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Background: Calcitonin gene-related peptide (CGRP) is part of the calcitonin peptide family, which includes calcitonin (CT), amylin (AMY), and adrenomedullin (ADM). CGRP and its receptor are highly present in the trigeminovascular system (TVS). Recent research suggests that other members of the calcitonin family could be feasible therapeutic targets in the treatment of migraine. The present study aims to elucidate the distribution of ADM, AMY, CT, and their receptors in the rat TVS, and to explore potential sex differences in their expression. Methods: Trigeminal ganglia (TG) were dissected from male and female adult rats. Protein and gene expression were assessed through immunohistochemistry and RT-qPCR. Additionally, the dura mater was isolated for further investigation of protein expression and fiber localization using immunohistochemistry. Results: Quantitative gene expression analysis revealed the presence of all genes in male and female TGs, except for calcitonin receptor (CTR). Notably, CGRP mRNA levels in TG were several folds higher than those of other genes. The receptor activity-modifying protein-1 (RAMP1) mRNA levels were significantly higher in female compared to male. No AMY or CT immunoreactivity was observed in the TVS. In contrast, immunoreactivity for ADM, CGRP, RAMP1, CTR, and calcitonin-like receptor (CLR) were observed in the cytoplasm of TG neurons. Immunoreactive Aδ-fibers storing RAMP1, ADM and CLR were also identified. RAMP2 and RAMP3 were expressed in nucleus of TG neurons and in satellite glial cells. Furthermore, RAMP1 and CLR were co-localized with CASPR in the nodes of Ranvier located in Aδ-fibers. Conclusions: This study provides valuable insights into the distribution of the CGRP family of peptides and their receptors in the TVS. CGRP mRNA levels in the TG were markedly higher than those of other genes, demonstrating the key role of CGRP. The co-localization of CLR and RAMP1 on Aδ-fibers with CASPR suggests a potential role for this receptor in modulating trigeminal nerve function and neuronal excitability, with implications for migraine pathophysiology. Additionally, RAMP1 mRNA levels were significantly higher in female TG compared to males, indicating sex-specific differences in gene expression. These findings underscore the need for further research into the functional significance of gender-related variations. [ABSTRACT FROM AUTHOR]

Background and purpose: Trigeminal neuralgia (TN) is a severe chronic pain condition, typically affecting patients over 50-year-old, caused by the compression of the nerve at the root entry zone (REZ) by blood vessels. While the diagnosis is clinical, advanced imaging like diffusion tensor imaging (DTI) is crucial to identify underlying causes and assessing nerve damage. DTI may help develop neuroimaging markers to improve understanding of TN and predict surgical outcomes. The goal of the present systematic review is to evaluate the effectiveness of DTI and tractography in order to better assess treatment planning and outcome prediction through the analysis of trigeminal nerve alterations. Methods: The authors conducted a systematic review and meta-analysis of the literature to compare radiological parameters identified in pre- and post-operative MRI with DTI sequences, including fractional anisotropy (FA), quantity of anisotropy (QA), radial diffusivity (RD), and to correlate these findings with post-operative clinical outcomes. A comprehensive search of the PubMed and Scopus databases was carried out for studies published between April 2010 and January 2024. Results: This review included 11 studies and 603 patients. Of the 363 patients with trigeminal neuralgia (TN), 193 underwent microvascular decompression (MVD), with 72.5% showing clinical improvement and 27.5% not improving, possibly due to chronic nerve damage. Four studies assessed radiological parameters before and after MVD, while two focused only on post-MVD data. The mean fractional anisotropy (FA) in affected nerves increased from 0.328 before MVD to 0.382 afterward. Five studies did not report postoperative outcomes, just comparing radiological parameters in TN patients versus healthy controls. Conclusions: Recent studies show that MRI-DTI parameters, including FA, RD, and QA, are useful for diagnosing trigeminal neuralgia and predicting treatment outcomes. Lower FA and higher RD values indicate better results after surgery. More research is mandatory to guide treatment decisions and enhance patients' care. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to develop a clinical-radiomics nomogram to predict the long-term outcomes of patients with classical trigeminal neuralgia (CTN) following microvascular decompression (MVD). Materials and methods: This retrospective study included 455 patients with CTN who underwent MVD from three independent institutions A total of 2030 radiomics features from the cistern segment of the trigeminal nerve were extracted computationally from the three-dimensional steady-state free precession and three-dimensional time-of-flight magnetic resonance angiography sequences. Using the least absolute shrinkage and selection operator regression, 16 features were chosen to develop radiomics signatures. A clinical-radiomics nomogram was subsequently developed in the development cohort of 279 patients via multivariate Cox regression. The predictive performance and clinical application of the nomogram were assessed in an external cohort consisting of 176 patients. Results: Sixteen highly outcome-related radiomics features extracted from multisequence images were used to construct the radiomics model, with concordance indices (C-index) of 0.804 and 0.796 in the development and test cohorts, respectively. Additionally, a clinical-radiomics nomogram was developed by incorporating both radiomics features and clinical characteristics (i.e., pain type and degree of neurovascular compression) and yielded higher C-indices of 0.865 and 0.834 in the development and test cohorts, respectively. K‒M survival analysis indicated that the nomogram successfully stratified patients with CTN into high-risk and low-risk groups for poor outcomes (hazard ratio: 37.18, p < 0.001). Conclusion: Our study findings indicated that the clinical-radiomics nomogram exhibited promising performance in accurately predicting long-term pain outcomes following MVD. Clinical relevance statement: This model had the potential to aid clinicians in making well-informed decisions regarding the treatment of patients with CTN. Key Points: Trigeminal neuralgia recurs in about one-third of patients after undergoing MVD. The clinical-radiomics nomogram stratified patients into high- and low-risk groups for poor surgical outcomes. Using this nomogram could better inform patients of recurrence risk and allow for discussion of alternative treatments. [ABSTRACT FROM AUTHOR]

Background: In addition to its critical role in neurogenesis, brain-derived neurotrophic factor (BDNF) modulates pain and depressive behaviors. Methods: In a translational perspective, we tested the anti-migraine activity of highly purified and characterized recombinant human BDNF (rhBDNF) in an animal model of cephalic pain based on the chronic and intermittent NTG administration (five total injections over nine days), used to mimic recurrence of attacks over a given period. To achieve this, we assessed the effects of two doses of rhBDNF (40 and 80 µg/kg) administered intranasally to adult male Sprague–Dawley rats, on trigeminal hyperalgesia (by orofacial formalin test), gene expression (by rt-PCR) of neuropeptides and inflammatory cytokines in specific areas of the brain related to migraine pain. Serum levels of CGRP, PACAP, and VIP (by ELISA) were also evaluated. The effects of rhBDNF were compared with those of sumatriptan (5 mg/kg i.p), administered 1 h before the last NTG administration. Results: Both doses of rhBDNF significantly reduced NTG-induced nocifensive behavior in Phase II of the orofacial formalin test. The anti-hyperalgesic effect of intranasal high-dose rhBDNF administration in the NTG-treated animals was associated with a significant modulation of mRNA levels of neuropeptides (CGRP, PACAP, VIP) and cytokines (IL-1beta, IL-10) in the trigeminal ganglion, medulla-pons, and hypothalamic area. Of note, the effects of rhBNDF treatment were comparable to those induced by the administration of sumatriptan. rhBDNF administration at both doses significantly reduced serum levels of PACAP, while the higher dose also significantly reduced serum levels of VIP. Conclusions: The findings suggest that intranasal rhBDNF has the potential to be a safe, non-invasive and effective therapeutic approach for the treatment of primary headache, particularly migraine. [ABSTRACT FROM AUTHOR]

Background: Glossopharyngeal neuralgia (GN) is a rare pain syndrome often underdiagnosed. This study aimed to assess the challenges in diagnosing GN and identify patients at risk of misdiagnosis. Methods: Between 2010 and 2019, nine patients underwent microvascular decompression (MVD) of the glossopharyngeal nerve at two tertiary care hospitals. A retrospective analysis examined symptom characteristics, time to correct diagnosis, operative technique, and clinical outcomes. Barrow Neurological Institute (BNI) pain scores were assessed before surgery and on follow-up. Results: Six women and three men, aged 55 ± 14.3 years, with unilateral GN were included. Pain was predominantly in the ear (otalgic type) in four patients (44.4%), the pharynx or base of the tongue (pharyngeal type) in four (44.4%), and mixed in one (11.1%). Five patients reported pain radiating to the mandible, all initially misdiagnosed with trigeminal neuralgia (TN) and treated for 2.4(± 3.1) years before presenting to our institution. One case resulted in MVD of the trigeminal nerve and subsequent thermocoagulation of the Gasserian ganglion due to persistent pain. The correct diagnosis of GN was established later in patients with otalgic or mixed pain (3.8 ± 3.4 years) compared to those with pharyngeal pain (0.5 ± 1.0 years), showing a trend (U = 17.0, p = 0.07). There was a significant association between pain radiation to the mandible and misdiagnosis (x2 = 9.00, p = 0.003). Endoscopically assisted MVD via the median suboccipital subtonsillary approach was performed, resolving neurovascular conflicts with the PICA (9/9) and vertebral artery (3/9). Follow-up after 15.7(± 18.2) months showed significant pain reduction according to the BNI (preoperative BNI = 5.0 ± 0.0, postoperative BNI = 1.7 ± 1.0,t (8) = 10,CI [1.6–5.1], p < 0.001). No permanent surgery-related deficits occurred. Conclusion: Patients with GN, especially those with predominant otalgic pain and pain radiating to the mandible, are at higher risk of misdiagnosis due to similarities with TN. Despite the rarity of GN, increased awareness of its various pain manifestations may lead to earlier correct diagnoses, which is crucial for surgical treatment. [ABSTRACT FROM AUTHOR]

This retrospective study examined the clinical outcomes and complications in 6 cases of compound Meige's syndrome, presenting with blepharospasm and masticatory muscle spasm, following treatment with CT-guided radiofrequency ablation targeting bilateral facial nerves and mandibular branches of the trigeminal nerve. After the operation, the symptoms of eyelid spasm and masticatory muscle spasm resolved, but mild facial paralysis and numbness of mandibular nerve innervation persisted. Follow-up for 4–28 months showed that the symptoms of facial paralysis resolved within 2–5 (3.17 ± 0.94) months after the operation, whereas the numbness in the mandibular region persisted, accompanied by a decrease in masticatory function. During the follow-up period, none of the 6 patients experienced a recurrence of Meige's syndrome. These findings suggest that CT-guided radiofrequency ablation of the bilateral facial nerve and mandibular branches of the trigeminal nerve may offer a promising approach to treating compound Meige's syndrome. [ABSTRACT FROM AUTHOR]

One mechanism by which transcranial direct current stimulation (tDCS) has been proposed to improve attention is by transcutaneous stimulation of cranial nerves, thereby activating the locus coeruleus (LC). Specifically, placement of the electrodes over the frontal bone and mastoid is thought to facilitate current flow across the face as a path of least resistance. The face is innervated by the trigeminal nerve, and the trigeminal nerve is interconnected with the LC. In this study, we tested whether stimulating the trigeminal nerve impacts indices of LC activity and performance on a sustained attention task. We replicated previous research that shows deterioration in task performance, increases in the rate of task-unrelated thoughts, and reduced pupil responses due to time on task irrespective of tDCS condition (sham, anodal, and cathodal stimulation). Importantly, tDCS did not influence pupil dynamics (pretrial or stimulus-evoked), self-reported attention state, nor task performance in active versus sham stimulation conditions. The findings reported here are consistent with theories about arousal centered on a hypothesized link between LC activity indexed by pupil size, task performance, and self-reported attention state but fail to support hypotheses that tDCS over the trigeminal nerve influences indices of LC function. [ABSTRACT FROM AUTHOR]

Background: Chronic migraine is closely related to the dysregulation of neurochemical substances in the brain, with metabolic imbalance being one of the proposed causes of chronic migraine. This study aims to evaluate the metabolic changes between energy metabolism and excitatory and inhibitory neurotransmitters in key brain regions of mice with chronic migraine-like state and to uncover the dysfunctional pathways of migraine. Methods: A chronic migraine-like state mouse model was established by repeated administration of nitroglycerin (NTG). We used von Frey filaments to assess the mechanical thresholds of the hind paw and periorbital in wild-type and familial hemiplegic migraine type 2 mice. After the experiments, tissue was collected from five brain regions: the somatosensory cortex (SSP), hippocampus, thalamus (TH), hypothalamus, and the spinal trigeminal nucleus caudalis (TNC). Proton magnetic resonance spectroscopy (1H-MRS) was employed to study the changes in brain metabolites associated with migraine, aiming to explore the mechanisms underlying metabolic imbalance in chronic migraine-like state. Results: In NTG-induced chronic migraine-like state model, we observed a significant reduction in energy metabolism during central sensitization, an increase in excitatory neurotransmitters such as glutamate, and a tendency for inhibitory neurotransmitters like GABA to decrease. The TNC and thalamus were the most affected regions. Furthermore, the consistency of N-acetylaspartate levels highlighted the importance of the TNC-TH-SSP pathway in the ascending nociceptive transmission of migraine. Conclusion: Abnormal energy metabolism and neurotransmitter imbalance in the brain region of NTG-induced chronic migraine-like state model are crucial mechanisms contributing to the chronicity of migraine. [ABSTRACT FROM AUTHOR]

Objective: Trigeminal schwannomas are rare benign tumors originating from the Schwann cells of the trigeminal nerve. Despite the common occurrence of trigeminal neuropathy in trigeminal schwannomas, a detailed analysis has not yet been performed because of the rarity of this disease. This study aimed to analyze trigeminal neuropathy in trigeminal schwannoma resection and identify the risk factors for postoperative worsening of trigeminal neuropathy. Methods: A retrospective analysis of 86 surgical cases was performed at our institution between 1975 and 2018. Obtained parameters included age, sex, diagnosis, reoperation, tumor size, tumor location, presence or absence of cysts, surgical approach, degree of tumor removal, and pre/postoperative trigeminal neuropathy. Uni- and multivariate analyses were performed to identify the risk factors for worsening postoperative sensory disturbances. Results: Of 83 patients, 58.1% had preoperative trigeminal neuropathy. Postoperative sensory disturbance occurred in 27.9%, with worsening in two cases and de novo symptoms in 22 cases. Regarding risk factors for worsening postoperative sensory disturbances, older age, smaller tumor size, middle and posterior (MP) type, gross total removal (GTR), and anterior transpetrosal approach were identified in the univariate analysis, while MP type and GTR were identified in the multivariate analysis. Conclusions: This study analyzed trigeminal neuropathy in trigeminal schwannomas in detail and identified tumor location and removal rate as risk factors for worsening postoperative sensory disturbances. Treatment strategies to reduce the risk of trigeminal neuropathy should be considered. [ABSTRACT FROM AUTHOR]

Background: Cranial neuropathy is a principal disease manifestation of neurosarcoidosis, but many forms remain poorly described, including trigeminal nerve disease despite its frequency in reported cohorts (5–12%). Herein, we characterize the clinical course of patients with neurosarcoidosis involving the trigeminal nerve. Methods: A single-center retrospective cohort analysis of patients with biopsy-proven sarcoidosis involving the trigeminal nerve was conducted between 1/1/2000-3/7/2023. Results: The trigeminal nerve was affected in 14/245 (5.7%) patients, being clinically symptomatic in 5/245 (2.0%) and asymptomatic with radiographic involvement in 9/245 (3.7%). 14/14 (100.0%) patients had systemic sarcoidosis. In the symptomatic group, trigeminal neuropathy was an inaugural feature in 4/5 (80.0%), unilateral in 5/5 (100.0%) with the V1 subdivision most affected (4/5, 80.0%), and associated with neuralgia in 2/5 (40.0%). On MRI, the cisternal nerve roots (9/14, 64.3%), Meckel's cave (7/14, 50.0%), and cavernous sinus (5/14, 35.7%) were most commonly affected, and 14/14 (100.0%) patients had extra-trigeminal neuroinflammation on cranial MRI. CSF was abnormal in at least one dimension in 11/12 (91.7%) tested. All three treated patients with symptomatic trigeminal neuropathy responded to immunomodulatory treatment, and symptomatic treatments for trigeminal neuralgia were helpful in two patients. After a median follow-up period of 63 months, the median modified Rankin scale score was 1 for both subgroups. Conclusion: Neurosarcoidosis may involve any portion of the trigeminal apparatus, and when affected, it frequently demonstrates a mismatch in radiographic involvement from its clinical manifestations of facial numbness and pain, and typically occurs in association with other clinical or radiographic manifestations of neurosarcoidosis. [ABSTRACT FROM AUTHOR]

Introduction: Conditioned pain modulation (CPM) is a quantitative estimation of the capacity for endogenous pain modulation. Reduced CPM enables chronic painful event development or exacerbates pre-existing pain symptoms. Emerging reports indicate that patients with trigeminal neuralgia (TN) have dysregulated endogenous pain modulation. Transauricular vagus nerve stimulation (taVNS) is known to alleviate both acute and chronic pain symptoms. Its role in modulation or management of TN remains unknown. Here, we evaluated the taVNS efficacy in modulating CPM among TN patients. Conclusions from this investigation may facilitate establishment of novel non-invasive adjunctive approaches to treating TN patients. Methods: All research work was conducted at the First Affiliated Hospital of the University of Science and Technology of China (Anhui Provincial Hospital). In all, we recruited 62 study participants, 31 TN patients and 31 healthy volunteers, for a 2-day experimental test. At the beginning of the experiment (Day 1), all subjects received 30 min of active taVNS. On Day 2, they received sham taVNS with the same duration and intensity. Meanwhile, technicians documented participant pressure pain thresholds (PPT) and CPM values at baseline, and at 15 and 30 min post-active or sham taVNS. Results: A 30-min active taVNS exposure substantially elevated the PPT and CPM effect (P < 0.05) among TN patients, and we also observed a notable rise in the PPT and CPM effect (P < 0.05) among healthy controls. Additionally, there were no serious adverse events from the administered treatment. Conclusion: Exposure to 30 min of active taVNS strongly augmented the CPM effect and elevated the PPT among TN patients and healthy controls. These effects were not observed with sham stimulation. Despite the limitations inherent to survey studies, such as duration and compliance biases, we consider that taVNS is a promising, safe, and cost-effective therapy. In future investigations, we recommend assessment of long-term taVNS application and its effects on CPM and clinical pain. Trial Registration: ChiCTR2300078673 (www.Chictr.org.cn). [ABSTRACT FROM AUTHOR]

Background: Percutaneous balloon compression (PBC) is an effective, low-cost, and simple treatment for primary trigeminal neuralgia (TN). However, PBC has poor efficacy and no better solution for the third branch (V3) of TN. Methods: Clinical data of 52 patients with trigeminal neuralgia treated with PBC were retrospectively analyzed. Postoperative numbness of the patient was evaluated by facial numbness at the Barrow Neurological Institute (BNI-N). The main observation was the incidence of higher numbness in the V3 than in the other two branches or equally strong numbness in the three branches in the immediate postoperative period. Results: The efficacy values in the pear-shaped balloon group at the first postoperative day (T1), the first month (T2), in the third month (T3), and the sixth month (T4) were 96.7%, 93.3%, 93.3%, and 90%, respectively, and 1 patient (3.3%) had recurrence. The efficacy value for the extracapsular capsule group was 95.5% at all times and there were no patients with recurrence within 6 months after surgery. In the immediate postoperative period, the effective compression rate of V3 in the pear-shaped balloon group was 43.3%, and 86.4% in the extracapsular capsule group (P = 0.020). At six months of follow-up, the effective compression rate of V3 was higher in the extracapsular capsule group than in the pear-shaped balloon group. Conclusions: The riveted structure of the extracapsular capsule can effectively compress V3, thus performing PBC with a balloon shaped as an extracapsular capsule is a new, effective, and safe treatment option for TN V3. Trial registration: ClinicalTrials.gov ChiCTR2300067313. [ABSTRACT FROM AUTHOR]

Background: Orally administered second-generation gepants are effective for the treatment of migraine. The intranasal administration of the third-generation gepant zavegepant might have additional benefits including a rapid onset of action, but it is not clear yet to which extent this has clinical relevance. Methods: We examined the effect of zavegepant on the relaxations induced by calcitonin gene-related peptide (CGRP) in human isolated middle meningeal arteries. Furthermore, we connected the pharmacodynamics and pharmacokinetics of gepants by combining data from clinical and basic research. Results: We showed that 10 nM zavegepant potently antagonized the functional response to CGRP. We also showed that all gepants are effective at inhibiting functional responses to CGRP at their therapeutic plasma concentrations. Conclusions: The relatively low predicted potency of zavegepant to inhibit CGRP-induced relaxation at therapeutic systemic plasma concentrations may point to the relevance of local delivery to the trigeminovascular system through intranasal administration. This approach may have additional benefits for various groups of patients, including overweight patients. [ABSTRACT FROM AUTHOR]

Purpose: The trigeminocardiac reflex (TCR) has traditionally been characterized by a sudden decrease in heart rate, asystole, or hypotension during the manipulation of the trigeminal nerve (MTN) or its branches. While this classical TCR is well-documented, there is limited literature on alternative forms of TCR, such as the development of intraoperative hypertension (HTN) or tachycardia, and the underlying pathogenesis. Furthermore, a gap exists in understanding the correlation between intraoperative blood pressure readings and postoperative outcomes, particularly regarding pain relief in patients with trigeminal neuralgia (TN). Our study aims to examine intraoperative blood pressure trends during microvascular decompression (MVD) for TN and assess their impact on postoperative outcomes. Methods: We selected 90 patients who underwent MVD for TN treatment. Blood pressure and heart rate were recorded both preoperatively and during the procedure, specifically during the MTN period, using an arterial line. The Barrow Neurological Institute (BNI) Pain Scale was calculated for all patients both pre- and post-operatively to evaluate pain relief after surgery. Results: The mean age of the patients was 61.0 ± 12.35 years, with 64.4% being females. Classical TCR (hypotension) was observed in only 2.2% of patients, whereas 80% of patients developed hypertension (≥ 140/90) during MTN. The mean preoperative systolic blood pressure was 128 ± 22.25, and the mean intraoperative systolic blood pressure during MTN was 153.1 ± 20.2. An analysis of covariance, utilizing either preoperative BNI or duration of symptoms as covariate variables, revealed a statistically significant association between intraoperative HTN and postoperative BNI. A linear regression model demonstrated that intraoperative HTN following MTN significantly predicted a lower postoperative BNI score (p = 0.006). Conclusions: Intraoperative HTN during MTN, an observed yet underexplored phenomenon, demonstrated a correlation with improved postoperative outcomes. Furthermore, it is recommended to conduct additional investigations into potential neurovascular conflicts in patients not manifesting intraoperative HTN following MTN. A comprehensive understanding of TCR, encompassing its various forms, is vital for optimizing surgical management. This study underscores the imperative for further research to unravel the mechanisms linking intraoperative HTN to surgical outcomes in TN patients. [ABSTRACT FROM AUTHOR]

Background: The present systematic review intended to evaluate the current evidence on the modalities used for treating iatrogenic late paresthesia in the oral tissues innervated by the mandibular branch of the trigeminal nerve. Main text: As a common side effect of dental procedures, paresthesia can exert a profound adverse effect on patients' quality of life. The inferior alveolar nerve (IAN) and lingual nerve (LN) have the highest chance of injury during several dental procedures, including mandibular orthognathic surgeries, implant placement, extraction of the third molar, anesthetic injections, flap elevation, and endodontic treatments. Moreover, several methods have been proposed for treating iatrogenic late paresthesia, including photobiomodulation (PBM), microsurgery, medication, and close observation until achieving spontaneous recovery of sensation. However, no gold standard treatment for iatrogenic paresthesia has been agreed upon up to now. The present study included a comprehensive search of the databases of PubMed, Embase, Scopus, and Web of Science up to December 04, 2023, resulting in a total of 3122 related studies. Then, the titles, abstracts, and full texts of the studies were evaluated. Ultimately, seven controlled randomized trials (RCTs) were included in the final analysis. Also, the risk of bias was assessed using the Joanna Briggs Institute (JBI) critical appraisal checklist. Among all fields, randomization, allocation concealment, and data analysis were found to have the highest chance of bias in the included studies. Conclusions: In conclusion, PBM, vitamin B12, and corticosteroids could accelerate the recovery of late paresthesia. However, considering the low sample size of the included studies and the high risk of methodological bias, it is recommended to perform further RCTs with robust study designs following Good Clinical Practice (GCP) guidelines to achieve more reliable results. [ABSTRACT FROM AUTHOR]

Background: Pediatric headache is an increasing medical problem that has adverse effects on children's quality of life, academic performance, and social functioning. Children with primary headaches exhibit enhanced sensory sensitivity compared to their healthy peers. However, comprehensive investigations including multimodal sensory sensitivity assessment are lacking. This study aimed to compare sensory sensitivity of children with primary headaches with their healthy peers across multiple sensory domains. Methods: The study included 172 participants aged 6 to 17 years (M = 13.09, SD = 3.02 years; 120 girls). Of these 80 participants were patients with migraine, 23 were patients with tension-type headache, and 69 were healthy controls. The following sensory measures were obtained: Mechanical Detection Threshold (MDT), Mechanical Pain Threshold (MPT), Mechanical Pain Sensitivity (MPS), detection and pain threshold for Transcutaneous Electrical Nerve Stimulation (TENS), olfactory and intranasal trigeminal detection threshold, and odor identification ability. Sensory sensitivity was compared between groups with a series of Kruskal-Wallis tests. Binomial regression models were used to compare the relative utility of sensory sensitivity measures in classifying participants into patients and healthy controls, as well as into patients with migraine and tension-type headache. Results: Patients with migraine had lower MPT measured at the forearm than patients with tension-type headaches and healthy controls. MPS was higher in patients with migraine than in healthy controls. All patients with headaches had lower detection threshold of TENS and higher olfactory sensitivity. Healthy controls showed increased intranasal trigeminal sensitivity. Scores in MPS, TENS, and olfactory and trigeminal thresholds were significantly predicting presence of primary headaches. Additionally, scores in MPT, olfactory and trigeminal threshold were positive predictors of type of headache. Conclusions: Children with primary headaches exhibit different sensory profiles than healthy controls. The obtained results suggest presence of increased overall, multimodal sensitivity in children with primary headaches, what may negatively impact daily functioning and contribute to further pain chronification. Trial registration: The study was registered in the German Registry of Clinical Trials (DRKS) DRKS00021062. [ABSTRACT FROM AUTHOR]

Immunoglobulin G4 (IgG4)-related disease is a clinical entity characterized by elevated serum IgG4 concentrations and infiltration of IgG4-immunopositive plasmacytes in various organs, including ophthalmic lesions. Diagnostic criteria for IgG4-related ophthalmic disease (IgG4-ROD) were established in 2014 and describe the most affected ocular adnexal tissues such as lacrimal glands, trigeminal nerves and extraocular muscles, but do not mention optic neuropathy, the most severe indication of ophthalmic lesions. We reviewed published case reports of optic neuropathy in IgG4-related disease (n = 44), and in many cases, decreased visual acuities recovered well following treatment such as systemic corticosteroids, rituximab, and orbital surgery. However, some patients did not recover, especially when pretreatment visual acuities were as low as light perception or less. Herein, we propose a 2023 revised diagnostic criteria for IgG4-ROD, which include a reminder not to overlook optic neuropathy. The 2014 diagnostic criteria specify mucosa-associated lymphoid tissue (MALT) lymphoma as an important differential diagnosis for the relationship between IgG4-ROD and orbital lymphoma. The 2023 revision directs physicians' attention toward lymphomas other than MALT lymphoma, considering that the 2014 criteria might have placed too much emphasis on MALT lymphoma. [ABSTRACT FROM AUTHOR]

Background: Neurosarcoidosis is rare, and among its manifestations, nerve root involvement has been reported in only a few cases. Therefore, magnetic resonance imaging (MRI) findings of neurosarcoidosis, particularly those involving nerve roots, are scarce in the literature. Methods: We presented the case of neurosarcoidosis involving cervical nerve roots and cranial nerves, alongside a systematic literature review. Results: A 28-year-old female suddenly developed right facial numbness as well as left upper extremity and left hand pain. Initial brain and spine MRI showed a bulging mass of T2 iso-to-high signal intensity in the left Meckel's cave/trigeminal nerve, as well as diffuse enlargement of the right C6 and C7 nerve roots. Follow-up MRI at 2 months revealed a reduction in the size of the initial lesion and the appearance of new similar lesions on the contralateral side (right Meckel's cave, left C3–C8 nerve roots). In particular, the lesions involving the nerve roots demonstrated central enlargement along the nerve roots, without involvement of the adjacent spinal cord. All these lesions exhibited enhancement, leading to the differentiation between sarcoidosis and lymphoma. Sarcoidosis was subsequently confirmed through biopsy of a hilar lymph node. Conclusions: This report presents a distinctive MRI feature of neurosarcoidosis involving spinal nerve roots, representing the first of its kind, and describes the evolution of MRI findings throughout the clinical course. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to evaluate the effect of deep learning-based reconstruction (DLR) on high-spatial-resolution three-dimensional T2-weighted fast asymmetric spin-echo (HR-3D T2-FASE) imaging in the preoperative evaluation of cerebellopontine angle (CPA) tumors. Methods: This study included 13 consecutive patients who underwent preoperative HR-3D T2-FASE imaging using a 3 T MRI scanner. The reconstruction voxel size of HR-3D T2-FASE imaging was 0.23 × 0.23 × 0.5 mm. The contrast-to-noise ratios (CNRs) of the structures were compared between HR-3D T2-FASE images with and without DLR. The observers' preferences based on four categories on the tumor side on HR-3D T2-FASE images were evaluated. The facial nerve in relation to the tumor on HR-3D T2-FASE images was assessed with reference to intraoperative findings. Results: The mean CNR between the tumor and trigeminal nerve and between the cerebrospinal fluid and trigeminal nerve was significantly higher for DLR images than non-DLR-based images (14.3 ± 8.9 vs. 12.0 ± 7.6, and 66.4 ± 12.0 vs. 53.9 ± 8.5, P < 0.001, respectively). The observer's preference for the depiction and delineation of the tumor, cranial nerves, vessels, and location relation on DLR HR-3D T2FASE images was superior to that on non-DLR HR-3D T2FASE images in 7 (54%), 6 (46%), 6 (46%), and 6 (46%) of 13 cases, respectively. The facial nerves around the tumor on HR-3D T2-FASE images were visualized accurately in five (38%) cases with DLR and in four (31%) without DLR. Conclusion: DLR HR-3D T2-FASE imaging is useful for the preoperative assessment of CPA tumors. [ABSTRACT FROM AUTHOR]

Background: Radiofrequency thermorhizotomy (TRZ) is an established treatment for trigeminal neuralgia (TN). TRZ can result risky and painful in a consistent subset of patients, due to the need to perform multiple trajectories, before a successful foramen ovale cannulation. Moreover, intraoperative x-rays are required. Method: TRZ has been performed by using a neuronavigated stylet, before trajectory planning on a dedicated workstation. Conclusion: Navigated-TRZ (N-TRZ) meets the expectations of a safer and more tolerable procedure due to the use of a single trajectory, avoiding critical structures. Moreover, N-TRZ is x-ray free. Efficacy outcomes are similar to those reported in literature. [ABSTRACT FROM AUTHOR]

Background: Trigeminal schwannoma is a rare type of tumor that arises from the Schwann cells of the trigeminal nerve. Method: We present a case of a patient with a giant V2 trigeminal schwannoma with painful swelling in the left maxilla. A complete resection using a combined open maxillectomy and endoscopic endonasal approach was performed. Conclusion: This case highlights the importance of a multidisciplinary approach to perform a combined open and endoscopic approach for safe resection while preserving adequate speech and swallowing. [ABSTRACT FROM AUTHOR]

Trigeminal neuralgia causes excruciating pain in patients. Microvascular decompression is indicated for drug-resistant s trigeminal neuralgia. Unlike facial spasms, any part of the nerve can be the culprit, not only the root entry zone. Intraoperative monitoring does not yet exist for trigeminal neuralgia. We successfully used intermittent stimulation of the superior cerebellar artery during surgery and confirmed the disappearance of the trigeminal nerve motor branch reaction after the release of the compression. Intermittent direct stimulation of the culprit blood vessel using the motor branch of the trigeminal nerve may assist in intraoperative monitoring of decompression during trigeminal nerve vascular decompression surgery. [ABSTRACT FROM AUTHOR]

Background: Pain, an evolutionarily conserved warning system, lets us recognize threats and motivates us to adapt to those threats. Headache pain from migraine affects approximately 15% of the global population. However, the identity of any putative threat that migraine or headache warns us to avoid is unknown because migraine pathogenesis is poorly understood. Here, we show that a stress-induced increase in pituitary adenylate cyclase-activating polypeptide-38 (PACAP38), known as an initiator of allosteric load inducing unbalanced homeostasis, causes headache-like behaviour in male mice via mas-related G protein-coupled receptor B2 (MrgprB2) in mast cells. Methods: The repetitive stress model and dural injection of PACAP38 were performed to induce headache behaviours. We assessed headache behaviours using the facial von Frey test and the grimace scale in wild-type and MrgprB2-deficient mice. We further examined the activities of trigeminal ganglion neurons using in vivo Pirt-GCaMP Ca2+ imaging of intact trigeminal ganglion (TG). Results: Repetitive stress and dural injection of PACAP38 induced MrgprB2-dependent headache behaviours. Blood levels of PACAP38 were increased after repetitive stress. PACAP38/MrgprB2-induced mast cell degranulation sensitizes the trigeminovascular system in dura mater. Moreover, using in vivo intact TG Pirt-GCaMP Ca2+ imaging, we show that stress or/and elevation of PACAP38 sensitized the TG neurons via MrgprB2. MrgprB2-deficient mice showed no sensitization of TG neurons or mast cell activation. We found that repetitive stress and dural injection of PACAP38 induced headache behaviour through TNF-a and TRPV1 pathways. Conclusions: Our findings highlight the PACAP38-MrgprB2 pathway as a new target for the treatment of stress-related migraine headache. Furthermore, our results pertaining to stress interoception via the MrgprB2/PACAP38 axis suggests that migraine headache warns us of stress-induced homeostatic imbalance. [ABSTRACT FROM AUTHOR]

The trigeminal system is key to the pathophysiology of migraine and cluster headache, two primary headache disorders that share many features. Recently, MER proto-oncogene tyrosine kinase (MERTK), a cell surface receptor, was strongly associated with cluster headache through genetic studies. Further, the MERTK ligand galectin-3 has been found to be elevated in serum of migraine patients. In this study, MERTK and MERTK ligands were investigated in key tissue to better understand their potential implication in the pathophysiology of primary headache disorders. Immunohistochemistry was used to map MERTK and galectin-3 expression in rat trigeminal ganglia. RT-qPCR was used to assess MERTK gene expression in blood, and ELISA immunoassays were used for MERTK ligand quantification in serum from study participants with and without cluster headache. MERTK gene expression was elevated in blood samples from study participants with cluster headache compared to controls. In addition, MERTK ligand galectin-3 was found at increased concentration in the serum of study participants with cluster headache, whereas the levels of MERTK ligands growth arrest specific 6 and protein S unaffected. MERTK and galectin-3 were both expressed in rat trigeminal ganglia. Galectin-3 was primarily localized in smaller neurons and to a lesser extent in C-fibres, while MERTK was found in satellite glia cells and in the outer membrane of Schwann cells. Interestingly, a strong MERTK signal was found specifically in the region proximal to the nodes of Ranvier. The overexpression of MERTK and galectin-3 in tissue from study participants with cluster headache, as well as the presence of MERTK in rat peripheral satellite glia cells and Schwann cells in the trigeminal ganglia, further highlights MERTK signalling as an interesting potential future therapeutic target in primary headache. [ABSTRACT FROM AUTHOR]

Purpose: Olfactory dysfunction (OD) can be a long-term consequence of various viral infections, including COVID-19. Dysfunction includes hyposmia/anosmia and parosmia (odor distortions). Interactions of the virus with the olfactory nerve have been extensively researched, but little is known about the interactions of the intranasal trigeminal nerve system in modulating this sensory loss. Methods: We investigated intranasal trigeminal function across COVID-19 OD patients with and without parosmia compared to normosmic controls, to determine whether (1) post-viral hyposmia and/or (2) post-viral hyposmia with parosmia is associated with altered trigeminal function. OD patients (n = 27) were tested for olfactory function using the extended Sniffin' Sticks olfactory test and for trigeminal function through three methods—odor lateralization, subjective ratings of nasal patency, and ammonium vapor pain intensity ratings. This group was subsequently compared to controls, normosmic subjects (n = 15). Results: Our findings revealed that post-COVID OD patients without parosmia experienced decreased sensitivity in ammonium vapor pain intensity ratings and odor lateralization scores—but similar nasal patency ratings—compared to normosmic controls. There were no significant differences in trigeminal function between OD patients with and without parosmia. Conclusions: Based on our results, we conclude that the trigeminal nerve dysfunction may partially explain post-viral OD, but does not seem to be a major factor in the generation of parosmia pathophysiology. [ABSTRACT FROM AUTHOR]

A correction to the article " Valproate ameliorates nitroglycerin-induced migraine in trigeminal nucleus caudalis in rats through inhibition of NF-кB," published online, is presented.

Varicella zoster is found exclusively in humans. Infected people with this virus result in chickenpox followed by dormant virus within neural ganglia. This dormant virus, once activated, may affect any ganglia or nerves of the body but most commonly involves the thoracic, cervical and trigeminal nerves in decreasing order of frequency. We review three such cases in which manipulation of the trigeminal ganglion resulted in reactivation of varicella at homologous operative sites. Each patient underwent surgeries in which the trigeminal ganglion was manipulated for the resection of trigeminal schwannoma under a microscope through various approaches. All three patients developed reactivation of varicella at homologous operative sites. A thorough history of chickenpox infection should be taken in patients who are undergoing surgeries for trigeminal pathology. Early diagnosis should be made once any vesicular lesions are seen with prompt treatment. Reassurance and counselling are necessary in these patients. If possible, prophylaxis may be started in all such patients. Further studies are warranted to determine the exact cause of reactivation. [ABSTRACT FROM AUTHOR]

This case study describes anatomical variations in the branching pattern of the posterior division of the trigeminal nerve and its clinical implications for dental and craniofacial surgery. The study presents two uncommon variations observed in an elderly male cadaver. A communicating branch connecting one of three roots of the auriculotemporal nerve and inferior alveolar nerve just before entering the mandibular foramen on the right side, and three communicating branches between the IAN and lingual nerve on the left side. The presence of such variations may complicate anesthesia associated with oral surgery procedures. [ABSTRACT FROM AUTHOR]

Purpose: Gamma Knife radiosurgery (GKRS) has emerged as an effective treatment option for trigeminal neuralgia (TN) in patients with multiple sclerosis (MS). To date, the outcomes of repeat GKRS for patients with TN and MS with recurrent pain have been investigated in a few patients. This study aims to report the outcomes and predictive factors of pain reduction for MS patients undergoing repeat GKRS for recurrent TN. Methods: Eighteen patients with MS underwent repeat GKRS for recurrent TN. A retrospective chart review and telephone interviews were conducted to determine background medical history, dosimetric data, and outcomes of the procedure. Facial pain and sensory function were evaluated using the Barrow Neurological Institute (BNI) scales. Results: Fifteen patients achieved a BNI pain score of IIIa or better, indicating pain reduction, within a median period of 21 days after repeat GKRS. The maximum dose for repeat GKRS ranged from 70 to 85 Gy. Pain recurred in 5 patients after a median period of 12 months after GKRS. Percentages of patients with pain reduction at 1, 2, 3, 5, and 7 years were 60%, 60%, 50%, 50%, and 50%, respectively. Older age at repeat GKRS predicted sustained pain reduction (P = 0.01). Seven patients developed facial sensory disturbances, which were bothersome in two patients. Conclusions: Repeat GKRS may be used as an effective treatment modality for prolonging the duration of pain reduction time in patients with MS and TN. After repeat GKRS, facial sensory disturbances are common; however, they are often not bothersome. [ABSTRACT FROM AUTHOR]

Radiofrequency thermocoagulation (RFTC) of the peripheral branches of the trigeminal nerve has been used for trigeminal neuralgia. However, the long-term outcomes of radiofrequency thermocoagulation have not been established. To evaluate the long-term efficacy of RFTC of peripheral branches in patients with refractory trigeminal neuralgia. A retrospective cohort study was conducted in a comprehensive medical center in China. Patients who underwent radiofrequency thermocoagulation of peripheral branches for refractory trigeminal neuralgia from May 2014 to March 2021 were included for analysis. A total of 84 patients with refractory trigeminal neuralgia underwent 105 procedures. BNI I–II which represents treatment success was achieved in 76/84 (90%) patients and 93/105 (89%) procedures. During follow-up, BNI I and II were maintained in 64/76 (84%), 40/73 (55%), 20/67 (30%), 17/65 (26%), 12/61 (20%), and 8/58 (14%) of patients at 1, 2, 3, 4, 5, and 6 years, after the first procedure, respectively. For all the 105 procedures, BNI I and II were maintained in 68/93 (73%), 41/89(46%), 22/82(27%), 15/79 (19%), 8/74 (11%), and 3/72 (4%) at 1, 2, 3, 4, 5, and 6 years, respectively. There is no significant difference between the first and repeat thermocoagulation in terms of immediate (90% vs. 81%, P=0.140) and long-term efficacies (24 months vs.18 months, P=0.266). Radiofrequency thermocoagulation resulted in better long-term outcomes in patients with typical purely paroxysmal pain (24 months vs. 11 months, P=0.033). Radiofrequency ablation of the peripheral branches of the trigeminal nerve might be a safe and effective method in the treatment of refractory trigeminal neuralgia. [ABSTRACT FROM AUTHOR]

Objective: Microvascular decompression (MVD) is a well-accepted treatment modality for trigeminal neuralgia (TN) with high initial success rates. The causes for recurrence of TN after previously successful MVD have not been fully clarified, and its treatment is still a matter of debate. Here, we present the surgical findings and the clinical outcome of patients with recurrent TN after MVD who underwent posterior fossa re-exploration. Methods: Microsurgical posterior fossa re-exploration was performed in 26 patients with recurrent TN (mean age 59.1 years) who underwent MVD over a period of 10 years. The trigeminal nerve was exposed, and possible factors for recurrent TN were identified. Arachnoid scars and Teflon granulomas were dissected meticulously without manipulating the trigeminal nerve. Outcome of posterior fossa re-exploration was graded according to the Barrow Neurological Institute (BNI) pain intensity score. Follow-up was analyzed postoperatively at 3, 12, and 24 months and at the latest available time point for long-term outcome. Results: The mean duration of recurrent TN after the first MVD was 20 months. Pain relief was achieved in all patients with recurrent TN on the first postoperative day. Intraoperative findings were as follows: arachnoid scar tissue in 22/26 (84.6%) patients, arterial compression in 1/26 (3.8%), venous contact in 8/26 (30.8%), Teflon granuloma in 14/26 (53.8%), compression by an electrode in Meckel's cave used for treatment of neuropathic pain in 1/26 (3.8%), evidence of pulsations transmitted to the trigeminal nerve through the Teflon inserted previously/scar tissue ("piston effect") in 15/26 (57.7%), and combination of findings in 18/26 (69.2%). At long-term follow-up (mean 79.5 months; range, 29–184 months), 21/26 (80.8%) patients had favorable outcome (BNI I-IIIa). New hypaesthesia secondary to microsurgical posterior fossa re-exploration occurred in 5/26 (19.2%) patients. Conclusions: Posterior fossa re-exploration avoiding manipulation to the trigeminal nerve, such as pinching or combing, may be a useful treatment option for recurrent TN after previously successful MVD providing pain relief in the majority of patients with a low rate of new hypaesthesia. [ABSTRACT FROM AUTHOR]

Objective: Whether nerve atrophy can affect the prognosis of primary trigeminal neuralgia (PTN) patients undergoing percutaneous balloon compression (PBC) remains unclear. This study aimed to determine the association between nerve characteristics observed on preoperative magnetic resonance imaging (MRI) and PBC outcomes. Methods: Between January 2019 and December 2022, a cohort of 58 patients with unilateral PTN treated with PBC were analysed retrospectively and included in this study. The relationship between MRI findings, including the proximal and distal nerve cross-sectional areas (CSAs), and favourable pain outcomes (BNI Grades I–III) was analysed through Kaplan‒Meier analysis. Results: After a mean follow-up period of 23.8 ± 13.0 months (range, 6–50 months), 48 (82.8%) patients with PTN were pain free with or without medication. A smaller proximal CSA ratio (proximal CSA of the affected nerve/proximal CSA of the unaffected nerve) was significantly associated with favourable outcomes. The Kaplan–Meier survival analysis showed that patients with proximal nerve atrophy (proximal CSA ratio ≤ 87% after receiver operating characteristic curve analysis) had a higher estimated 4-year probability of maintaining a favourable outcome than those without nerve atrophy (94.4% vs. 30.8%, p = 0.005). In addition, patients with proximal nerve atrophy were more likely to suffer from postoperative persistent facial numbness. Conclusions: Proximal nerve atrophy is correlated with both favourable outcomes and persistent facial numbness following PBC. Prospective studies are required to determine the optimal duration and pressure of balloon compression in relation to the proximal CSA ratio to achieve better pain outcomes and less facial numbness. [ABSTRACT FROM AUTHOR]

Neurofibroma is a benign tumor of the peripheral nervous system affecting Schwann cells as well as neural sheath cells. It is usually considered as a component of Von Recklinghausen's disease, but solitary lesions have also been reported, though not very frequently. It is mostly reported on the skin. In the head and neck region, trigeminal nerve and the cervical nerves are frequently affected; in the oral cavity, tongue is the most commonly affected site. Intra-osseous neurofibromas of the oral cavity are extremely rare and only 22 cases have been reported in the last two decades. The present review is an attempt to know if there is any clinical or radiological feature that can assist in the diagnosis of solitary intra-osseous neurofibroma of the jaws? The literature was reviewed from 01.01.2000 to 05.06.2022 exclusively for case reports, case series, and reviews using the keywords: neurofibroma; neurinoma, maxilla; mandible; jaws, single; solitary; one. Search engines: PubMed Central, Lilac, and Science Direct were used by applying the Boolean operator "OR" and "AND". The review has been submitted for registration in PROSPERO (receipt 340775). [ABSTRACT FROM AUTHOR]

Aim: We retrospectively analyse and review the results of microvascular decompression performed for trigeminal neuralgia. We also discuss the surgical nuances, complication avoidance and compare our results with other reported studies. Materials and methods: This is a retrospective study in which the data of eighty-four patients who underwent microvascular decompression for trigeminal neuralgia in the last ten years from 2013 till May 2023 at our institute (Neuron hospital and SSG Hospital, Vadodara, India) was reviewed. The preoperative pain characteristics, radiology reports and the degree and duration of post-operative pain relief and neurologic outcome was assessed. MRI was done preoperatively in all the cases to rule out a secondary cause for trigeminal neuralgia. All the cases of secondary trigeminal neuralgia were excluded from the study. A favourable outcome was defined as a post-operative Barrow Neurological Institute pain intensity score of 1. Results: Eighty patients had excellent immediate postoperative pain relief without any need for medications. None of these patients have developed any recurrence of pain till date. Four operated patients did not experience any pain relief after surgery. Conclusion: Microvascular decompression for trigeminal neuralgia is a safe and effective procedure which treats the root cause of the disease and hence provides good long term pain relief. [ABSTRACT FROM AUTHOR]

Background: Women are disproportionately affected by migraine, representing up to 75% of all migraine cases. This discrepancy has been proposed to be influenced by differences in hormone levels between the sexes. One such hormone is progesterone. Calcitonin gene-related peptide (CGRP) system is an important factor in migraine pathophysiology and could be influenced by circulating hormones. The purpose of this study was to investigate the distribution of progesterone and its receptor (PR) in the trigeminovascular system, and to examine the role of progesterone to modulate sensory neurotransmission. Methods: Trigeminal ganglion (TG), hypothalamus, dura mater, and the basilar artery from male and female rats were carefully dissected. Expression of progesterone and PR proteins, and mRNA levels from TG and hypothalamus were analyzed by immunohistochemistry and real-time quantitative PCR. CGRP release from TG and dura mater were measured using an enzyme-linked immunosorbent assay. In addition, the vasomotor effect of progesterone on male and female basilar artery segments was investigated with myography. Results: Progesterone and progesterone receptor -A (PR-A) immunoreactivity were found in TG. Progesterone was located predominantly in cell membranes and in Aδ-fibers, and PR-A was found in neuronal cytoplasm and nucleus, and in satellite glial cells. The number of positive progesterone immunoreactive cells in the TG was higher in female compared to male rats. The PR mRNA was expressed in both hypothalamus and TG; however, the PR expression level was significantly higher in the hypothalamus. Progesterone did not induce a significant change neither in basal level nor upon stimulated release of CGRP from dura mater or TG in male or female rats when compared to the vehicle control. However, pre-treated with 10 µM progesterone weakly enhanced capsaicin induced CGRP release observed in the dura mater of male rats. Similarly, in male basilar arteries, progesterone significantly amplified the dilation in response to capsaicin. Conclusions: In conclusion, these results highlight the potential for progesterone to modulate sensory neurotransmission and vascular responses in a complex manner, with effects varying by sex, tissue type, and the nature of the stimulus. Further investigations are needed to elucidate the underlying mechanisms and physiological implications of these findings. [ABSTRACT FROM AUTHOR]

Pharmacokinetics (PK) includes how a drug is absorbed, distributed, metabolized and eliminated. The compartment providing this information is usually the plasma. This is as close to the tissue of interest that we can get, although biopsies may be obtained to give "tissue levels" of drugs. Ultimately, the goal of PK is to understand how long the drug is actually engaged with the target in the tissue of interest after a dose has been administered. Most drugs at some point in their development will have been administered intravenously (IV), which acts as the standard for 100% bioavailability. By comparing various routes of administration to IV, the percentage of drug delivered to the plasma, on a dose-normalized basis, can be calculated and is referred to as the "absolute bioavailability". As pharmacology has advanced and more drugs have become available, many older products have been reformulated to be given by routes other than those originally intended (often oral). As the drawbacks of oral (or IV) administration have become better appreciated, non-oral, non-IV formulations and methods of administration have become more popular. Nasal administration is one route that has historically been overlooked as an alternative to oral administration—particularly for products needing rapid and non-invasive access to the target tissue—mostly via the blood stream. But attention is now focused on nasal administration for direct access to the brain, as that has the potential to bypass the blood-brain-barrier (BBB), which not even IV administration can always achieve. Assessing PK for these drugs targeting the brain may require serial sampling of the cerebrospinal fluid (CSF), making PK assessments of CNS drugs more invasive and complex, but still possible in future product development. However, we are now seeing more drugs reformulated for nasal delivery to gain faster systemic levels than oral administration (especially in patients with known or suspected gastrointestinal dysmotility), while avoiding the use of needles. For example, in recent years several different formulations and delivery methods for an old drug, dihydroergotamine (DHE), have been developed and these show very different characteristics, suggesting that delivery to different parts of the nose may have very different PK profiles. This review summarizes the systemic PK of different nasal DHE options that have been, or are being, developed and suggests that delivery of drugs to the upper nasal space (UNS) may represent an optimal target. Further research is required to ascertain if this route could also be utilized for direct administration to the CNS (as an attractive alternative to intrathecal delivery) via the olfactory or trigeminal nerves—but already preclinical data (and some human data) suggest this is entirely possible. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the use of diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) for detection of microstructural changes in the trigeminal nerves of trigeminal neuralgia (TN) patients. Methods: Forty TN patients and 40 healthy controls were examined using 3 T magnetic resonance imaging (MRI) to evaluate DTI and DKI parameters in trigeminal nerves. One-way ANOVA was used to test the differences in age, sex, and DTI and DKI parameters between the TN-affected sides, TN-unaffected sides, and controls. For parameters with inter-group differences, pairwise comparisons were performed. Then, the difference ratios (DRs) of the parameters with statistical differences were calculated and used for the receiver operating characteristic (ROC) analysis to assess their diagnostic performance. In addition, for the DTI and DKI parameter values with differences, we used pure DTI and DKI values to perform the ROC analysis. Results: Compared to the unaffected sides and controls, the FA, MK, and Kr of the affected sides of TN patients were significantly reduced, while ADC was significantly increased (p < 0.05). The diagnostic efficiency of the FA DRs (AUC: 0.974; cutoff value: 0.038; sensitivity: 100%; specificity: 95.0%) was the highest among all DTI and DKI parameters. The DRs of FA and MK more efficiently diagnosed TN than pure FA and MK values. Conclusions: DTI and DKI allowed detection of microstructural changes in TN-affected trigeminal nerves. FA DR was the best independent predictor of microstructural changes in TN. Clinical relevance statement: Both DTI and DKI can be used for noninvasive quantitative evaluation of the changes in the microstructure of the cisternal segment of the cranial nerves in clinical practice. Key Points: • Diffusion tensor imaging (DTI) can be used to evaluate the in vivo integrity of white matter and nerve fiber pathway. • Diffusion kurtosis imaging (DKI) has been shown to be considerable sensitive to microstructural changes. • DTI combined with DKI can comprehensively evaluate the status of the TN-affected trigeminal nerve. [ABSTRACT FROM AUTHOR]

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The significance of hyperactive astrocytes in neuropathic pain is crucial. However, the association between medullary astrocytes and trigeminal neuralgia (TN)-related pain processing is unclear. Here, we examined how optogenetic inhibition of medullary astrocytes in the trigeminal nucleus caudalis (TNC) regulates pain hypersensitivity in an infraorbital nerve (ION) constricted TN model. We used adult Sprague Dawley rats subjected to infraorbital nerve (ION) constriction to mimic TN symptoms, with naive and sham rats serving as controls. For in vivo optogenetic manipulations, rats stereotaxically received AAV8-GFAP-eNpHR3.0-mCherry or AAV8-GFAP-mCherry at the trigeminal nucleus caudalis (TNC). Open field, von Frey, air puff, and acetone tests measured pain behavioral flexibility. In vivo thalamic recordings were obtained simultaneously with optogenetic manipulation in the TNC. Orofacial hyperalgesia and thalamic hyperexcitability were both accompanied by medullary astrocyte hyperactivity, marked by upregulated GFAP. The yellow laser-driven inhibition of TNC astrocytes markedly improved behavioral responses and regulated thalamic neuronal responses. Halorhodopsin-mediated inhibition in medullary astrocytes may modify the nociceptive input transmitted through the trigeminothalamic tract and pain perception. Taken together, these findings imply that this subpopulation in the TNC and its thalamic connections play a significant role in regulating the trigeminal pain circuitry, which might aid in the identification of new therapeutic measures in TN management. [ABSTRACT FROM AUTHOR]

Objective: To observe the evolution and outcomes of postoperative trigeminal neuropathy following surgery of tumor involving the trigeminal nerve. Methods: A prospective observational study was conducted between October 2018 and February 2019 involving 25 patients with tumors confirmed to involve the trigeminal nerve during surgery by senior author. Pre- and postoperative trigeminal nerve function status and clinical data were recorded. Results: This study included 18 cases of meningioma and seven of trigeminal schwannoma. Among the meningioma cases, 55.6% of the patients reported facial sensory dysfunction before surgery, 33.3% presented ocular discomfort, and 5.6% had masticatory muscle atrophy. Postoperatively, all patients experienced facial paresthesia, 94.4% complained of eye dryness, and one (5.56%) exhibited keratitis. Additionally, one patient (5.56%) showed new-onset masticatory weakness. During follow-up, 50.0% of patients reported improvement in facial paresthesia, and one (5.56%) experienced deterioration. Eye dryness resolved in 35.3% of patients, and keratitis remission was observed in one patient. However, one patient (5.56%) developed neurotrophic keratitis. Overall, 55.6% of patients displayed mild masticatory weakness without muscle atrophy. In the cases of schwannoma, 28.6% of patients had facial paresthesia before surgery, 42.9% showed ocular discomfort, and one (14.3%) complained of masticatory dysfunction. Postoperatively, 85.7% of patients reported facial paresthesia and eye dryness, with one patient (16.7%) experiencing keratitis. During follow-up, 66.7% of patients demonstrated improvement in facial paresthesia, 28.6% showed eye dryness remission, and one patient (16.7%) recovered from keratitis. However, one patient (16.7%) developed new-onset neurotrophic keratitis. One patient (16.7%) experienced relief of masticatory dysfunction, but 42.9% reported mild deterioration. Another patient (14.3%) had facial anesthesia that had not improved. Conclusion: Postoperative trigeminal neuropathy is a common complication with a high incidence rate and poor recovery outcomes after surgery for tumors involving the trigeminal nerve. When trigeminal nerve damage is unavoidable, it is essential to provide a multidisciplinary and careful follow-up, along with active management strategy, to mitigate the more severe effects of postoperative trigeminal neuropathy. [ABSTRACT FROM AUTHOR]

Objective: To explore and analyze the clinical efficacy of a stepwise decompression technique in the treatment of trigeminal neuralgia (TN) caused by vertebrobasilar dolichoectasia (VBD). Methods: A total of 918 patients with TN admitted to our hospital from June 2015 to May 2020 were divided into the VBD group (n = 61) and the conventional group (n = 857). The VBD group underwent stepwise decompression, while the conventional group received traditional microvascular decompression (MVD) surgery. Patients associated with the VBD were divided into direct compression (n = 14) and indirect compression group (n = 47) who had compression by other vessels in the presence of the VBD. Thereafter, the clinical data, intraoperative findings, efficacy, and complications were analyzed. Results: The curative ratio, efficacy, and recurrence rate for the VBD and conventional group were 83.6% and 89.6%, 93.4% and 95.3%, and 8.2% and 5.3%, respectively. The curative ratio, efficacy, and recurrence rate for the direct compression and indirect compression group were 85.7% and 83.0%, 92.9% and 93.6%, and 7.1% and 8.5%, separately. There were no significant differences in the curative ratio, efficacy, recurrence rate, and the incidence of complications between the two series (P > 0.05). Conclusion: For TN caused by VBD, stepwise decompression not only reduces the direct compression of the trigeminal nerve by VBA but also allows identification and decompression of the actual vessels responsible for the compression. It has a good curative ratio, efficacy, and long-term pain relief rate, and it does not significantly increase the incidences of complications after surgery. [ABSTRACT FROM AUTHOR]

Background: Extradural disconnection of the cavernous sinus (CS) with preservation of the internal carotid artery (ICA) is indicated for aggressive and recurrent tumors, in patients presenting loss of oculomotor function and non-functional circle of Willis. Method: Extradural resection of the anterior clinoid process disconnects the CS anteriorly. The ICA is dissected in the foramen lacerum via extradural subtemporal approach. The intracavernous tumor is split and removed following the ICA. Bleeding control of the inferior and superior petrosal and intercavernous sinuses completes posterior CS disconnection. Conclusion: This technique can be proposed for recurrent CS tumors and need of ICA preservation. [ABSTRACT FROM AUTHOR]

Background: Migraine is a disorder associated with neuropeptide release, pain and inflammation. Tau protein has recently been linked to inflammatory diseases and can be influenced by neuropeptides such as CGRP, a key neurotransmitter in migraine. Here, we report serum concentrations of total-tau protein in migraine patients and healthy controls. Methods: In this cross-sectional study, interictal blood samples from n = 92 patients with episodic migraine (EM), n = 93 patients with chronic migraine (CM), and n = 42 healthy matched controls (HC) were studied. We assessed serum total-tau protein (t-tau) and for comparison neurofilament light chain protein (NfL), glial fibrillary acidic protein (GFAP), and ubiquitin carboxy-terminal hydrolase L (UCH-L1) concentrations using the Neurology 4-plex kit, on a single molecule array HD-X Analyzer (Quanterix Corp Lexington, MA). Matched serum/cerebrospinal fluid (CSF) samples were used for post-hoc evaluations of a central nervous system (CNS) source of relevant findings. We applied non-parametric tests to compare groups and assess correlations. Results: Serum t-tau concentrations were elevated in EM [0.320 (0.204 to 0.466) pg/mL] and CM [0.304 (0.158 to 0.406) pg/mL] patients compared to HC [0.200 (0.114 to 0.288) pg/mL] (p = 0.002 vs. EM; p = 0.025 vs. CM). EM with aura [0.291 (0.184 to 0.486 pg/mL); p = 0.013] and EM without aura [0.332 (0.234 to 0.449) pg/mL; p = 0.008] patients had higher t-tau levels than HC but did not differ between each other. Subgroup analysis of CM with/without preventive treatment revealed elevated t-tau levels compared to HC only in the non-prevention group [0.322 (0.181 to 0.463) pg/mL; p = 0.009]. T-tau was elevated in serum (p = 0.028) but not in cerebrospinal fluid (p = 0.760). In contrast to t-tau, all proteins associated with cell damage (NfL, GFAP, and UCH-L1), did not differ between groups. Discussion: Migraine is associated with t-tau elevation in serum but not in the CSF. Our clinical study identifies t-tau as a new target for migraine research. [ABSTRACT FROM AUTHOR]

Purpose: We sought to investigate the sympathetic mechanism controlling coronary circulation during trigeminal nerve stimulation in healthy women. Methods: The protocol consisted of 3 min of trigeminal nerve stimulation (TGS) with cold stimuli to the face, in two conditions: (1) control and β-blockade (oral propranolol), and (2) control and α-blockade (oral prazosin). Results: Thirty-one healthy young subjects (women: n = 13; men: n = 18) participated in the study. By design, TGS decreased heart rate (HR), and increased blood pressure (BP) and cardiac output (CO). Before the β-blockade coronary blood velocity (CBV—Δ1.4 ± 1.3 cm s−1) increased along with the decrease of coronary vascular conductance index (CVCi—Δ-0.04 ± 0.04 cm s−1 mmHg−1) during TGS and the β-blockade abolished the CBV increase and a further decrease of CVCi was observed with TGS (Δ-0.06 ± 0.07 cm s−1 mmHg−1). During the α-blockade condition before the blockade, the CBV increased (Δ0.93 ± 1.48 cm s−1) along with the decrease of CVCi (Δ-0.05 ± 1.12 cm s−1 mmHg−1) during TGS, after the α-blockade CBV (Δ0.98 ± cm s−1) and CVCi (Δ-0.03 ± 0.06 cm s−1 mmHg−1) response to TGS did not change. Conclusion: Coronary circulation increases during sympathetic stimulation even with a decrease in heart rate. [ABSTRACT FROM AUTHOR]

Purpose: To describe tumor response and cranial nerve function outcomes after administration of anti-PD-1 to patients with cutaneous squamous cell carcinoma (CSCC) with perineural spread to cranial nerves (CN) extending into the cavernous sinus. Methods: Electronic patient records from a single institution were queried for patients with CSCC of the head and neck causing diplopia (ICD-10 H53.2) who were treated with anti-PD-1. Data extracted included demographics, duration of anti-PD-1 therapy, immune-mediated adverse reactions, tumor response per adapted RECIST v1.1, and changes in CN function and symptoms (e.g., pain). All patients were prescribed cemiplimab 350 mg IV q3 weeks. Results: Four patients met inclusion criteria. They had varying degrees of pain and sensory deficits in branches of the trigeminal nerve (CN V). One, 2, 3 and 1 patients had baseline involvement of CN III, IV, VI and VII, respectively. MRI confirmed perineural cavernous sinus involvement in all patients. Duration of anti-PD-1 therapy ranged 15–60 weeks. All patients experienced an objective anti-tumor response to anti-PD-1; partial response n = 2, complete response n = 2. At a median follow-up of 22 months, responses were ongoing in all patients. All patients demonstrated improvement in ocular motility deficits and pain with resolution of symptoms in 3 and 1 patients, respectively. Conclusion: Administration of anti-PD-1 to patients with CSCC with perineural spread into the cavernous sinus can generate durable anti-tumor regressions and restore CN function, while sparing the morbidity associated with surgical resection and/or radiotherapy. Our findings add to emerging literature supporting this treatment approach for this patient population. [ABSTRACT FROM AUTHOR]

This letter to the editor critiques a recent publication titled "The extracapsular capsule phenomenon of percutaneous balloon compression provides adequate compression of the third branch of the trigeminal nerve: A Retrospective Study." The study examines the effectiveness of the extracapsular capsule technique in treating trigeminal neuralgia (TN) with percutaneous balloon compression (PBC), specifically focusing on the trigeminal nerve's third branch (V3). The results suggest that the extracapsular capsule approach may be a more effective treatment for TN affecting the V3 branch, leading to better compression rates and postoperative outcomes. However, the letter identifies limitations in the study's design, sample size, and consideration of demographic factors, emphasizing the need for further research to validate and expand these findings. [Extracted from the article]

Background: Dandy's superior petrosal vein (SPV) anatomy is highly relevant for neurosurgeons. The SPV drains into the superior petrosal sinus (SPS), closely related to the trigeminal and internal auditory pores. Method: The archived enhanced MRI files of a male patient were studied. Results: An infratentorial ring-shaped (RS) SPV was found on the petrosal surface of the right cerebellar hemisphere. It was inserted in the SPS above the internal auditory pore, postero-lateral to the trigeminal pore. The anterior arm of that venous ring received a delicate supratrigeminal plexus of veins from the pontine surface and continued as a single venous trunk on the cerebellar surface. Conclusion: Such previously unreported RS-SPV is of utmost importance to be identified before subtemporal transtentorial and retrosigmoid approaches for different neurosurgical reasons. [ABSTRACT FROM AUTHOR]

Background: Migraine is a disabling neurological disorder, characterized by recurrent headaches. During migraine attacks, individuals often experience sensory symptoms such as cutaneous allodynia which indicates the presence of central sensitization. This sensitization is prevented by oral administration of propranolol, a common first-line medication for migraine prophylaxis, that also normalized the activation of the locus coeruleus (LC), considered as the main origin of descending noradrenergic pain controls. We hypothesized that the basal modulation of trigeminal sensory processing by the locus coeruleus is shifted towards more facilitation in migraineurs and that prophylactic action of propranolol may be attributed to a direct action in LC through beta-adrenergic receptors. Methods: We used simultaneous in vivo extracellular recordings from the trigeminocervical complex (TCC) and LC of male Sprague–Dawley rats to characterize the relationship between these two areas following repeated meningeal inflammatory soup infusions. Von Frey Hairs and air-puff were used to test periorbital mechanical allodynia. RNAscope and patch-clamp recordings allowed us to examine the action mechanism of propranolol. Results: We found a strong synchronization between TCC and LC spontaneous activities, with a precession of the LC, suggesting the LC drives TCC excitability. Following repeated dural-evoked trigeminal activations, we observed a disruption in coupling of activity within LC and TCC. This suggested an involvement of the two regions' interactions in the development of sensitization. Furthermore, we showed the co-expression of alpha-2A and beta-2 adrenergic receptors within LC neurons. Finally propranolol microinjections into the LC prevented trigeminal sensitization by desynchronizing and decreasing LC neuronal activity. Conclusions: Altogether these results suggest that trigemino-coerulean coupling plays a pivotal role in migraine progression, and that propranolol's prophylactic effects involve, to some extent, the modulation of LC activity through beta-2 adrenergic receptors. This insight reveals new mechanistic aspects of LC control over sensory processing. [ABSTRACT FROM AUTHOR]

Purpose: Dilatation of the trigeminal cavum, or Meckel's cave (MC), is usually considered a radiological sign of idiopathic intracranial hypertension. However, the normal size of the trigeminal cavum is poorly characterized. In this study, we describe the anatomy of this meningeal structure. Methods: We dissected 18 MCs and measured the length and width of the arachnoid web and its extension along the trigeminal nerve. Results: Arachnoid cysts were clearly attached to the ophthalmic (V1) and maxillary (V2) branches until they entered the cavernous sinus and foramen rotundum, respectively, without extension to the skull base. Arachnoid cysts were close to the mandibular branch toward the foramen ovale, with a median anteromedial extension of 2.5 [2.0–3.0] mm, lateral extension of 4.5 [3.0–6.0] mm, and posterior extension of 4.0 [3.2–6.0] mm. The trigeminal cavum arachnoid had a total width of 20.0 [17.5–25.0] mm and length of 24.5 [22.5–29.0] mm. Conclusion: Our anatomical study revealed variable arachnoid extension, which may explain the variability in size of the trigeminal cavum in images and calls into question the value of this structure as a sign of idiopathic intracranial hypertension. The arachnoid web extends beyond the limits described previously, reaching almost double the radiological size of the cavum, particularly at the level of V3 afference of the trigeminal nerve. It is possible that strong adhesion of the arachnoid to the nerve elements prevents the formation of a true subarachnoid space that can be visualized by magnetic resonance imaging. [ABSTRACT FROM AUTHOR]

Purpose: The peripheral course of the trigeminal nerves is complex and spans multiple bony foramen and tissue compartments throughout the face. Diffusion tensor imaging of these nerves is difficult due to the complex tissue interfaces and relatively low MR signal. The purpose of this work is to develop a method for reliable diffusion tensor imaging-based fiber tracking of the peripheral branches of the trigeminal nerve. Methods: We prospectively acquired imaging data from six healthy adult participants with a 3.0-Tesla system, including T2-weighted short tau inversion recovery with variable flip angle (T2-STIR-SPACE) and readout segmented echo planar diffusion weighted imaging sequences. Probabilistic tractography of the ophthalmic, infraorbital, lingual, and inferior alveolar nerves was performed manually and assessed by two observers who determined whether the fiber tracts reached defined anatomical landmarks using the T2-STIR-SPACE volume. Results: All nerves in all subjects were tracked beyond the trigeminal ganglion. Tracts in the inferior alveolar and ophthalmic nerve exhibited the strongest signal and most consistently reached the most distal landmark (58% and 67%, respectively). All tracts of the inferior alveolar and ophthalmic nerve extended beyond their respective third benchmarks. Tracts of the infraorbital nerve and lingual nerve were comparably lower-signal and did not consistently reach the furthest benchmarks (9% and 17%, respectively). Conclusion: This work demonstrates a method for consistently identifying and tracking the major nerve branches of the trigeminal nerve with diffusion tensor imaging. [ABSTRACT FROM AUTHOR]