Pathophysiology Of Trigeminal Neuralgia Research Articles

Trigeminal neuralgia.

Trigeminal neuralgia (TN) is a facial pain disorder characterized by intense and paroxysmal pain that profoundly affects quality of life and presents complex challenges in diagnosis and treatment. TN can be categorized as classical, secondary and idiopathic. Epidemiological studies show variable incidence rates and an increased prevalence in women and in the elderly, with familial cases suggesting genetic factors. The pathophysiology of TN is multifactorial and involves genetic predisposition, anatomical changes, and neurophysiological factors, leading to hyperexcitable neuronal states, central sensitization and widespread neural plasticity changes. Neurovascular compression of the trigeminal root, which undergoes major morphological changes, and focal demyelination of primary trigeminal afferents are key aetiological factors in TN. Structural and functional brain imaging studies in patients with TN demonstrated abnormalities in brain regions responsible for pain modulation and emotional processing of pain. Treatment of TN involves a multifaceted approach that considers patient-specific factors, including the type of TN, with initial pharmacotherapy followed by surgical options if necessary. First-line pharmacological treatments include carbamazepine and oxcarbazepine. Surgical interventions, including microvascular decompression and percutaneous neuroablative procedures, can be considered at an early stage if pharmacotherapy is not sufficient for pain control or has intolerable adverse effects or contraindications.

Causal interactions in brain networks predict pain levels in trigeminal neuralgia

Trigeminal neuralgia (TN) is a highly debilitating facial pain condition. Magnetic resonance imaging (MRI) is the main method for generating insights into the central mechanisms of TN pain in humans. Studies have found both structural and functional abnormalities in various brain structures in TN patients as compared with healthy controls. Whereas studies have also examined aberrations in brain networks in TN, no studies have to date investigated causal interactions in these brain networks and related these causal interactions to the levels of TN pain. We recorded fMRI data from 39 TN patients who either rested comfortably in the scanner during the resting state session or tracked their pain levels during the pain tracking session. Applying Granger causality to analyze the data and requiring consistent findings across the two scanning sessions, we found 5 causal interactions, including: (1) Thalamus → dACC, (2) Caudate → Inferior temporal gyrus, (3) Precentral gyrus → Inferior temporal gyrus, (4) Supramarginal gyrus → Inferior temporal gyrus, and (5) Bankssts → Inferior temporal gyrus, that were consistently associated with the levels of pain experienced by the patients. Utilizing these 5 causal interactions as predictor variables and the pain score as the predicted variable in a linear multiple regression model, we found that in both pain tracking and resting state sessions, the model was able to explain ∼36 % of the variance in pain levels, and importantly, the model trained on the 5 causal interaction values from one session was able to predict pain levels using the 5 causal interaction values from the other session, thereby cross-validating the models. These results, obtained by applying novel analytical methods to neuroimaging data, provide important insights into the pathophysiology of TN and could inform future studies aimed at developing innovative therapies for treating TN.

Monocyte to high-density lipoprotein ratio and neutrophil to lymphocyte ratio in trigeminal neuralgia patients: A retrospective cohort study

Background/Aim: Trigeminal neuralgia (TN) is a prevalent cranial nerve disorder. While inflammation has been implicated in neuropathic pain in numerous recent studies, its role in TN has remained uncertain. Given the increasing significance of neuroinflammation, this study aims to explore the association between inflammation and TN and to assess whether there are disparities in the monocyte to high-density lipoprotein ratio (MHR) and neutrophil to lymphocyte ratio (NLR) values between TN patients and healthy individuals. There is a dearth of literature concerning the link with MHR, a parameter extensively studied in cardiac research but unexplored in the context of TN. Methods: This retrospective cohort study encompassed 48 patients diagnosed with classical TN and 40 healthy controls treated at the neurology and pain clinic of Dokuz Eylül University. Demographic and clinical variables, such as age and gender, along with monocyte, neutrophil, lymphocyte, and high-density lipoprotein (HDL) levels, were retrospectively retrieved from medical records. Inflammation markers, namely MHR and NLR, were calculated. Nonparametric tests were employed to compare these markers between TN patients and healthy controls. Results: Regarding sociodemographic data, the average age of the patient group was 59.8, while that of the healthy group was 47.4. A significant age difference was observed between the patient and healthy groups (P<0.001). However, no significant differences between the groups regarding MHR or NLR values were detected. Conclusions: These findings may suggest the presence of an inflammatory process characterized by local neurogenic inflammation in the pathophysiology of TN. Further comprehensive studies are required to assess the utility of MHR as a readily applicable marker in neurological disorders with neuroinflammatory and neuropathic pain etiologies.

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.

Classifier Using Pontine Radial Diffusivity and Symptom Duration Accurately Predicts Recurrence of Trigeminal Neuralgia After Microvascular Decompression: A Pilot Study and Algorithm Description.

Preprocedure diffusion tensor magnetic resonance imaging (MRI) may predict the response of trigeminal neuralgia (TN) patients to Gamma Knife (Elekta AB) and microvascular decompression (MVD). To test this hypothesis using pontine-segment diffusion tensor MRI radial diffusivity (RD), a known biomarker for demyelination, to predict TN recurrence following MVD. RD from the pontine segment of the trigeminal tract was extracted in a semiautomated and blinded fashion and normalized to background pontine RD. Following validation against published results, the relationship of normalized RD to symptom duration (DS) was measured. Both parameters were then introduced into machine-learning classifiers to group patient outcomes as TN remission or recurrence. Performance was evaluated in an observational study with leave-one-out cross-validation to calculate accuracy, sensitivity, specificity, and receiver operating characteristic curves. The study population included 22 patients with TN type 1 (TN1). There was a negative correlation of normalized RD and preoperative symptom duration (P=.035, R2=.20). When pontine-segment RD and DS were included as input variables, 2 classifiers predicted pain-free remission versus eventual recurrence with 85% accuracy, 83% sensitivity, and 86% specificity (leave-one-out cross-validation; P=.029) in a cohort of 13 patients undergoing MVD. Pontine-segment RD and DS accurately predict MVD outcomes in TN1 and provide further evidence that diffusion tensor MRI contains prognostic information. Use of a classifier may allow more accurate risk stratification for neurosurgeons and patients considering MVD as a treatment for TN1. These findings provide further insight into the relationship of pontine microstructure, represented by RD, and the pathophysiology of TN.

Comparison of neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in patients diagnosed with trigeminal neuralgia and healthy controls

Aim: Trigeminal neuralgia (TN) is a common cranial nerve disease, but its pathogenesis has not yet been fully elucidated. The neutrophil-lymphocyte ratio (NLR) and the platelet-lymphocyte ratio (PLR) have been investigated in recent years as markers of systemic inflammation, and their determination presents as a lower-cost, more practical, and simpler method compared to other inflammation markers. This study aimed to evaluate the possible role of systemic inflammation in TN etiopathogenesis based on NLR and PLR values.Materials and Methods: The study included 55 male and female patients aged 18 to 60 years, who were diagnosed with TN at the Neurology Clinic of our university according to the criteria of Headache Classification Committee of the International Headache Society 2018 (Cephalalgia2018), and 48 healthy controls. Demographic and clinical variables, such as age and gender were retrospectively obtained from medical records.Results: In terms of sociodemographic data, both groups had similar characteristics. The NLR values were 1.84±0.81 for the patient group and 1.92±0.79 for the control group. There was no statistically significant difference in NLR between the two groups (p = 0.447). The PLR values were 101.91±30.24 and 97.84±30.24 for the patient and control groups, respectively, indicating no statistically significant difference (p = 0.439). Conclusions: The role of systemic inflammation in TN pathophysiology remains controversial. It is considered that an inflammatory process may occur in the pathophysiology of TN, but this is characterized by local neurogenic inflammation rather than the effect of a systemic inflammatory response.

Trigeminal Neuralgia: Etiology, Diagnosis, and Treatment

Trigeminal neuralgia (TN), the most common of the facial neuralgias, is an extremely debilitating disorder that is characterized by severe electric shock-like neuropathic pain that is localized to one or more branches of the trigeminal nerve. It can have a serious impact on an individual’s life and is often first encountered by dentists and general practitioners. Although a treatable and usually manageable condition, appropriate diagnosis remains a factor that plagues this disease. The objective of this article is to summarize the current literature surrounding the classification, epidemiology, presentation, and pathophysiology of TN while also including the current and evidence-based knowledge on the diagnosis and treatment options. It provides a baseline from which dental and medical colleagues alike can help manage patients suffering from this devastating neuralgia.

Improvement of Trigeminal Neuralgia Following Endoscopic Third Ventriculostomy in a Patient With Normal Pressure Hydrocephalus: A Case Report and Review of the Literature

Normal-pressure hydrocephalus (NPH) has rarely been reported to be associated with trigeminal neuralgia (TN). We report a case of NPH with trigeminal neuralgia, whose symptoms completely resolved after endoscopic third ventriculostomy. We will notify another surgical management of trigeminal neuralgia, considering the different pathophysiology of TN and a brief review of the literature.

Trigeminal Neuralgia: Role of Interventional Pain Physician

Trigeminal neuralgia (TN) or tic douloureux is one of the commonest cause of fascial pain after 50 years of age. It is characterized by recurrent, episodic, lancinating pain over the distribution of trigeminal nerve. There is a lack of certainty regarding the aetiology and pathophysiology of TN. Evidence suggests that the likely etiology is vascular compression of the trigeminal nerve leading to focal demyelination and aberrant neural discharge. Secondary causes such as multiple sclerosis or brain tumors can also produce symptomatic TN. The treatment of TN can be very challenging despite the numerous options patients and physicians can choose from. This multitude of treatment options poses the question as to which treatment fits which patient best. For patients refractory to medical therapy, Gasserian ganglion percutaneous techniques, gamma knife surgery and microvascular decompression are the most promising invasive treatment options. Among them three common interventions commonly carried out by interventional pain physician to provide pain relief are balloon compression, Glycerol rhizolysis and RF rhizotomy.
 J Shaheed Suhrawardy Med Coll, June 2019, Vol.11(1); 73-77

Primary Nongestational Ovarian Choriocarcinoma Mistaken for Ectopic Pregnancy: A Case Report

Trigeminal neuralgia (TN) or tic douloureux is one of the commonest cause of fascial pain after 50 years of age. It is characterized by recurrent, episodic, lancinating pain over the distribution of trigeminal nerve. There is a lack of certainty regarding the aetiology and pathophysiology of TN. Evidence suggests that the likely etiology is vascular compression of the trigeminal nerve leading to focal demyelination and aberrant neural discharge. Secondary causes such as multiple sclerosis or brain tumors can also produce symptomatic TN. The treatment of TN can be very challenging despite the numerous options patients and physicians can choose from. This multitude of treatment options poses the question as to which treatment fits which patient best. For patients refractory to medical therapy, Gasserian ganglion percutaneous techniques, gamma knife surgery and microvascular decompression are the most promising invasive treatment options. Among them three common interventions commonly carried out by interventional pain physician to provide pain relief are balloon compression, Glycerol rhizolysis and RF rhizotomy.
 J Shaheed Suhrawardy Med Coll, June 2019, Vol.11(1); 73-77

Different Pain States of Trigeminal Neuralgia Make Significant Changes in the Plasma Proteome and Some Biochemical Parameters: a Preliminary Cohort Study.

Trigeminal neuralgia (TN) with chronic and severe neuropathic pain leads to remarkable interference in daily living activities of patients. Unknown molecular mechanisms involved in TN pathophysiology are a challenge for complete treatment of the disease. The present study was conducted to investigate changes in the plasma proteome beside biochemical parameters, including calcitonin gene-related peptide (CGRP), nitric oxide (NO), amino acids, and vitamin D (Vit D) in different pain states in TN patients. Plasma samples were obtained from the control group (#13) and patients with purely paroxysmal type of classical TN (#13) before and after microvascular decompression (MVD). We analyzed plasma proteome using two-dimensional gel electrophoresis (2-DE) and identified altered proteins by applying MALDI-TOF/TOF mass spectrometry. The plasma levels of neurotransmitters (CGRP, NO, and amino acids) and Vit D were investigated by ELISA and liquid chromatography-tandem mass spectrometry (LC-MS/MS). The pain-rating index (PRI) was specified using a McGill pain questionnaire, which indicated a significant pain reduction after MVD. Plasma proteome analysis showed upregulated expression of transthyretin (TTR), retinol-binding protein 4 (RBP4), and alpha-1-acid glycoprotein 2 (AGP2) in TN patients compared to control group; whereas, TTR and RBP expression was downregulated after surgery. Moreover, the elevated NO and CGRP and decreased Vit D concentrations were observed in patients. After surgery, NO, Arg, Cit, and Gly levels were decreased along with pain relief. Our findings support the role of altered proteins in TN pathophysiology and suggest involvement of the evaluated neurotransmitters and Vit D in pain pathway sensitization during the disease.

Dysregulation of Pain- and Emotion-Related Networks in Trigeminal Neuralgia.

Classical trigeminal neuralgia (TN) is a severe neuropathic facial pain disorder associated with increased risks of anxiety and depression. Converging evidence suggests that chronic pain pathophysiology involves dysfunctional pain-related and emotion-related networks. However, whether these systems are also among the culprit networks for TN remains unclear. Here, we aimed to assess TN-related anatomical and functional brain anomalies in pain-related and emotion-related networks. We investigated differences in gray matter (GM) volume and the related resting-state functional connectivity (rsFC) between 29 classical TN patients and 34 matched healthy controls. Relationships between brain measurement alterations, clinical pain and emotional states were identified. A longitudinal observation was further conducted to determine whether alterations in the brain could renormalize following pain relief. Reduced GM volumes in the bilateral amygdala, periaqueductal gray (PAG) and right insula were found in TN patients compared with healthy control subjects. Whole-brain rsFC analyses with the four above-mentioned anatomical regions as seeds identified three significantly altered functional circuits, including amygdala-DLPFC, amygdala-mPFC and amygdala-thalamus/putamen circuitry. The amygdala-DLPFC and amygdala-mPFC circuits were associated with clinical pain duration and emotional state ratings, respectively. Further longitudinal analysis found that rsFC strength abnormalities in two fronto-limbic circuits (left amygdala/left DLPFC and right amygdala/right PFC) were resolved after pain relief. Together, structural and functional deficits in pain-related and emotion-related networks were associated with TN patients, as demonstrated by our multimodal results. Pain relief had protective effects on brain functional connectivity within fronto-limbic circuits. Our study provides novel insights into the pathophysiology of TN, which may ultimately facilitate advances in TN intervention.

A technique to assess perineuronal mediators

Perineural activity of a variety of inflammatory and immune system mediators can activate peripheral nerves leading to the perception of pain. One example of such effects includes the activity of interleukin 1 beta (IL-1β); this inflammatory mediator, upon binding to IL-1R1 neuronal membrane receptors will rapidly induce protein kinases in damage-sensing neurons, consequently altering heat-activated ionic inward currents leading to increased neuronal sensitivity to harmful heat. The ability to detect such mediators in proximity to sensory nerves is therefore crucial to investigating the contributing roles of inflammation in human chronic pain. To date there is no recognized method to assess mediator profiles around human sensory nerve roots in vivo. A novel method is described that can assess these mediators in the human trigeminal system where the nerve leaves the brain stem in its pre-ganglionic portion. Mediator levels are shown to change between sample locations on the trigeminal nerve root in patients with trigeminal neuralgia. This methodology may therefore be used to shed insights as to the pathophysiology of trigeminal neuralgia, which may in turn influence clinical decisions concerning the natural history, and treatment options.

Structural and functional abnormalities of the insular cortex in trigeminal neuralgia: a multimodal magnetic resonance imaging analysis.

Trigeminal neuralgia (TN) is a chronic neuropathic pain disorder characterized by intense, lancinating attacks of facial pain. Increasing evidence suggests that TN is accompanied by abnormalities in brain morphology, white matter microstructure, and function. However, whether these abnormalities are linked or reflect independent etiologies remains unknown. Using multimodal magnetic resonance imaging data of 20 patients with TN and 21 healthy controls, we investigated cortical gyrification abnormalities, their relationships with abnormalities of the underlying white matter microstructure and gray matter morphology, as well as their functional significance in TN. Compared with controls, patients with TN showed significant local gyrification index (LGI) reductions predominantly in the left insular cortex, which were negatively correlated with pain intensity. In this cluster, patients with TN had concurrent cortical thickness reductions but unaltered cortical surface area. Meanwhile, LGI of this cluster was not correlated with overlying cortical thickness or surface area but was positively correlated with the fractional anisotropy of 2 nearby white matter clusters, suggesting that insular LGI reductions may be primarily driven by microstructural abnormalities of the underlying white matter tracts, rather than by abnormalities in cortical thickness and surface area. In addition, patients with TN exhibited increased insula functional connectivity to the left posterior cingulate cortex and thalamus, which was positively correlated with disease duration. These findings provide new evidence for the involvement of insular abnormalities in the pathophysiology of TN.

S66 Pathophysiological implications and current evidence for the treatment of trigeminal neuralgia

Aim Appreciate how current understanding of the pathophysiology of trigeminal neuralgia has impacted on treatments. The ignition theory puts forward the hypothesis that some form of trauma to the trigeminal nerve at any level results in abnormal firing of neurons which result in episodic pain. It is likely that patients with trigeminal neuralgia have some form of abnormality of their sodium channels. Currently the most effective medications are sodium channel blockers whereas other drugs such as opioids whose mode of action is different are not effective. Current drugs act centrally and so result in significant side effects especially cognitive ones which often result in cessation of the medication. The episodic nature of the disorder also means patients can stop their medication for weeks or months and have no pain attacks. However if pain is poorly controlled or quality of life is significantly affected then surgical options can be utilised. It is postulated that pressure from a significant artery in the root entry zone leads to demyelination and consequently allows for ectopic impulses to be generated. Separating the vessel from the trigeminal nerve can lead to complete resolution of pain in 70% of cases for ten years. However some of the impulses may be generated at the Gasserian ganglion level and so destructive procedures at that level result in pain relief for an average of five years. These do however result in sensory changes.

The effectiveness of percutaneous balloon compression in the treatment of trigeminal neuralgia in patients with multiple sclerosis.

Trigeminal neuralgia (TN) is more common in multiple sclerosis (MS) patients than in the general population and among the former has an incidence of approximately 2%. The pathophysiology of TN in MS patients is believed to be caused by a demyelinating plaque at the root entry zone, and therefore procedures that cause direct nerve damage are thought to be the most effective surgical modality. The authors aimed to compare the efficacy of percutaneous balloon compression (PBC) in TN patients with and without MS. Retrospectively collected clinical data on 80 consecutive patients who underwent 144 procedures and who received PBC for TN treatment between January 2000 and January 2010 were analyzed. The cohort included 17 MS and 63 non-MS patients. The mean age at first operation was significantly younger in the MS group compared with the non-MS group (59 years vs 72 years, respectively, p < 0.0001). After a mean follow-up of 43 months (MS group) and 25 months (non-MS group), the symptom recurrence rate following the first operation was higher in the MS group compared with that in the non-MS group (86% vs 47%, respectively, p < 0.01). During long-term follow-up, more than 70% of MS patients required multiple procedures compared with only 44% of non-MS patients. Excellent or satisfactory outcomes were not significantly different between the MS and non-MS cohorts, respectively, at 1 day postoperatively (82% vs 91%, p = 0.35), 3 months postoperatively (65% vs 81%, p = 0.16), and at last follow-up (65% vs 76%, p = 0.34). A similar incidence of postoperative complications was observed in the 2 groups. PBC is effective in the treatment of trigeminal neuralgia in patients with MS, but, compared with that in non-MS patients, symptom recurrence is higher and requires multiple procedures.

Treatment Options in Trigeminal Neuralgia an Update

Trigeminal neuralgia(TN) is a severe unilateral paroxys¬mal facial pain that causes intense distress and often compromises the quality of life of the patient. The aetiology and pathophysiology of TN is still not clear. Numerous treatment options for TN are available. Medical therapy is the first choice and surgical modalities are used only when medical therapy fails. The challenge lies in assessing and selecting the treatment which best fits each patient. This article reviews the various treatment options available for trigeminal neuralgia.

Gray matter volume reduction reflects chronic pain in trigeminal neuralgia

Trigeminal neuralgia (TN) is supposedly caused by an ectatic blood vessel affecting the trigeminal nerve at the root entry zone of the brain stem. Recent evidence suggests an additional central component within trigeminal pain-processing in the pathophysiology of TN. Therefore, we aimed to identify specific brain regions possibly associated with the development or maintenance of TN using magnetic resonance imaging (MRI) voxel-based morphometry (VBM). Sixty patients with classical TN were compared to 49 healthy controls. Eighteen patients had TN with concomitant constant facial pain, a condition previously described as a predictor of worse treatment outcome. We found gray matter (GM) volume reduction in TN patients compared to healthy controls in the primary somatosensory and orbitofrontal cortices, as well as the in the secondary somatosensory cortex, thalamus, insula, anterior cingulate cortex (ACC), cerebellum, and dorsolateral prefrontal cortex. GM volume decrease within the ACC, parahippocampus, and temporal lobe correlated with increasing disease duration in TN. There were no differences comparing patients with and without concomitant constant facial pain. No GM increase was found comparing patient subgroups with each other and with healthy controls. The observed changes probably reflect the impact of multiple, daily attacks of trigeminal pain in these patients similar to what was previously described in other chronic pain conditions and may be interpreted as adaptation mechanism to chronic pain in regard to neuronal plasticity. The ACC, parahippocampus and temporal lobe volume reduction in parallel with disease duration may point to a pivotal role of these structures in chronic pain.

Trigeminal neuralgia and persistent idiopathic facial pain

Trigeminal neuralgia (TN) and persistent idiopathic facial pain (PIFP) are two of the most puzzling orofacial pain conditions and affected patients often are very difficult to treat. TN is characterized by paroxysms of brief but crucial pain, followed by asymptomatic periods without pain. In some patients a constant dull background pain may persist. This constant dull pain sometimes makes the distinction from PIFP difficult. PIFP is defined as continuous facial pain, typically localized in a circumscribed area of the face, which is not accompanied by any neurological or other lesion identified by clinical examination or clinical investigations. The pain usually does not stay within the usual anatomic boundaries of the trigeminal nerve distribution and is a diagnosis of exclusion. Epidemiologic evidence on TN and even more so on PIFP is quite scarce, but generally both conditions are considered to be rare diseases. The aetiology and underlying pathophysiology of TN and more so PIFP remain unknown. Treatment is based on only few randomized controlled clinical trials and insufficiently evaluated surgical procedures.

Trigeminal neuralgia and persistent idiopathic facial pain

Trigeminal neuralgia (TN) and persistent idiopathic facial pain (PIFP) are two of the most puzzling orofacial pain conditions and affected patients are often very difficult to treat. TN is characterized by paroxysms of brief but severe pain followed by asymptomatic periods without pain. In some patients a constant dull background pain may persist. This constant dull pain sometimes makes the distinction from PIFP difficult. PIFP is defined as continuous facial pain, typically localized in a circumscribed area of the face, which is not accompanied by any neurological or other lesion identified by clinical examination or clinical investigations. The pain usually does not stay within the usual anatomic boundaries of the trigeminal nerve distribution and is a diagnosis of exclusion. Epidemiologic evidence on TN, and even more so on PIFP, is quite scarce, but generally both conditions are considered to be rare diseases. The etiology and underlying pathophysiology of TN, and more so PIFP, remain unknown. Treatment is based on only few randomized controlled clinical trials and insufficiently evaluated surgical procedures.