).ELISA showed that IL-1β in the thalamus and trigeminal ganglion in Ion-CCI+L group were lower than those in ion-CCI group (p < 0.05) but higher than those in Sham group (p < 0.05). Western blot showed that the expression levels of P2X7 and p-p38 in the thalamus of rats in Ion-CCI+L group were lower than those in Ion-CCI group (p < 0.01) and higher than thaose in Sham group (p < 0.01),while the expression levels of IL-1β in the thalamus in Ion-CCI+L group were lower than those in Ion-CCI group (p < 0.05) and higher than those in Sham group (p < 0.01). Immunofluorescence showed that p-p38 in the thalamus in Ion-CCI+L group was lower than that in Ion-CCI group (p < 0.05) and higher than that in Sham group (p < 0.05). Lidocaine can reduce the inflammatory response of the central nervous system and increase the pain threshold of trigeminal neuralgia rats by inhibiting p2x7-p38-IL-1β signaling pathway.This pathway play an important role in the pathogenesis of trigeminal neuralgia, and it may be one of the targets for the treatment of trigeminal neuralgia.

Recent update on trigeminal neuralgia

Trigeminal neuralgia (TN), a long-term disorder affecting the trigeminal nerve, is a form of debilitating neuropathic pain. Although the underlying pathogenesis of TN is debatable, loss of myelin along the trigeminal nerve due to direct compression from a blood vessel or secondary to other conditions such as multiple sclerosis or stroke is thought to be the principal cause. Paroxysmal sporadic pain, with unilateral onset, is the main phenomenon of TN. TN is typically diagnosed clinically. Medications, surgery, and complementary techniques are among the current therapy options for altering the neural circuits associated with TN. Nevertheless, anti-epileptic and tricyclic antidepressant medications are recognized as first-line treatments, and surgical treatment may be required for patients who have not obtained a therapeutic effect with at least three medications, have experienced intolerable side effects, or have symptoms that are not resolving. Stimulation of brain regions is an emerging off-label technique that has the potential to offer pain relief from TN, but sufficient data and more extensive studies on both animals and humans are yet to be published. More specifically, convenient diagnostic techniques and affordable treatment modalities for TN have become crucial needs in order to reduce the psychological and socio-economical losses caused by TN.

The Molecular Basis and Pathophysiology of Trigeminal Neuralgia.

Trigeminal neuralgia (TN) is a complex orofacial pain syndrome characterized by the paroxysmal onset of pain attacks in the trigeminal distribution. The underlying mechanism for this debilitating condition is still not clearly understood. Decades of basic and clinical evidence support the demyelination hypothesis, where demyelination along the trigeminal afferent pathway is a major driver for TN pathogenesis and pathophysiology. Such pathological demyelination can be triggered by physical compression of the trigeminal ganglion or another primary demyelinating disease, such as multiple sclerosis. Further examination of TN patients and animal models has revealed significant molecular changes, channelopathies, and electrophysiological abnormalities in the affected trigeminal nerve. Interestingly, recent electrophysiological recordings and advanced functional neuroimaging data have shed new light on the global structural changes and the altered connectivity in the central pain-related circuits in TN patients. The current article aims to review the latest findings on the pathophysiology of TN and cross-examining them with the current surgical and pharmacologic management for TN patients. Understanding the underlying biology of TN could help scientists and clinicians to identify novel targets and improve treatments for this complex, debilitating disease.

Morphometric examination of trigeminal nerve and its adjacent structures in patients with trigeminal neuralgia: a case-control study.

Morphological differences that can lead the trigeminal nerve to neurovascular conflict and a new solitary pontine lesion are associated with the pathogenesis of trigeminal neuralgia (TN). In this case-control study, we aimed to contribute to the current discussions about the pathogenesis of TN by investigating the anatomical structures that may have an effect on the morphometric parameters of the trigeminal nerve. This study included 25 patients with TN followed up for pain in the Department of Algology, Faculty of Medicine, and 25 age- and gender-matched controls. We performed morphometric measurements including the length and volume of the trigeminal nerve, cerebellopontine cistern, pons, and posterior fossa in the MRIs of these individuals. Comparative analyses were performed for the mean of the affected and unaffected sides of the TN patients and the right, left, and both sides of the control group. In patients with TN, on the affected side, length and volume of the trigeminal nerve and cerebellopontine cistern volume were found smaller than controls (p < 0.05). Pons volume was higher in patients with TN compared to controls (p < 0.05). The length of the affected nerve was significantly related to prepontine cistern length and cerebellopontine cistern volume (p < 0.05). The cerebellopontine cistern volume has a significant impact on the morphometric characteristics of the trigeminal nerve. Especially, whether the increase in the volume of pons causes a decrease in the volume of cerebellopontine cistern should be clarified with further research.

The Up-regulation of TNF-α Maintains Trigeminal Neuralgia by Modulating MAPKs Phosphorylation and BKCa Channels in Trigeminal Nucleus Caudalis.

Trigeminal neuralgia (TN) is a severe chronic neuropathic pain. Despite numerous available medical interventions, the therapeutic effects are not ideal. To control the pain attacks, the need for more contemporary drugs continues to be a real challenge. Our previous study reported that Ca2+-activated K+ channels (BKCa) channels modulated by mitogen-activated protein kinases (MAPKs) in the trigeminal ganglia (TG) neurons play crucial roles in regulating TN, and some research studies demonstrated that inflammatory cytokine tumor necrosis factor alpha (TNF-α) could promote neuropathic pain. Meanwhile, the trigeminal nucleus caudalis (TNC), the first central site of the trigeminal nociceptive pathway, is responsible for processing sensory and pain signals from the peripheral orofacial area. Thus, this study is aimed to further investigate whether TNF-α and MAPKs phosphorylation in the TNC could mediate the pathogenesis of TN by modulating BKCa channels. The results showed that TNF-α of the TNC region is upregulated significantly in the chronic constriction injury of infraorbital nerve (ION-CCI) rats model, which displayed persistent facial mechanical allodynia. The normal rats with target injection of exogenous TNF-α to the fourth brain ventricle behaved just like the ION-CCI model rats, the orofacial mechanical pain threshold decreased clearly. Meanwhile, the exogenous TNF-α increased the action potential frequency and reduced the BKCa currents of TNC neurons significantly, which could be reversed by U0126 and SB203580, the inhibitors of MAPK. In addition, U0126, SB203580, and another MAPK inhibitor SP600125 could relieve the facial mechanical allodynia by being injected into the fourth brain ventricle of ION-CCI model rats, respectively. Taken together, our work suggests that the upregulation of TNF-α in the TNC region would cause the increase of MAPKs phosphorylation and then the negative regulation of BKCa channels, resulting in the TN.

Activation of SK3 channel plays a pivotal role in modulation of trigeminal neuralgia

ABSTRACT Objective: To investigate whether small conductance Ca2+ activatedK+ channels; Trigeminal ganglion; Trigeminal neuralgia. (SK3) exists in normal rats’ trigeminal ganglions (TG) and its effect on their pain thresholds. Methods: In total, 110 healthy adult male Sprague–Dawley (SD) rats were involved in this study. Ten rats were dissected to collect their liver tissues, TG and DRG. The rest of the rats were randomly assigned to either the experimental group or the control group. The animal model of trigeminal neuralgia (TN) was established by infraorbital nerve ligation. The expression of SK3 channels in their livers, TG and dorsal root ganglions (DRG) were detected. And different doses of SK3 channel activator and inhibitor were administered to the rats in both groups 15 days after the operation; meanwhile, their pain thresholds were also measured. Results: The expression of SK3 channel was found in TG. In the experimental group, the pain threshold was significantly decreased and there was a decreased level of SK3 than that in the control group at 15 days after operation. The administration of SK3 channel agonist (CyPPA) could significantly improve the pain threshold, while, the pain threshold decreased after administration of SK3 channel antagonist (Apamin). Conclusion: The SK3 channel may play a pivotal role in the pathogenesis of trigeminal neuralgia, and it may be one of the potential targets for the treatment of trigeminal neuralgia.

Using RNA-Seq to Explore the Hub Genes in the Trigeminal Root Entry Zone of Rats by Compression Injury

Mechanical compression on the trigeminal root entry zone (TREZ) by microvascular is the main etiology of primary trigeminal neuralgia (TN). To study the pathogenesis of TN, hub genes screening in the TREZ of TN in an animal model was performed. A double blind, randomized study was designed in a controlled animal trial. The research took place in the Laboratory of Clinical Applied Anatomy at the School of Basic Medical Science of Fujian Medical University. Twelve male rats were randomly divided into a sham operation group and a TN animal model group. TN animal model was induced by chronic compression of trigeminal nerve root (CCT) operation. Gene expression in the TREZ were analyzed by RNA sequencing (RNA-Seq) technique. KEGG analysis, GO analysis, and PPI analysis were performed in the DEGs. Key signaling pathways analyzing by GSEA and the hub genes in the DEGs were also studied. Reverse transcription real-time polymerase chain reaction (RT-qPCR) was used to verify the RNA-Seq results. Transcriptome data showed that 352 genes up-regulated and 59 genes down-regulated in DEGs on post-operation day 21, after CCT operation in the TN group. KEGG analysis revealed that, "neuroactive ligand receptor interaction" and "cytokine cytokine receptor interaction" may be related to the pathogenesis of TN. GO analysis showed "regulation of signing receptor activity", "chemokine activity", and "carbohydrate binging" may be related to TN. The RT-qPCR results were consistent with the test results, indicating that the transcriptome sequencing results were reliable. Although the incidence of TN in female rats was higher than in male rats, we only used male SD rats to establish the TN animal model, to avoid the effect of estrogen on experimental results. This study only presents some respects of RNA-Seq technique and, therefore, did not identify the DEGs at the protein level. The relationship between the DEGs at different levels shoud be done in the future. Based on the results of RNA-seq, this study discovered 6 hub genes in the TREZ that are closely related to the TN animal model, which provide a potential breakthrough point to explore the pathogenesis of TN.

The diagnostic value of pain evoked potential by electrical stimulation combined with noceciptive blink reflex in trigeminal neuralgia

Microvascular decompression is the first choice for treating the primary trigeminal neuralgia to provide the most extended duration of pain freedom. However, in microvascular decompression, we found that this kind of operation is only suitable for some patients. It is of great value to objectively judge the function and abnormality of the trigeminal pain conduction pathway in guiding the operation process. This brief report investigates the value of pain evoked potential by electrical stimulation and noceciptive blink reflex in trigeminal neuralgia. We detected the pain evoked potential in 34 patients with trigeminal neuralgia and 48 healthy controls treated by electrical stimulation and blink reflex. We demonstrated no significant differences in the latencies of V1, V2, V3, and R2 of the affected side and the contralateral side in patients with trigeminal neuralgia. The latencies of those four indicators of the affected side in patients with trigeminal neuralgia were notably decreased compared to those on the same side in healthy controls. The receiver operating characteristic curve analysis showed that the area under curve, sensitivity and specificity of the combined diagnosis of latency and amplitude were significantly higher than the single diagnosis. The latency and amplitude of V1 were highly sensitive, while those of V2 was highly specific. Trigeminal neuralgia can be effectively diagnosed by combining pain evoked potential by electrical stimulation and noceciptive blink reflex. The pathogenesis of trigeminal neuralgia should be combined with peripheral pathogenicity and the theory of central pathogenicity.

Immunohistochemical analysis of the arterial supply and mast cells of the trigeminal ganglion

The aim of this study was to quantify the distribution of microvessels and mast cells in all three parts of the trigeminal ganglion (TG). Statistical analyses were applied to investigate possible micromorphological regional differences in their density. Five serially sectioned human TGs were prepared for CD34 and mast cell tryptase immunostaining. The following quantifications were performed in microscopic fields of three parts of the TG: microvessel density (MVD), mast cell density (MCD) and ganglionic cell count. The density of CD34-positive microvessels was not significantly different in any of the three observed parts of the TG. The distribution of neurons showed no significant statistical difference in three parts of the TG. There was no difference in the density of tryptase-positive mast cells within the TG, but there was an abundant presence of mast cells in the periganglionic dural and subdural tissues, a finding hitherto not reported. We can say that there is a homogenous vascular pattern within the TG which excludes local predominance in pathogenesis of trigeminal neuralgia. Second, and more important, the finding of peri-trigeminal mast cells indicates their important role in migraine pain and confirms their degranulation as the main therapeutic goal for this condition.

Trigeminal neuralgia and genetics: A systematic review.

Trigeminal neuralgia (TN) is a severe facial pain disease of unknown cause and unclear genetic background. To examine the existing knowledge about genetics in TN, we performed a systematic study asking about the prevalence of familial trigeminal neuralgia, and which genes that have been identified in human TN studies and in animal models of trigeminal pain. MedLine, Embase, Cochrane Library and Web of Science were searched from inception to January 2021. 71 studies were included in the systematic review. Currently, few studies provide information about the prevalence of familial TN; the available evidence indicates that about 1–2% of TN cases have the familial form. The available human studies propose the following genes to be possible contributors to development of TN: CACNA1A, CACNA1H, CACNA1F, KCNK1, TRAK1, SCN9A, SCN8A, SCN3A, SCN10A, SCN5A, NTRK1, GABRG1, MPZ gene, MAOA gene and SLC6A4. Their role in familial TN still needs to be addressed. The experimental animal studies suggest an emerging role of genetics in trigeminal pain, though the animal models may be more relevant for trigeminal neuropathic pain than TN per se. In summary, this systematic review suggests a more important role of genetic factors in TN pathogenesis than previously assumed.

Exome Sequencing Implicates Impaired GABA Signaling and Neuronal Ion Transport in Trigeminal Neuralgia.

SummaryTrigeminal neuralgia (TN) is a common, debilitating neuropathic face pain syndrome often resistant to therapy. The familial clustering of TN cases suggests that genetic factors play a role in disease pathogenesis. However, no unbiased, large-scale genomic study of TN has been performed to date. Analysis of 290 whole exome-sequenced TN probands, including 20 multiplex kindreds and 70 parent-offspring trios, revealed enrichment of rare, damaging variants in GABA receptor-binding genes in cases. Mice engineered with a TN-associated de novo mutation (p.Cys188Trp) in the GABAA receptor Cl− channel γ-1 subunit (GABRG1) exhibited trigeminal mechanical allodynia and face pain behavior. Other TN probands harbored rare damaging variants in Na+ and Ca+ channels, including a significant variant burden in the α-1H subunit of the voltage-gated Ca2+ channel Cav3.2 (CACNA1H). These results provide exome-level insight into TN and implicate genetically encoded impairment of GABA signaling and neuronal ion transport in TN pathogenesis.

Familial trigeminal neuralgia - a systematic clinical study with a genomic screen of the neuronal electrogenisome.

ObjectiveThis cross-sectional study examined, for the first time, a large cohort of patients with trigeminal neuralgia, to ascertain the occurrence of familial cases, providing a systematic description of clinical features of familial disease. Since there is evidence linking hyperexcitability of trigeminal ganglion neurons to trigeminal neuralgia, we also carried out an exploratory genetic analysis of the neuronal electrogenisome in these patients.MethodsWe recorded familial occurrence by systematically interviewing all patients with a definite diagnosis of classical or idiopathic trigeminal neuralgia. We found 12 occurrences of trigeminal neuralgia with positive family history out of 88 enrolled patients. Whole-exome sequencing was carried out in 11 patients. We concentrated on the genetic variants within a 173-gene panel, comprising channel genes encoding sodium, potassium, calcium, chloride, transient receptor potential channels, and gap junction channels. Gene expression profiles were based on published RNA sequencing datasets of rodent/human trigeminal ganglia tissues, with a focus on genes related to neuronal excitability.ResultsIn patients with familial trigeminal neuralgia, pain was more often located in the right, second division. All patients reported triggers. Four patients experienced concomitant continuous pain. Whole-exome sequencing analysis within the trigeminal ganglion electrogenisome identified 41 rare variants in ion channels, consisting of variants in sodium channels (6), potassium channels (10), chloride channels (5), calcium channels (7), transient receptor potential channels (12), and gap junction channels (1). In one patient, a previously profiled gain-of-function mutation in SCN10A (Nav1.8 p.Ala1304Thr), previously reported in painful neuropathy, was found; this variant was not present in unaffected siblings.ConclusionsOur results suggest that familial occurrence of trigeminal neuralgia is more common than previously considered. Although our results demonstrate variants in genes encoding voltage-gated ion channels and transient receptor potential channels within these patients, further study will be needed to determine their roles in the pathogenesis of trigeminal neuralgia.