[Features of olfactory impairment connected with trigeminal nerve system]. / Osobennosti narusheniya obonyaniya v aspekte sistemy troinichnogo nerva.

Data on the state of sense of smell in patients who had a new coronavirus infection caused by the SARS-CoV-2 virus are currently reduced because of the impairment of the olfactory nerve system. There are practically no results in studies of disorders in the trigeminal nerve system. OBJECTIVE: Qualitative assessment of olfactory disorders after COVID-19 according to the system of olfactory and trigeminal nerves with a targeted assessment of the functional component of olfactory disorders. MATERIAL AND METHODS: We examined 40 patients aged 19 to 66 who had a coronavirus infection. All patients underwent neurological, otorhinolaryngological examinations, olfactometry, filled out the hospital anxiety and depression scale. RESULTS: Anosmia was diagnosed in 5 (12.5%) patients, hyposmia in 21 (52.5%) patients, and normosmia in 14 (35%) patients. Formed: the 1st group - 14 patients (35%) with normogram according to olfactometry; the 2nd group - 26 patients (65%) with anosmia/hyposmia. In the 1st group, disorders of the anxiety-depressive spectrum were significantly more common. In the 2nd group, a low identification of odors was found, lying in the spectrum of fresh, sharp, unpleasant, irritating, compared with sweet and pleasant or neutral, which indicates a predominant lesion of the trigeminal system. CONCLUSION: In patients with complaints of impaired sense of smell after undergoing COVID-19, the possible functional nature of anosmia/hyposmia should be taken into account, which requires the referral of such patients to psychotherapeutic specialists, and the possible entry of olfactory disorders into the 'trigeminal' spectrum.

Corneal Neurotization: A Novel Surgical Procedure for Neurotrophic Keratopathy.

PURPOSE: The aim of this study is to describe techniques, results, and open issues of corneal neurotization (CN) for the treatment of neurotrophic keratopathy (NK). METHODS: An overview of the most important studies of CN is provided. The 2 main surgical approaches (namely, direct CN and indirect CN) with specific advantages and disadvantages are described. The results regarding changes of corneal sensitivity and clarity, visual acuity, and in vivo confocal microscopy metrics are summarized. Ex vivo studies with histopathology of the neurotized cornea are reported. Intraoperative and early and late postoperative complications are described along with current open issues to be further clarified. RESULTS: Corneal sensitivity improves after both direct and indirect CN. Corneal reinnervation allows the healing of NK in almost the totality of the operated eyes, determining a corresponding improvement of corneal clarity and visual acuity. Regeneration of corneal nerve fibers is confirmed by means of either in vivo confocal microscopy or ex vivo histopathology. Few self-limiting complications are reported during the postoperative course. Current open issues concern the identification of the technique of choice, the use of autograft or allograft, and the timing of CN either when performed alone or when combined with other surgeries. CONCLUSIONS: CN represents a game-changing surgical procedure for NK, which has the potential to restore corneal sensitivity in all stages of the disease regardless of the mechanism of denervation. Further long-term results are needed to confirm its efficacy over time. The design of randomized clinical trials comparing CN with noninterventional therapies could further validate the adoption of this technique.

Suppression of Pain in the Late Phase of Chronic Trigeminal Neuropathic Pain Failed to Rescue the Decision-Making Deficits in Rats.

Trigeminal neuropathic pain (TNP) led to vital cognitive functional deficits such as impaired decision-making abilities in a rat gambling task. Chronic TNP caused hypomyelination in the anterior cingulate cortex (ACC) associated with decreased synchronization between ACC spikes and basal lateral amygdala (BLA) theta oscillations. The aim of this study was to investigate the effect of pain suppression on cognitive impairment in the early or late phases of TNP. Blocking afferent signals with a tetrodotoxin (TTX)-ELVAX implanted immediately following nerve lesion suppressed the allodynia and rescued decision-making deficits. In contrast, the TTX used at a later phase could not suppress the allodynia nor rescue decision-making deficits. Intra-ACC administration of riluzole reduced the ACC neural sensitization but failed to restore ACC-BLA spike-field phase synchrony during the late stages of chronic neuropathic pain. Riluzole suppressed allodynia but failed to rescue the decision-making deficits during the late phase of TNP, suggesting that early pain relief is important for recovering from pain-related cognitive impairments. The functional disturbances in ACC neural circuitry may be relevant causes for the deficits in decision making in the chronic TNP state.

Trigeminal neuropathy causes hypomyelination in the anterior cingulate cortex, disrupts the synchrony of neural circuitry, and impairs decision-making in male rats.

Infraorbital nerve-chronic constriction injury (ION-CCI) has become the most popular chronic trigeminal neuropathic pain (TNP) injury animal model which causes prolonged mechanical allodynia. Accumulative evidence suggests that TNP interferes with cognitive functions, however the underlying mechanisms are not known. The aim of this study was to investigate decision-making performance as well as synaptic and large-scale neural synchronized alterations in the spinal trigeminal nucleus (SpV) circuitry and anterior cingulate cortex (ACC) neural circuitry in male rats with TNP. Rat gambling task showed that ION-CCI led to decrease the proportion of good decision makers and increase the proportion of poor decision makers. Electrophysiological recordings showed long-lasting synaptic potentiation of local field potential in the trigeminal ganglia-SpV caudalis (SpVc) synapses in TNP rats. In this study, TNP led to disruption of ACC spike timing and basolateral amygdala (BLA) theta oscillation associated with suppressed synchronization of theta oscillation between the BLA and ACC, indicating reduced neuronal communications. Myelination is critical for information flow between brain regions, and myelin plasticity is an important feature for learning. Neural activity in the cortical regions impacts myelination by regulating oligodendrocyte (OL) proliferation, differentiation, and myelin formation. We characterized newly formed oligodendrocyte progenitor cells, and mature OLs are reduced in TNP and are associated with reduced myelin strength in the ACC region. The functional disturbances in the BLA-ACC neural circuitry is pathologically associated with the myelin defects in the ACC region which may be relevant causes for the deficits in decision-making in chronic TNP state.

The NLRP3-related inflammasome modulates pain behavior in a rat model of trigeminal neuropathic pain.

AIMS: Nod-like receptor family pyrin domain containing 3 (NLRP3) may play an important role in neuropathic pain. Treatment for trigeminal neuropathic pain remains a challenge, as common drugs either do not demonstrate beneficial therapeutic effects or induce intolerance in patients. MAIN METHODS: In a rat model of trigeminal neuropathic pain, pain caused by the malpositioning of dental implants is similar to that experienced by humans. We used masculine Sprague-Dawley rats with inferior alveolar nerve damage as a model to investigate the differential regulation of NLRP3. First, we confirmed the level of NLRP3 in the medullary dorsal horn and variation of pain response behavior after silencing the expression of NLRP3 inflammasome bodies in rats with trigeminal neuropathic pain. Second, under localized anesthesia, we extracted the lower left second molar, implanted a micro-dental implant, and deliberately injured the inferior alveolar nerve. KEY FINDINGS: After nerve damage, the level of NLRP3-related inflammasomes was upregulated in microglia and the expression of a component of the inflammasome gradually increased during postoperative days 3-21. The suppression of adenovirus-shRNA-NLRP3 on postoperative day 1 markedly inhibited the expression of pro-inflammatory cytokines and the activation of the inflammasome and mechanical allodynia. Furthermore, it attenuated cell death in microglia, as evidenced by increased Bcl-2, Bcl-xL, Bax, and Bik expression. SIGNIFICANCE: The level of NLRP3 in the dorsal horn is a pivotal factor in trigeminal neuropathic pain, and inhibition of the early expression of NLRP3 might serve as a potential therapeutic approach.

Acute Unilateral Masseter Muscle Paralysis Caused by Pontine Infarction.

In the present report, we discussed the case of a 57-year-old man with unilateral masticatory muscle weakness, nystagmus, skew deviation and facial hypesthesia due to pontine tegmental infarction. Trigeminal motor neuropathy attributed to brain infarction is very rare. Brain magnetic resonance imaging revealed a small dot-like infarction lesion in the pontine tegmentum. Masticatory muscle weakness was confirmed by an electrophysiological study performed on the day after admission in which there was an incomplete interference pattern without spontaneous denervation activity, suggesting that the patient's masseter muscle weakness was caused by an infarction of the trigeminal motor nucleus proper or trigeminal motor nerve fascicles rather than Wallerian degeneration of the trigeminal nerve or the progression of masseter muscle degeneration.

Case Report: Ocular Tilt Reaction with Internuclear Ophthalmoplegia and Multiple Cranial Nerve Palsies.

SIGNIFICANCE: Ocular tilt reaction (OTR) is an abnormal eye-head postural reaction that consists of skew deviation, head tilt, and bilateral ocular torsion. Understanding of the pathway of the vestibulo-ocular reflex (VOR) is essential because this will help to localize the pathology. PURPOSE: The aim of this study was to report a case of OTR with contralateral internuclear ophthalmoplegia (INO) and fifth and seventh cranial nerve palsies. CASE REPORT: A 51-year-old gentleman with underlying diabetes mellitus presented with sudden onset of diplopia for 3 days. On examination, his visual acuity was 20/30 bilaterally without a relative afferent pupillary defect. He had a right OTR consisting of a right head tilt, a skew deviation with a left eye hypertropia, and bilateral ocular torsion (right excyclotorsion and left incyclotorsion) with nystagmus. He also had a left adduction deficit and right abduction nystagmus consistent with a left INO. Ocular examination revealed evidence of proliferative diabetic retinopathy bilaterally. Two days after the initial presentation, the patient developed left seventh and fifth cranial nerve palsies. MRI showed left pontine infarction and multiple chronic lacunar infarctions. There was an incidental finding of a vascular loop compression on cisternal portions of the left trigeminal, facial, and vestibulocochlear nerves. Antiplatelet treatment was started on top of a better diabetic control. The diplopia was gradually resolved with improved clinical signs. In this case, the left pontine infarction had likely affected the terminal decussated part of the vestibulocochlear nerve from the right VOR pathway, medial longitudinal fasciculus, and cranial nerve nuclei in the left pons. CONCLUSIONS: The OTR can be ipsilateral to the lesion if the lesion is before the decussation of the VOR pathway in the pons, or it can be contralateral to the lesion if the lesion is after the decussation. In case of an OTR that is associated with contralateral INO and other contralateral cranial nerves palsy, a pathology in the pons that is contralateral to the OTR should be considered. Neuroimaging study can hence be targeted to identify the possible cause.

Optic, trigeminal, and facial neuropathy related to anti-neurofascin 155 antibody.

OBJECTIVE: To characterize the frequency and patterns of optic, trigeminal, and facial nerve involvement by neuroimaging and electrophysiology in IgG4 anti-neurofascin 155 antibody-positive (NF155+ ) chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: Thirteen IgG4 NF155+ CIDP patients with mean onset age of 34 years (11 men) were subjected to neurological examination, blink reflex, and visual-evoked potential (VEP) testing, and axial and/or coronal T2-weighted head magnetic resonance imaging (MRI). RESULTS: Among 13 patients, facial sensory impairment, facial weakness, and apparent visual impairment were observed in three (23.1%), two (15.4%), and two (15.4%) patients, respectively. All 12 patients tested had blink reflex abnormalities: absent and/or delayed R1 in 11 (91.7%), and absent and/or delayed R2 in 10 (83.3%). R1 latencies had strong positive correlations with serum anti-NF155 antibody levels (r = 0.9, P ≤ 0.0001 on both sides) and distal and F wave latencies of the median and ulnar nerves. Absent and/or prolonged VEPs were observed in 10/13 (76.9%) patients and 17/26 (65.4%) eyes. On MRI, hypertrophy, and high signal intensity of trigeminal nerves were detected in 9/13 (69.2%) and 10/13 (76.9%) patients, respectively, whereas optic nerves were normal in all patients. The intra-orbital trigeminal nerve width on coronal sections showed a significant positive correlation with disease duration. INTERPRETATION: Subclinical demyelination frequently occurs in the optic, trigeminal, and facial nerves in IgG4 NF155+ CIDP, suggesting that both central and peripheral myelin structures of the cranial nerves are involved in this condition, whereas nerve hypertrophy only develops in myelinated peripheral nerve fibers.

Molecular mechanisms of painful traumatic trigeminal neuropathy-Evidence from animal research and clinical correlates.

Painful traumatic trigeminal neuropathy (PTTN) may occur following major craniofacial or oral trauma, or may be subsequent to relatively minor dental interventions. Following injury, pain may originate from a peripheral nerve, a ganglion, or from the central nervous system. In this review, we focus on molecular mechanisms of pain resulting from injury to the peripheral branch of the trigeminal nerve. This syndrome has been termed painful traumatic trigeminal neuropathy (PTTN) by the International Headache Society and replaces previous terms including atypical odontalgia, deafferentation pain, traumatic neuropathy and phantom toothache. We emphasize the scientific evidence supporting the events purported to lead to PTTN by reviewing the pathophysiology of PTTN based on relevant animal models. Additionally, we briefly overview clinical correlates and pathophysiological manifestations of PTTN.

Topical Recombinant Human Nerve Growth Factor (Cenegermin) for Neurotrophic Keratopathy: A Multicenter Randomized Vehicle-Controlled Pivotal Trial.

PURPOSE: To evaluate the efficacy and safety of topical cenegermin (recombinant human nerve growth factor) in patients with neurotrophic keratopathy. DESIGN: Multicenter, randomized, double-masked, vehicle-controlled trial. PARTICIPANTS: Patients with neurotrophic persistent epithelial defect with or without stromal thinning. METHODS: The NGF0214 trial, conducted among 11 sites in the United States, randomized 48 patients 1:1 to cenegermin 20 µg/ml or vehicle eye drops, 6 drops daily for 8 weeks of masked treatment. Follow-up was 24 weeks. Safety was assessed in all patients who received study drug. Efficacy was assessed by intention to treat. MAIN OUTCOME MEASURES: The primary end point was healing of the neurotrophic lesion (persistent epithelial defect or corneal ulcer) after 8 weeks of masked treatment. Masked central readers measured neurotrophic lesions in randomized clinical pictures, then assessed healing status conventionally (<0.5 mm of fluorescein staining in the greatest dimension of the lesion area) and conservatively (0-mm lesion staining and no other residual staining). Secondary variables included corneal healing at 4 weeks of masked treatment (key secondary end point), overall changes in lesion size, rates of disease progression, and changes in visual acuity and corneal sensitivity from baseline to week 8. RESULTS: Conventional assessment of corneal healing showed statistically significant differences at week 8: compared to 7 of 24 vehicle-treated patients (29.2%), 16 of 23 cenegermin-treated patients (69.6%) achieved less than 0.5 mm of lesion staining (+40.4%; 95% confidence interval [CI], 14.2%-66.6%; P = 0.006). Conservative assessment of corneal healing also reached statistical significance at week 8: compared to 4 of 24 vehicle-treated patients (16.7%), 15 of 23 cenegermin-treated patients (65.2%) achieved 0 mm of lesion staining and no other residual staining (+48.6%; 95% CI, 24.0%-73.1%; P < 0.001). Moreover, the conservative measure of corneal healing showed statistical significance at week 4 (key secondary end point). Compared to vehicle, cenegermin-treated patients showed statistically significant reductions in lesion size and disease progression rates during masked treatment. Cenegermin was well tolerated; adverse effects were mostly local, mild, and transient. CONCLUSIONS: Cenegermin treatment showed higher rates of corneal healing than vehicle in neurotrophic keratopathy associated with nonhealing corneal defects.

Trigeminal-Targeted Treatments in Migraine: Is 60% the Magic Number?

Trigeminal-targeted treatments (TTTs), the most specific and selective therapeutic migraine approach to date, are effective in approximately 60% of patients regardless of treatment type or mechanism, at least if used alone. Sixty percent is also the proportion of migraineurs who develop migraine-like episodes following experimental intravenous administration of trigeminal neuropeptides and roughly 60% is the percentage of patients with a unilateral migraine tracing the area of cutaneous distribution of the trigeminal ophthalmic branch. Hence, mechanisms other than the trigeminovascular activation are probably involved in the 40% of migraineurs who do not respond to TTTs. A closer cooperation between clinical and basic neuroscientists is needed to explore migraine models because only a careful appraisal of migraine endophenotypes may help to unravel their underlying multifaceted pathophysiological machinery.

Quantitative and qualitative sensory testing results are associated with numbness rather than neuropathic pain in patients with post-implant trigeminal neuropathy: a cross-sectional pilot study.

Purpose: This study aimed to characterize the sensory profile of patients with post-implant trigeminal neuropathy and identify the association between subjective symptoms and objective signs including psychophysical testing and radiographic imaging. This study further evaluated to the association between quantitative sensory testing (QST)/qualitative sensory testing (QualST) and the severity of nerve injury graded by radiographic imaging. Materials and methods: This retrospective study included 34 patients diagnosed with post-implant trigeminal neuropathy. Data on the neuropathic pain symptom inventory (NPSI), thermal and electric QST, bedside QualST, and cone beam computed tomography (CBCT) was collected and the association between these variables were analysed. Results: Numbness was the most common subjective symptom and evoked pain was the most frequent neuropathic pain. There was no significant correlation between negative and positive symptoms. Spearman's rank correlation analyses indicated that objective findings including QST/QualST correlated with a sensory loss profile rather than a gain of function profile. Moderate positive correlations between some positive symptoms and the score of QualST were observed. The Mann-Whitney U test showed that subjective symptoms did not differ according to the severity of nerve damage according to CBCT, but the electric QST and QualST was discriminative. Conclusions: This study suggests that QST/QualST associated with the severity of nerve damage according to CBCT might be useful in assessing numbness in patients with negative and positive symptoms after implant surgery, but may be of marginal utility in the evaluation of neuropathic pain within the limitation of this cross-sectional study with small sample size.

A Salivation Abnormality with Trigeminal Nerve Dysfunction in Dogs.

Trigeminal nerve pathology can lead to sensory and motor dysfunction to structures of the head that are easily recognized. The trigeminal nerve is a conduit for the distribution of postganglionic parasympathetic innervation to structures of the head. Parasympathetic innervation to the salivary glands is provided by preganglionic parasympathetic neurons of the facial and glossopharyngeal nerves. Postganglionic axons course with branches of the mandibular branch of the trigeminal nerve to reach the salivary glands. Denervation of the salivary glands impacts glandular function, leading to a reduction in the volume and composition of the saliva produced. Saliva plays an important role in oral health. Poor oral health has widespread systemic implications. This article describes a group of dogs with unilateral or bilateral dysfunction of the trigeminal nerve and/or its branches. In all dogs, an accumulation of thick, foamy saliva was observed accumulating in the dorsal aspect of the caudal oral cavity on the ipsilateral side to the affected nerve. In dogs with magnetic resonance imaging (MRI), there was a reduction in size based on the largest cross-sectional area measurement and an increase in mean signal intensity of the salivary glands ipsilateral to the affected nerves compared to the glands on the normal side. The authors hypothesize that the abnormal saliva and MRI changes observed were consequent to parasympathetic denervation of the salivary glands. The recognition of this clinical observation is the first step in understanding the impact that denervation has on salivation and ultimately on overall oral and systemic health in dogs.

Treatment of neurotrophic keratopathy with minimally invasive corneal neurotisation: long-term clinical outcomes and evidence of corneal reinnervation.

AIM: To report clinical outcomes and evidence of corneal innervation in patients with neurotrophic keratopathy (NK) treated with minimally invasive corneal neurotisation (MICN) using a sural nerve graft and donor sensory nerves from the face. METHODS: Patients undergoing MICN at The Hospital for Sick Children, Toronto, Canada were prospectively recruited. Data on central corneal sensation (CCS, measured with Cochet-Bonnet aesthesiometer), best-corrected visual acuity (BCVA) and corneal epithelial integrity were collected. In four patients who subsequently underwent keratoplasty, immunohistochemical analysis was performed on the corneal explants. One patient underwent magnetoencephalography (MEG) after MICN to characterise the neurophysiological pathways involved. RESULTS: Between November 2012 and February 2017, 19 eyes of 16 patients underwent MICN. Mean follow-up was 24.0±16.1 months (range, 6-53). Mean CCS significantly improved from 0.8±2.5 mm to 49.7±15.5 mm at final follow-up (p<0.001). Mean BCVA remained stable, and the number of episodes of corneal epithelial defects after MICN was significantly reduced compared with the year leading up to the procedure (21% vs 89%, respectively; p<0.0001). In the four eyes that underwent keratoplasties after MICN, all transplants fully re-epithelialised and regained sensation subsequently. Immunohistochemistry of the corneal explants demonstrated evidence of corneal reinnervation. In one patient who was 8 months after MICN, novel neuroactivity was detected on MEG in the ipsilateral somatosensory cortex on mechanical stimulation of the reinnervated cornea. CONCLUSIONS: By providing an alternative source of innervation, MICN improves corneal sensation and stabilises the corneal epithelium, permitting optical keratoplasty for patients with NK-related corneal opacity.

Update on corneal neurotisation.

Corneal neurotisation describes surgical restoration of nerve growth into the cornea to restore corneal sensation and trophic function. It represents an exciting and effective emerging treatment for neurotrophic keratopathy. Techniques described to date involve either direct nerve transfer or an interpositional nerve graft coapted to a healthy donor nerve. We review the experience to date with particular emphasis on a detailed review of techniques, outcomes and current thoughts.

Dopamine receptor D2, but not D1, mediates descending dopaminergic pathway-produced analgesic effect in a trigeminal neuropathic pain mouse model.

Neuropathic pain represents a challenge to clinicians because it is resistant to commonly prescribed analgesics due to its largely unknown mechanisms. Here, we investigated a descending dopaminergic pathway-mediated modulation of trigeminal neuropathic pain. We performed chronic constriction injury of the infraorbital nerve from the maxillary branch of trigeminal nerve to induce trigeminal neuropathic pain in mice. Our retrograde tracing showed that the descending dopaminergic projection from hypothalamic A11 nucleus to spinal trigeminal nucleus caudalis is bilateral. Optogenetic/chemogenetic manipulation of dopamine receptors D1 and D2 in the spinal trigeminal nucleus caudalis produced opposite effects on the nerve injury-induced trigeminal neuropathic pain. Specific excitation of dopaminergic neurons in the A11 nucleus attenuated the trigeminal neuropathic pain through the activation of D2 receptors in the spinal trigeminal nucleus caudalis. Conversely, specific ablation of the A11 dopaminergic neurons exacerbated such pain. Our results suggest that the descending A11-spinal trigeminal nucleus caudalis dopaminergic projection is critical for the modulation of trigeminal neuropathic pain and could be manipulated to treat such pain.

Extended Duration of Hyperglycemia Result in Human-Like Corneal Nerve Lesions in Mice With Alloxan- and Streptozotocin-Induced Type 1 Diabetes.

Purpose: Previous experimental studies assessing corneal nerves as a measure of the severity of diabetic peripheral neuropathy have yielded discordant results; this may have been due to the effect of the short duration of the induced diabetes. We investigated whether increases in the duration of hyperglycemia result in the development of corneal lesions in a mouse model of alloxan (AL)- or streptozotocin (STZ)-induced type 1 diabetes. We further determined whether corneal nerve fiber density, intraepidermal nerve fiber density (IENFD), and sural nerve morphology can be used as morphologic markers of diabetic peripheral neuropathy in rodent models. Methods: A total of 30 female ICR mice were divided into three groups: those with STZ-induced (STZ group) and AL-induced (AL group) diabetes, and a control group. Hyperglycemia was maintained in diabetic mice for 35 weeks. Animals were euthanized at 41 weeks of age. Results: Subbasal nerve plexus density (SBNPD) and terminal epithelial nerve density (TEND) in the cornea, as well as IENFD, were significantly lower, and mean sural nerve axon sizes were smaller in mice in the STZ and AL groups than in the control group. There were significant correlations between IENFD and SBNPD, and between IENFD and TEND. Conclusions: These results indicate that the TEND and SBNTD of the cornea may be useful morphologic markers for diabetic peripheral neuropathy.

Molecular basis of trigeminal nerve disorders and healing.

OBJECTIVE: This review aims to describe trigeminal neuralgia and the molecular basis contributing to the pathophysiology of this condition by focusing on the state of the art. PATIENTS AND METHODS: An electronic search of PubMed was performed using the following keywords: "trigeminal neuralgia" AND "classification", "pathophysiology," "molecular basis" and "mitochondrial role." RESULTS: Mitochondrial abnormality, whether functional or morphological, can contribute to neurological disorders. Additionally, one recent finding showed that gain-of-function mutation in the voltage-gated sodium channel NaV1.6 contributes to the pathophysiology of trigeminal neuralgia by increasing the excitability of trigeminal nerve ganglion neurons. It also exacerbates the pathophysiology of vascular compression. Healing of the trigeminal nerve is controlled by many molecular signaling pathways, including extracellular-signal-regulated kinase, c-Jun, p38, Notch, and mitogen-activated protein kinases. CONCLUSIONS: More investigations regarding the gain-of-function mutation of NaV1.6 sodium channels are essential for the diagnosis and treatment of trigeminal nerve disorders, regardless of whether these are associated with vascular compression or not.