PAR2-dependent phosphorylation of TRPV4 at the trigeminal nerve terminals contributes to tongue cancer pain.

OBJECTIVE: This study aimed to clarify the interactions between the tongue and primary afferent fibers in tongue cancer pain. METHODS: A pharmacological analysis was conducted to evaluate mechanical hypersensitivity of the tongues of rats with squamous cell carcinoma (SCC). Changes in trigeminal ganglion (TG) neurons projecting to the tongue were analyzed using immunohistochemistry and western blotting. RESULTS: SCC inoculation of the tongue caused persistent mechanical sensitization and tumor formation. Trypsin expression was significantly upregulated in cancer lesions. Continuous trypsin inhibition or protease-activated receptor 2 (PAR2) antagonism in the tongue significantly inhibited SCC-induced mechanical sensitization. No changes were observed in PAR2 and transient receptor potential vanilloid 4 (TRPV4) levels in the TG or the number of PAR2-and TRPV4-expressing TG neurons after SCC inoculation. In contrast, the relative amount of phosphorylated TRPV4 in the TG was significantly increased after SCC inoculation and abrogated by PAR2 antagonism in the tongue. TRPV4 antagonism in the tongue significantly ameliorated the mechanical sensitization caused by SCC inoculation. CONCLUSIONS: Our findings indicate that tumor-derived trypsin sensitizes primary afferent fibers by PAR2 stimulation and subsequent TRPV4 phosphorylation, resulting in severe tongue pain.

[Clinical aspects of diagnosis and treatment of glossodynia in elderly and senile people.]

Glossodynia is a disease that is difficult to diagnose and treat. Persons of older age groups are in the most risk of its occurrence. This is due to the fact that its etiological factors are: age-related changes, general somatic diseases, usage of some pharmacological drugs, changes in the psycho-emotional background. Due to the similarity of the clinical picture of glossodynia with other diseases of the oral cavity, the doctor is required to be thoughtful when diagnosing and differentiating glossodynia. Clinical methods of examination are used, paying most attention to the anamnesis of life and disease, assessment of the personal and emotional sphere of the patient. Clinico-functional, clinico-instrumental, and laboratory methods of examination are also used. In the treatment of glossodynia, attention should be paid not only to the elimination of symptoms, but also to its prevention. The main efforts should be aimed at combating the main links of pathogenesis. Treatment should be comprehensive, differentiated and personalized. As a result of many researchers work, certain principles of diagnostics and treatment of glossodynia have been developed, which will be considered in our work.

[My tongue is burning!-Glossodynia/orofacial pain disorder]. / Meine Zunge brennt! ­ Glossodynie/orofaziales Schmerzsyndrom.

Glossodynia or orofacial pain disorder is known as burning mouth syndrome. It is a therapeutic challenge. Its etiology is not well defined. Recent studies show not only a correlation with neuropathic changes, but there are also indications of comorbidities such as depression, anxiety, and carcinophobia. These can also manifest as a reaction to the disease and are not necessarily considered causative. Burning mouth syndrome poses a diagnostic challenge since its differential diagnosis is broad. With regard to dermatological aspects, lichen planus mucosae, oral leucoplakia, pemphigus vulgaris, and aphthous mouth ulcers should be considered. Diabetes, anemia, vitamin deficiency, and endocrinological influences should be considered regarding the predominance of elderly and female patients. Meta-analyses of treatment studies usually show a low level of evidence of the randomized, controlled trials. According to the literature mainly psychotherapy and antidepressants are proposed for therapy. Alpha lipoic acid as a dietary supplement shows short-term improvement and low-level laser therapy might have some benefit.

Unilateral glossodynia as a harbinger of an occult cerebellopontine angle tumour.

A woman in her late 80s with severe bronchomalacia was referred to a tertiary orofacial pain clinic for unexplained right unilateral glossodynia of progressive and continuous evolution for the past 8 months, spreading to the ipsilateral labiomental region, associated with ipsilateral hypoacusia. Local and general clinical examinations were unremarkable and routine blood work could not reveal any underlying systemic disease explaining the glossodynia and burning/pricking labiomental pain. Suspecting a painful trigeminal neuropathy secondary to a space-occupying lesion, a cerebral MRI was prescribed, revealing an ipsilateral cerebellopontine angle lesion, compatible with either a schwannoma or meningioma. This lesion invaded the root entry zones of cranial nerves V and VIII explaining the patient's oral pain and hypoacusia. Following a neurosurgical consultation where surgical treatment was rejected, her pain was successfully managed by topical pregabalin mouthwashes, to prevent any risk of respiratory depression related to her underlying severe bronchomalacia.

Glossodynia, burning mouth syndrome, and COVID-19.

PURPOSE: To evaluate whether the prevalence of glossodynia increased among patients affected by COVID-19 compared to other hospital populations. METHODS: The i2b2 patient registry platform at the University of Florida Health Center was used to generate a count of patients using the international classification of diseases (ICD)-10 diagnosis codes from October 2015 to June 2021. Logistic regression of the aggregates was used for analysis. RESULTS: Of the patients with both glossodynia and COVID-19, 60% were females, 32% were African American, 64% were white, and 100% were adults. There were 72% females, 19% African Americans, 72% whites, and 93% adults with glossodynia only. For COVID-19 patients, 57% were females, 23% were African American, 56% whites, and 90% were adults. The odds ratio (OR) for glossodynia in the COVID-19 patients was significant (OR = 2.9; 95% CI, 1.94-4.32; P < 0.0001). CLINICAL SIGNIFICANCE: Glossodynia is significantly more common in COVID-19 patients and should be considered in the differential diagnoses among the oral complications of this infection.

[Pain syndromes and insomnia: the role of association with comorbid mental disorders (on the model of glossalgia)]. / Bolevye sindromy i insomniya: rol' assotsiatsii s komorbidnymi psikhicheskimi rasstroistvami (na modeli glossalgii).

OBJECTIVE: To test the association between pain severity and anxiety, depression, and somatoform symptoms in burning sleep syndrome (BMS). MATERIAL AND METHODS: The study included 36 patients (33 women, 3 men), mean age 58.0±14.8 years. Psychopathological, clinical-dermatological, parametric, statistical methods were used. Psychometric examination included the Visual Analogue Scale (VAS) for assessment of pain (severity of glossalgia), PHQ-4 for self-assessment of severity of anxiety (GAD-2) and depression (PHQ-2), the Hospital Anxiety and Depression Scale (HADS), the Screening for Somatoform Symptoms-2 (SOMS-2), the Pittsburgh Sleep Quality Index (PSQI), the EQ-5D-5L quality of life assessment scale. RESULTS AND CONCLUSION: Insomnia in chronic pain is very common. On the one hand, studies show that sleep deprivation can enhance pain perception. On the other hand, chronic pain can trigger a variety of sleep disorders. One of the localizations of chronic pain syndrome is the oral mucosa. Somatoform pain disorder related to oral mucosa called «glossalgia¼ or «burning mouth syndrome¼ (BMS). The prevalence of insomnia in the study sample was 61.1%. The statistically significant positive correlation was found between the severity of insomnia (PSQI) and the severity of anxiety on both GAD-2 and HADS, while insomnia showed no correlation with depression and pain severity. At the same time, the severity of anxiety showed statistically significant positive correlation with the severity of pain assessed by VAS.

[Glossalgia as a psychodermatological syndrome]. / Glossalgiya kak sindrom psikhodermatologicheskoi patologii.

OBJECTIVE: To study clinical characteristics of burning mouth syndrome or glossalgia is a functional disorder with painful sensations in the oral cavity with verification of the psychopathological structure, typology and nosology of the syndrome within the continuum of neurotic/psychotic disorders and dermatological pathology, i.e. lichen planus (LP). MATERIAL AND METHODS: The study sample (n=30, 27 female, mean age 59.3±15.6 years) was examined by dermatologist, neurologist and psychiatrist both clinically and psychometrically. The patients met the diagnostic criteria for glossalgia according to the IASP classification and ICD-10 for glossodynia (code K14.6). In 7 subjects, there was comorbidity with LP of the oral mucosa. RESULTS: The psychopathological picture of glossalgia syndrome has a binary structure. Basic coenesthesiopathies, ranging in severity from homonomous sensations (isteralgias) to heteronomic sensopathies (senestopathies, senesthesia), are associated with secondary hypochondriacal phenomena: from health anxiety and monopatophobia to mastery of ideas and somatopsychic confusion, respectively. According to the psychopathological register (neurotic/psychotic) and the fact of objective verification of a dermatological disease (hypochondria sine materia/cum materia), there are three types of glossalgic syndrome: 1) organo-neurotic; 2) somatopsychotic; 3) dermatological (stress-induced somatic reactions). CONCLUSION: BMS is a local syndrome limited to the oral cavity, however, in fact, it covers the entire clinical spectrum of psychosomatic pathology from mental diseases to psychodermatological ones.

A 78-year-old female with severe tongue pain: benefit of modern ultrasound.

BACKGROUND: Giant cell arteritis (GCA) is the most common form of systemic vasculitis in persons aged 50 years and older. Medium and large vessels, like the temporal and axillary arteries, are commonly affected. Typical symptoms are headache, scalp tenderness, jaw claudication and ophthalmological symptoms as loss of visual field, diplopia or amaurosis due to optic nerve ischemia. Tongue pain due to vasculitic affection of the deep lingual artery can occur and has so far not been visualized and followed up by modern ultrasound. CASE PRESENTATION: We report the case of a 78-year-old woman with typical symptoms of GCA, such as scalp tenderness, jaw claudication and loss of visual field, as well as severe tongue pain. Broad vasculitic affection of the extracranial arteries, vasculitis of the central retinal artery and the deep lingual artery could be visualized by ultrasound. Further did we observe a relevant decrease of intima-media thickness (IMT) values of all arteries assessed by ultrasound during follow-up. Especially the left common superficial temporal artery showed a relevant decrease of IMT from 0.49 mm at time of diagnosis to 0.23 mm on 6-months follow-up. This is the first GCA case described in literature, in which vasculitis of the central retinal artery and the lingual artery could be visualized at diagnosis and during follow-up using high-resolution ultrasound. CONCLUSION: High-resolution ultrasound can be a useful diagnostic imaging modality in diagnosis and follow-up of GCA, even in small arteries like the lingual artery or central retinal artery. Ultrasound of the central retinal artery could be an important imaging tool in identifying suspected vasculitic affection of the central retinal artery.

Lithium intoxication-induced dysgeusia accompanied by glossalgia in a patient receiving lithium carbonate: a case report.

BACKGROUND: Lithium carbonate is widely used as a first-line therapeutic agent for the depressive and manic phases of bipolar disorder. Although limb tremors and hypothyroidism are well-known side effects of lithium carbonate, other rare adverse reactions can also occur. CASE PRESENTATION: A 53-year-old Japanese woman diagnosed with lithium intoxication developed dysgeusia and glossalgia during treatment with lithium carbonate. She also showed symptoms of a swaying gait, finger tremors, and dysarthria. All of these symptoms subsided when her blood lithium concentration was reduced to a level below that which induces intoxication. CONCLUSIONS: We present a rare case of lithium carbonate-induced dysgeusia accompanied by glossalgia. Early detection of these symptoms is important in clinical settings because they can be overlooked until patients lose their appetite, which severely impairs their quality of life.

Examination of pain relief effect of Goreisan for glossodynia.

BACKGROUND: Pain in glossodynia may be severe; it may prevent patients from working, interfere with daily life activities, and necessitate a patient's visit to a medical institution for consultation and treatment. The pain may be described as persistent and burning (tingling, tingling) or stinging. Patients may complain of dry mouth (dryness), which is thought to cause inflammation of the tongue and gingival mucous membranes and increased pain. Medications are prescribed based on the symptoms of glossodynia, and the therapeutic effect is confirmed. However, each drug has side effects, for example, pain may reduce, but drowsiness and dizziness may occur; further, there is always a tendency of drowsiness.On the other hand, Goreisan, a Chinese herbal medicine, has already been used by physicians to treat pain in the oral and maxillofacial regions resulting from rapid changes in air pressure. However, the lack of high-quality clinical research has been of concern, and a randomized clinical trial to investigate the efficacy and safety of Goreisan for treatment of pain in glossodynia is warranted. METHODS/DESIGN: This multicenter, randomized, controlled study will involve patients treated for glossodynia-related pain. In the experimental group, Goreisan will be taken for 12 weeks in combination with conventional treatment. Participants in the control group will not take any Kampo medicine; only the standard treatment will be taken. Subsequently, the degree of pain will be assessed, and saliva tests of all the patients on their first visit will be performed. Goreisan will be taken at a dose of 7.5 g/d (minute 3) for 12 consecutive weeks. Twelve weeks later, the degree of pain of each patient will be assessed. DISCUSSION: The purpose of this study is to investigate the efficacy of Goreisan for pain reduction in patients undergoing treatment for glossodynia-related pain. If pain in glossodynia patients can be reduced by the administration of Goreisan, its candidacy as an alternative treatment for pain in glossodynia can be further supported by more reliable research. TRIAL REGISTRATION: The study was registered in the jRCTs071200017. URL https://jrct.niph.go.jp/latest-detail/jRCTs071200017.

Neuropathic Pain and Burning Mouth Syndrome: An Overview and Current Update.

Burning mouth syndrome/glossodynia and trigeminal neuropathic conditions can have serious negative impact on a patient's overall quality of life. These conditions are often hard to diagnose and even harder to fully treat and manage, but it is important for dentists/oral and maxillofacial surgeons to be aware of these conditions and modalities of their treatment. Often the only method for arriving at the proper diagnosis is for patients to undergo traditional approaches for treatment of presenting signs and symptoms, and it is the unexpected failure of interventional therapies that leads ultimately to a proper diagnosis.

Metastatic gastric adenocarcinoma of the tongue with initial symptoms of glossodynia.

A 60-year-old woman presented to our department with severe tongue pain. On initial examination, the mucosal surface of the tongue was intact but a hard submucosal mass on the dorsum of the tongue was detected on palpation. Magnetic resonance imaging demonstrated an ill-defined tumor in the intrinsic tongue muscles. Sequential whole-body positron emission tomography/computed tomography revealed a tumor of the pancreas apart from the tongue lesion, and upper gastrointestinal endoscopy revealed gastric mucosa ulceration. On biopsy, the tongue lesion was confirmed to be metastatic gastric adenocarcinoma, and the gastric ulcer was simultaneously diagnosed as poorly differentiated gastric adenocarcinoma. The definitive diagnosis was thus gastric adenocarcinoma and synchronous pancreatic cancer, with gastric carcinoma metastases to the tongue. We administered FOLFIRINOX treatment for pancreatic cancer and FLTAX treatment for gastric cancer. Because of difficulty with oral intake due to the growth of the tongue lesion, we administered palliative radiation therapy at a dose of 30 Gy in 10 fractions following which the patient was able to resume oral intake and was satisfied with this outcome. She died 8 months after her first visit to our department.

[Burning mouth syndrome]. / Sindrom 'pylaiushchego rta'.

A case-report of burning mouth syndrome is presented. A 27-year-old man complained of burning pain in the tongue and oral mucosa, taste disorder, and sensory impairment. All symptoms appeared after suffering a cold and had a wave-like course during self-medication with antibiotics. The pain has continued for 8 months. Diagnoses of atypical facial pain, glossodynia or secondary facial pain (craniomandibular dysfunction) were made. The effect of treatment in the hospital (carbamazepine, amitriptyline, haloperidol, phenozepam) was not achieved. A microbial test showed a higher number of pathogenic microbes. The final diagnosis was secondary facial pain (burning mouth syndrome) with concomitant lesions of the oral mucosa (Staphylococcus aureus, Candida sp.). The patient received a combined therapy with the pronounced positive effect.

Oral Burning With Dysphagia and Weight Loss.

Fibromyalgia is a disorder characterized by an abnormal pain regulation. Widespread pain, fatigue, and sleep disturbance are the prevalent symptoms. When unusual symptoms are overbearingly predominant at clinical presentation, the diagnosis becomes challenging.We report on the case of a patient with fibromyalgia, who presented with dysphagia, odynophagia, and glossodynia as prevalent symptoms. Difficulty in swallowing gradually developed over a month prior hospitalization, and worsened progressively so that nourishment and fluid intake were impeded.Because anemia with mild iron deficiency was found, esophagogastroduodenoscopy was performed, but no lesions were seen in the upper digestive tract. Levels of zinc and vitamin B12 were normal. Intense pain at pelvis and the inferior limbs, which was at a first glance referred to as osteoarthrosis, associated with oral symptoms and feeling of being in the clouds allowed us to diagnose fibromyalgia. Amitriptyline was used, with relief of symptoms.Although oropharyngeal symptoms were occasionally reported in fibromyalgia, they are often overlooked. The present case, therefore, testifies the need to consider the diagnosis of fibromyalgia when the patient presents with such symptoms that cannot be readily explained on other grounds.

Involvement of peripheral artemin signaling in tongue pain: possible mechanism in burning mouth syndrome.

Burning mouth syndrome is characterized by altered sensory qualities, namely tongue pain hypersensitivity. We found that the mRNA expression of Artemin (Artn) in the tongue mucosa of patients with burning mouth syndrome was significantly higher than that of control subjects, and we developed a mouse model of burning mouth syndrome by application of 2,4,6-trinitrobenzene sulfonic acid (TNBS) diluted with 50% ethanol to the dorsum of the tongue. TNBS treatment to the tongue induced persistent, week-long, noninflammatory tongue pain and a significant increase in Artn expression in the tongue mucosa and marked tongue heat hyperalgesia. Following TNBS treatment, the successive administration of the transient receptor potential vanilloid 1 (TRPV1) antagonist SB366791 or neutralizing anti-Artn antibody completely inhibited the heat hyperalgesia. The number of glial cell line-derived neurotrophic factor family receptor α3 (GFRα3)-positive and TRPV1-positive trigeminal ganglion (TG) neurons innervating the tongue significantly increased following TNBS treatment and was significantly reduced by successive administration of neutralizing anti-Artn antibody. The capsaicin-induced current in TG neurons innervating the tongue was enhanced following TNBS treatment and was inhibited by local administration of neutralizing anti-Artn antibody to the tongue. These results suggest that the overexpression of Artn in the TNBS-treated tongue increases the membrane excitability of TG neurons innervating the tongue by increasing TRPV1 sensitivity, which causes heat hyperalgesia. This model may be useful for the study of tongue pain hypersensitivity associated with burning mouth syndrome.

Cerebellopontine angle mass mimicking lingual nerve injury after dental implant placement: a case report.

This is a rare case report of a cerebellopontine angle (CPA) mass mimicking lingual nerve injury after a dental implant placement. Lingual nerve injury is a common complication following dental implant placement. CPA masses are likely to cause symptomatic trigeminal neuralgia, and thus can mimic and be easily confused with oral diseases. We experienced a case of CPA mass mimicking lingual nerve injury after dental implant placement. The patient was a 57-year-old Japanese female who complained of glossalgia. She underwent dental implant placement in the mandible before visiting our clinic. Panoramic x-ray radiography revealed no abnormalities; the salivary flow rate by gum test was 7.0 ml/10 min. She was diagnosed with lingual nerve injury and secondary burning mouth syndrome. Vitamin B12 and oral moisturizer did not provide relief; furthermore, numbness in the lower lip emerged. A Semmes Weinstein test demonstrated elevation of her sensitivity threshold. Finally, magnetic resonance imaging revealed a 20-mm diameter mass in the CPA. The patient is now being followed under conservative management. Our experience underscores the importance of including CPA mass in the differential diagnosis of dental diseases.