Temporomandibular joint pain: a critical role for Trpv4 in the trigeminal ganglion.

Temporomandibular joint disorder (TMJD) is known for its mastication-associated pain. TMJD is medically relevant because of its prevalence, severity, chronicity, the therapy-refractoriness of its pain, and its largely elusive pathogenesis. Against this background, we sought to investigate the pathogenetic contributions of the calcium-permeable TRPV4 ion channel, robustly expressed in the trigeminal ganglion sensory neurons, to TMJ inflammation and pain behavior. We demonstrate here that TRPV4 is critical for TMJ-inflammation-evoked pain behavior in mice and that trigeminal ganglion pronociceptive changes are TRPV4-dependent. As a quantitative metric, bite force was recorded as evidence of masticatory sensitization, in keeping with human translational studies. In Trpv4(-/-) mice with TMJ inflammation, attenuation of bite force was significantly less than in wildtype (WT) mice. Similar effects were seen with systemic application of a specific TRPV4 inhibitor. TMJ inflammation and mandibular bony changes were apparent after injections of complete Freund adjuvant but were remarkably independent of the Trpv4 genotype. It was intriguing that, as a result of TMJ inflammation, WT mice exhibited significant upregulation of TRPV4 and phosphorylated extracellular-signal-regulated kinase (ERK) in TMJ-innervating trigeminal sensory neurons, which were absent in Trpv4(-/-) mice. Mice with genetically-impaired MEK/ERK phosphorylation in neurons showed resistance to reduction of bite force similar to that of Trpv4(-/-) mice. Thus, TRPV4 is necessary for masticatory sensitization in TMJ inflammation and probably functions upstream of MEK/ERK phosphorylation in trigeminal ganglion sensory neurons in vivo. TRPV4 therefore represents a novel pronociceptive target in TMJ inflammation and should be considered a target of interest in human TMJD.

Severe Psychosocial Compromise in Idiopathic Trigeminal Neuralgia: Case Report

Objective. This article describes a 60-year-old man with 17 years of idiopathic trigeminal neuralgia (ITN) which affected tooth brushing for 6 years, causing severe dental complications and psychosocial problems. Methods. Case report. Results. Following ITN diagnosis, this patient underwent neurosurgery (microcompression of the trigeminal ganglion with a balloon) with immediate relief, but after three months, pain recurred and was accompanied by dysesthesia and periodontal disease. After dental treatment, he had complete alleviation of pain and no further need of medication over the following 3 years. The intense suffering of this patient represents the importance of a multidisciplinary evaluation for pain-caused secondary complications. Conclusion. ITN is a simple diagnosis but may have complex course. Appropriately trained health professionals are necessary to evaluate and treat these patients.

Incidence, morphology and morphometry of the foramen of Vesalius: complementary study for a safer planning and execution of the trigeminal rhizotomy technique

The foramen of Vesalius (FV) is located in the greater wing of the sphenoid bone between the foramen ovale (FO) and the foramen rotundum in an intracranial view. The FO allows the passage of the mandibular branch of trigeminal nerve, which is the target of the trigeminal radiofrequency rhizotomy. We analyzed its location, morphology, morphometry and interrelation among other foramina. 400 macerated adult human skulls were examined. A digital microscope (Dino-Lite plus(A (R))) was used to capture images from the FV. A digital caliper was used to perform the measurements of the distance between the FV and other foramina (FO, foramen spinosum and the carotid canal) in an extracranial view of the skull base. In the 400 analyzed skulls, the FV was identified in 135 skulls (33.75%) and absent on both sides in 265 skulls (66.25%). The FV was observed present bilaterally in 15.5% of the skulls. The incidence of unilateral foramen was 18.25% of the skulls of which 7.75% on right side and 10.5% on left side. The diameter of the FV was measured and we found an average value of 0.65 mm, on right side 0.63 mm and on the left side 0.67 mm. We verified that positive correlations were statistically significant among the three analyzed distances. This study intends to offer specific anatomical data with morphological patterns (macroscopic and mesoscopic) to increase the understanding of the FV features as frequency, incidence and important distances among adjacent foramina.

An anatomical investigation of the cervicothoracic ganglion

Anatomical variability within the autonomic nervous system has long been accepted. This study evaluated the anatomical variability of the cervicothoracic ganglion (CTG) according to its form and, in addition, provided precise measurements between the CTG and the anterior tubercle of the transverse process of the sixth cervical vertebra (C6TP), the first costovertebral articulation, and the vertebral artery. Forty-two adult cadavers were dissected, 22 male and 20 females. Five main forms of CTG were documented; spindle (31.9%), dumbbell (23.2%), truncated (21.7%), perforated (14.5%), and inverted-L (8.7%). The means for length, width, and thickness of the CTG were 18.5 mm, 8.2 mm, and 4.5 mm, respectively. The dimensions were found to be slightly larger in the males than females and on the left sides as compared to the right. The mean shortest distance between the CTGs and the vertebral artery was found to be 2.8 mm, whilst the mean shortest distances to C6TP was 25.7 mm and to the first costovertebral articulation was 1.7 mm. There is great variability in the morphology of the CTG with five common forms consistently seen. The relation to the vertebral artery may influence the form of the ganglion. Two previously undocumented forms are recorded; the truncated which describes the important juxtaposition of the CTG and the vertebral artery and the perforated which describes the piercing of the ganglion itself by the artery. The findings are considered to be of clinical importance to anesthetists, surgeons, neurosurgeons, and anatomists.

Expression of MMP-2 and MMP-9 in the rat trigeminal ganglion during the development of temporomandibular joint inflammation

Orofacial pain is a prevalent symptom in modern society. Some musculoskeletal orofacial pain is caused by temporomandibular disorders (TMDs). This condition has a multi-factorial etiology, including emotional factors and alteration of the masticator muscle and temporomandibular joints (TMJs). TMJ inflammation is considered to be a cause of pain in patients with TMD. Extracellular proteolytic enzymes, specifically the matrix metalloproteinases (MMPs), have been shown to modulate inflammation and pain. The purpose of this investigation was to determine whether the expression and level of gelatinolytic activity of MMP-2 and MMP-9 in the trigeminal ganglion are altered during different stages of temporomandibular inflammation, as determined by gelatin zymography. This study also evaluated whether mechanical allodynia and orofacial hyperalgesia, induced by the injection of complete Freund's adjuvant into the TMJ capsule, were altered by an MMP inhibitor (doxycycline, DOX). TMJ inflammation was measured by plasma extravasation in the periarticular tissue (Evans blue test) and infiltration of polymorphonuclear neutrophils into the synovial fluid (myeloperoxidase enzyme quantification). MMP expression in the trigeminal ganglion was shown to vary during the phases of the inflammatory process. MMP-9 regulated the early phase and MMP-2 participated in the late phase of this process. Furthermore, increases in plasma extravasation in periarticular tissue and myeloperoxidase activity in the joint tissue, which occurred throughout the inflammation process, were diminished by treatment with DOX, a nonspecific MMP inhibitor. Additionally, the increases of mechanical allodynia and orofacial hyperalgesia were attenuated by the same treatment.

Origin of sensory and autonomic innervation of the rat temporomandibular joint: A retrograde axonal tracing study with the fluorescent dye fast blue

Previous studies that have used retrograde axonal tracers (horseradish peroxidase alone or conjugated with wheat germ agglutinin) have shown that the temporomandibular joint (TMJ) is supplied with nerve fibers originating mainly from the trigeminal ganglion, in addition to other sensory and sympathetic ganglia. The existence of nerve fibers in the TMJ originating from the trigeminal mesencephalic nucleus is unclear, and the possible innervation by parasympathetic nerve fibers has not been determined. In the present work, the retrograde axonal tracer, fast blue, was used to elucidate these questions and re-evaluated the literature data. The tracer was deposited in the supradiscal articular space of the rat TMJ, and an extensive morphometric analysis was performed of the labeled perikaryal profiles located in sensory and autonomic ganglia. This methodology permitted us to observe labeled small perikaryal profiles in the trigeminal ganglion, clustered mainly in the posterior-lateral region of the dorsal, medial and ventral thirds of horizontal sections, with some located in the anterior-lateral region of the ventral third. Sensory perikarya were also labeled in the dorsal root ganglia from C2 to C5. No labeled perikaryal profiles were found in the trigeminal mesencephalic nucleus. on the other hand, autonomic labeled perikaryal profiles were distributed in the sympathetic superior cervical and stellate ganglia, and parasympathetic otic ganglion. Our results confirmed those of previous studies and also demonstrated that: (i) there is a distribution pattern of labeled perikaryal profiles in the trigeminal ganglion; (ii) some perikaryal profiles located in the otic ganglion were labeled; and (iii) the trigeminal mesencephalic nucleus did not show any retrogradely labeled perikaryal profiles.

AN ANATOMICAL STUDY OF THE LATEROTRIGEMINAL VENOUS SYSTEM

The middle cranial fossa of 100 cadavers were dissected under stereoscopic loupe in order to identify and systematize the venous vessels located along the lateral margin of the trigeminal cave. The author found that at the sensitive root and trigeminal ganglion level a dural venous canal was present in most individuals examined and that the upper side of this canal communicated with the superior petrosal sinus. However, at the level of the lateral border of the intracranial segment of the mandibular nerve, venous lacunae were found to prevail, and these lacunae communicated with several other venous formations in the peritrigeminal region. The author concludes that the venous vascularization of this area constitutes a major risk in surgical interventions made in the middle cranial fossa. In addition, it is a relevant factor in the hemodynamics of the intracranial circulation.

Bovine herpesvirus-5 infection in a rabbit experimental model: Immunohistochemical study of the cellular response in the CNS

Since little information is available regarding cellular antigen mapping and the involvement of non-neuronal cells in the pathogenesis of bovine herpesvirus type 5 (BHV-5) infection, it were determined the BHV-5 distribution, the astrocytic reactivity, the involvement of lymphocytes and the presence of matrix metalloproteinase (MMP)-9 in the brain of rabbits experimentally infected with BHV-5. Twelve New Zealand rabbits that were seronegative for BHV-5 were used for virus inoculation, and five rabbits were used as mock-infected controls. The rabbits were kept in separate areas and were inoculated intranasally with 500 μl of virus suspension (EVI 88 Brazilian isolate) into each nostril (virus titer, 107.5 TCID50). Control rabbits were inoculated with the same volume of minimum essential medium. Five days before virus inoculation, the rabbits were submitted to daily administration of dexamethasone. After virus inoculation, the rabbits were monitored clinically on a daily basis. Seven rabbits showed respiratory symptoms and four animals exhibited neurological symptoms. Tissue sections were collected for histological examination and immunohistochemistry to examine BHV-5 antigens, astrocytes, T and B lymphocytes and MMP-9. By means of immunohistochemical and PCR methods, BHV-5 was detected in the entire brain of the animals which presented with neurological symptoms, especially in the trigeminal ganglion and cerebral cortices. Furthermore, BHV-5 antigens were detected in neurons and/or other non-neural cells. In addition to the neurons, most infiltrating CD3 T lymphocytes observed in these areas were positive for MMP-9 and also for BHV-5 antigen. These infected cells might contribute to the spread of the virus to the rabbit brain along the trigeminal ganglia and olfactory nerve pathways. © 2013 Elsevier Ltd.

Assessment of the wind-up phenomenon in the equine nociceptive trigeminal system.

Repeated sub-threshold nociceptive electrical stimulation resulting in temporal summation of the limb nociceptive withdrawal reflex is a well-established non-invasive model to investigate the wind-up phenomenon in horses. Due to structural similarities of the trigeminal sensory nucleus to the dorsal horn of the spinal cord, temporal summation should be evoked by repeated transcutaneous electrical stimulation of trigeminal afferents. To evaluate this hypothesis repeated transcutaneous electrical stimulation was applied to the supraorbital and infraorbital nerves of 10 horses. Stimulation intensities varied between 0.5 and 1.3 times the trigemino-cervical reflex threshold defined for single stimulation. Evoked electromyographic activity of the orbicularis oculi, splenius and cleidomastoideus muscles was recorded and the signals analysed in the previously established epochs typical to the early and late component of the blink reflex and to the trigemino-cervical reflex. Behavioural reactions were evaluated with the aid of numerical rating scale. The nociceptive late component and the trigemino-cervical reflex were not elicited by sub-threshold intensity repeated transcutaneous electrical stimulation. Furthermore, the median reflex amplitude for the 10 horses showed a tendency to decline over the stimulation train so temporal summation of afferent trigeminal inputs could not be observed. Therefore, the modulation of trigeminal nociceptive processing attributable to repeated Aδ fibre stimulations seems to differ from spinal processing of similar inputs as it seems to have an inhibitory rather than facilitatory effect. Further evaluation is necessary to highlight the underlying mechanism.

Involvement of Islet-2 in the Slit signaling for axonal branching and defasciculation of the sensory neurons in embryonic zebrafish

In Drosophila melanogaster, Slit acts as a repulsive cue for the growth cones of the commissural axons which express a receptor for Slit, Roundabout (Robo), thus preventing the commissural axons from crossing the midline multiple times. Experiments using explant culture have shown that vertebrate Slit homologues also act repulsively for growth cone navigation and neural migration, and promote branching and elongation of sensory axons. Here, we demonstrate that overexpression of Slit2 in vivo in transgenic zebrafish embryos severely affected the behavior of the commissural reticulospinal neurons (Mauthner neurons), promoted branching of the peripheral axons of the trigeminal sensory ganglion neurons, and induced defasciculation of the medial longitudinal fascicles. In addition, Slit2 overexpression caused defasciculation and deflection of the central axons of the trigeminal sensory ganglion neurons from the hindbrain entry point. The central projection was restored by either functional repression or mutation of Robo2, supporting its role as a receptor mediating the Slit signaling in vertebrate neurons. Furthermore, we demonstrated that Islet-2, a LIM/homeodomain-type transcription factor, is essential for Slit2 to induce axonal branching of the trigeminal sensory ganglion neurons, suggesting that factors functioning downstream of Islet-2 are essential for mediating the Slit signaling for promotion of axonal branching. (C) 2004 Elsevier Ireland Ltd. All rights reserved.

Lead stimulus modality change and the attentional modulation of the acoustic and electrical blink reflex

Two experiments investigated the effects of the sensory modality of the lead and of the blink-eliciting stimulus during lead stimulus modality change on blink modulation at lead intervals of 2500 and 3500 ins. Participants were presented with acoustic, visual, or tactile change stimuli after habituation training with lead stimuli from the same or a different sensory modality. In Experiment 1, latency and magnitude of the acoustic blink were facilitated during a change to acoustic or visual lead stimuli, but not during a change to tactile lead stimuli. After habituation to acoustic lead stimuli, blink magnitude was smaller during tactile change stimuli than during habituation stimuli. The latter finding was replicated in Experiment 2 in which blink was elicited by electrical stimulation of the trigeminal nerve. The consistency of the findings across different combinations of lead stimulus and blink-eliciting stimulus modalities does not support a modality-specific account of attentional blink modulation. Rather, blink modulation during generalized orienting reflects modality non-specific processes, although modulation may not always be found during tactile lead stimuli. (C) 2002 Elsevier Science B.V. All rights reserved.

Traumatic Clivus Epidural Hematoma: Case Report and Review of the Literature

BACKGROUND: Traumatic clival epidural hematoma is an extremely rare reported entity. CASE DESCRIPTION: We describe the case of a 26-year-old woman involved in a car accident who presented with a Glasgow Coma Scale score of 13, bilateral abducens palsy, bilateral numbness on the mandibular territory of the trigeminal nerve, and left hypoglossal palsy. Radiological examinations revealed a clival epidural hematoma. The patient was managed conservatively, with clinical improvement of her neurological condition. This is the first traumatic clival epidural hematoma reported in an adult. From a review of the literature, we found only 8 cases. CONCLUSION: The pathophysiology of these hematomas is still a subject of debate; occipitoatlantoaxial ligamentous instability may play a role in it. In one third of the cases, bilateral cranial nerve palsies were associated. Apparently, they have a benign outcome.

Chromatic pupil responses: preferential activation of the melanopsin-mediated versus outer photoreceptor-mediated pupil light reflex.

OBJECTIVE: To weight the rod-, cone-, and melanopsin-mediated activation of the retinal ganglion cells, which drive the pupil light reflex by varying the light stimulus wavelength, intensity, and duration. DESIGN: Experimental study. PARTICIPANTS: Forty-three subjects with normal eyes and 3 patients with neuroretinal visual loss. METHODS: A novel stimulus paradigm was developed using either a long wavelength (red) or short wavelength (blue) light given as a continuous Ganzfeld stimulus with stepwise increases over a 2 log-unit range. The pupillary movement before, during, and after the light stimulus was recorded in real time with an infrared illuminated video camera. MAIN OUTCOME MEASURES: The percent pupil contraction of the transient and sustained pupil response to a low- (1 cd/m(2)), medium- (10 cd/m(2)), and high-intensity (100 cd/m(2)) red- and blue-light stimulus was calculated for 1 eye of each subject. From the 43 normal eyes, median and 25th, 75th, 5th, and 95th percentile values were obtained for each stimulus condition. RESULTS: In normal eyes at lower intensities, blue light evoked much greater pupil responses compared with red light when matched for photopic luminance. The transient pupil contraction was generally greater than the sustained contraction, and this disparity was greatest at the lowest light intensity and least apparent with bright (100 cd/m(2)) blue light. A patient with primarily rod dysfunction (nonrecordable scotopic electroretinogram) showed significantly reduced pupil responses to blue light at lower intensities. A patient with achromatopsia and an almost normal visual field showed selective reduction of the pupil response to red-light stimulation. A patient with ganglion cell dysfunction owing to anterior ischemic optic neuropathy demonstrated global loss of pupil responses to red and blue light in the affected eye. CONCLUSIONS: Pupil responses that differ as a function of light intensity and wavelength support the hypothesis that selected stimulus conditions can produce pupil responses that reflect phototransduction primarily mediated by rods, cones, or melanopsin. Use of chromatic pupil responses may be a novel way to diagnose and monitor diseases affecting either the outer or inner retina.

Unusual fatal petrositis presenting as myofascial pain and dysfunction of the temporal muscle.

Petrositis is a rare and severe complication of acute otitis media and mastoiditis. Although the extension of the inflammatory process from the petrous apex to the adjacent Meckel cave can lead to trigeminal pain, an irritation of the trigeminal nerve roots resulting in acute or chronic hyperactivity of masticatory muscles has never been reported. We report here the unusual case of an 86-year-old man who presented with a handicapping myofascial pain and dysfunction syndrome of the right temporal muscle as a heralding manifestation of an unusual form of petrositis. The patient progressively developed a retropharyngeal abscess, a right sphenoid sinusitis, and fatal meningitis. This case demonstrated that (1) myofascial pain and dysfunction syndrome that does not respond to conventional treatments may suggest an unusual etiology and warrant further medical investigations and a detailed medical history and that (2) petrositis can manifest itself with atypical clinical symptoms and radiologic signs. (Quintessence Int 2011;42:419-422).